melphalan and Neoplasms

We review drug conjugates combining a tumor-selective moiety with a cytotoxic agent as cancer treatments. Currently, antibody-drug conjugates (ADCs) are the most common drug conjugates used clinically as cancer treatments. While providing both efficacy and favorable tolerability, ADCs have limitations due to their size and complexity. Peptides as tumor-targeting carriers in peptide-drug conjugates (PDCs) offer a number of benefits. Melphalan flufenamide (melflufen) is a highly lipophilic PDC that takes a novel approach by utilizing increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside tumor cells. The only other PDC approved currently for clinical use is

Topics: Antineoplastic Agents; Cytotoxins; Drug Carriers; Drug Delivery Systems; Drug Design; Humans; Immunoconjugates; Melphalan; Neoplasms; Peptides; Pharmaceutical Preparations; Phenylalanine; Radiotherapy; Somatostatin

Melphalan is a bifunctional alkylating agent that elicits its cytotoxic activity by rapidly forming an initial DNA monoadduct, which then produces an inter-strand crosslink. Most studies exploring the role of inherited differences in DNA repair and melphalan outcomes focus on inter-strand crosslink repair, however, monoadduct repair likely plays a key role since it minimises the ultimate production of these crosslinks. The purpose of this systematic review was to assess evidence of an association between variation in monoadduct repair pathways and melphalan response.. A literature search was undertaken using Medline, Embase, Scopus and PubMed databases. Duplicates were removed and only full-text articles were included. To be included for critique in this systematic review, articles were assessed for relevance using strict inclusion/exclusion criteria.. Fourteen studies were identified that involved patients treated with melphalan, however, in 3, only a minority of the cohort received melphalan. Across the remaining 11 studies, 61 genes/proteins in DNA monoadduct repair pathways were assessed. Both germline SNP (CDKN1A, ERCC1, ERCC2, ERCC4, ERCC6, EXO1, MLH1, MNAT1, MUTYH, PARP4, PCNA, POLE, POLR1G, RAD23B, RFC1, RFC3, RPA1, RPA3, TREX1, UNG, XPC, XRCC1) and somatic expression (CDKN1A, PARP1, PCNA, MGMT, RECQL, RFC5) were associated with melphalan outcomes in ≥ 1 study.. It appears that inherited germline differences in monoadduct repair genes may be a risk factor for poor outcomes. However, the diversity of study design, patient cohorts, genes assessed and lack of replication, preclude any meta-analysis. Further prospective studies are required to validate these findings.

Topics: Antineoplastic Agents, Alkylating; DNA Adducts; DNA Repair; Gene Expression Regulation, Neoplastic; Humans; Melphalan; Neoplasms; Pharmacogenomic Variants; Progression-Free Survival; Treatment Outcome

Cancer is a leading cause of death worldwide. Even after the availability of numerous drugs and treatments in the market, scientists and researchers are focusing on new therapies because of their resistance and toxicity issues. The newly synthesized drug candidates are able to demonstrate in vitro activity but are unable to reach clinical trials due to their rapid metabolism and low bioavailability. Therefore there is an imperative requisite to expand novel anticancer negotiators with tremendous activity as well as in vivo efficacy. Tetrazole is a promising pharmacophore which is metabolically more stable and acts as a bioisosteric analogue for many functional groups. Tetrazole fragment is often castoff with other pharmacophores in the expansion of novel anticancer drugs. This is the first systematic review that emphasizes on contemporary strategies used for the inclusion of tetrazole moiety, mechanistic targets along with comprehensive structural activity relationship studies to provide perspective into the rational design of high-efficiency tetrazole-based anticancer drug candidates.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Molecular Structure; Neoplasms; Structure-Activity Relationship; Tetrazoles

The alkylating agent melphalan is used in the treatment of hematological malignancies, especially multiple myeloma. In the past, the usefulness of melphalan has been solely attributed to its cytotoxicity on fastgrowing cancerous cells. Although the immunomodulatory effects of melphalan were suggested many years ago, only recently has this aspect of melphalan's activity begun to be elucidated at the molecular level. Emerging evidence indicates that melphalan can foster an immunogenic microenvironment by inducing immunogenic cell death (ICD) as characterized by membrane translocation of endoplasmic reticulum protein calreticulin (CRT) and by release of chromatin-binding protein high-mobility group box 1 (HMGB1). In addition, the lympho-depletive effect of melphalan can induce the release of pro-inflammatory cytokines and growth factors, deplete regulatory T cells, and create space to facilitate the expansion of infused tumor-reactive T cells. These features suggest that melphalan can be used as a preparative chemotherapy for adoptive T-cell therapy. This notion is supported by our recent work demonstrating that the combination of melphalan and adoptive transfer of tumor-reactive CD4+ T cells can mediate potent antitumor effects in animal models. This review summarizes the recent advances in understanding and utilizing the immunomodulatory effects of melphalan.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; CD4-Positive T-Lymphocytes; Humans; Immunotherapy, Adoptive; Melphalan; Neoplasms

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Oral mucositis is a side effect of chemotherapy, head and neck radiotherapy, and targeted therapy, affecting over 75% of high risk patients. Ulceration can lead to severe pain and difficulty eating and drinking, which may necessitate opioid analgesics, hospitalisation and nasogastric or intravenous nutrition. These complications may lead to interruptions or alterations to cancer therapy, which may reduce survival. There is also a risk of death from sepsis if pathogens enter the ulcers of immunocompromised patients. Ulcerative oral mucositis can be costly to healthcare systems, yet there are few preventive interventions proven to be beneficial. Oral cryotherapy is a low-cost, simple intervention which is unlikely to cause side-effects. It has shown promise in clinical trials and warrants an up-to-date Cochrane review to assess and summarise the international evidence.. To assess the effects of oral cryotherapy for preventing oral mucositis in patients with cancer who are receiving treatment.. We searched the following databases: the Cochrane Oral Health Group Trials Register (to 17 June 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 5), MEDLINE via Ovid (1946 to 17 June 2015), EMBASE via Ovid (1980 to 17 June 2015), CANCERLIT via PubMed (1950 to 17 June 2015) and CINAHL via EBSCO (1937 to 17 June 2015). We searched the US National Institutes of Health Trials Registry, and the WHO Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching databases.. We included parallel-design randomised controlled trials (RCTs) assessing the effects of oral cryotherapy in patients with cancer receiving treatment. We used outcomes from a published core outcome set registered on the COMET website.. Two review authors independently screened the results of electronic searches, extracted data and assessed risk of bias. We contacted study authors for information where feasible. For dichotomous outcomes, we reported risk ratios (RR) and 95% confidence intervals (CI). For continuous outcomes, we reported mean differences (MD) and 95% CIs. We pooled similar studies in random-effects meta-analyses. We reported adverse effects in a narrative format.. We included 14 RCTs analysing 1280 participants. The vast majority of participants did not receive radiotherapy to the head and neck, so this review primarily assesses prevention of chemotherapy-induced oral mucositis. All studies were at high risk of bias. The following results are for the main comparison: oral cryotherapy versus control (standard care or no treatment). Adults receiving fluorouracil-based (5FU) chemotherapy for solid cancersOral cryotherapy probably reduces oral mucositis of any severity (RR 0.61, 95% CI 0.52 to 0.72, 5 studies, 444 analysed, moderate quality evidence). In a population where 728 per 1000 would develop oral mucositis, oral cryotherapy would reduce this to 444 (95% CI 379 to 524). The number needed to treat to benefit one additional person (NNTB), i.e. to prevent them from developing oral mucositis, is 4 people (95% CI 3 to 5).The results were similar for moderate to severe oral mucositis (RR 0.52, 95% CI 0.41 to 0.65, 5 studies, 444 analysed, moderate quality evidence). NNTB 4 (95% CI 4 to 6).Severe oral mucositis is probably reduced (RR 0.40, 95% CI 0.27 to 0.61, 5 studies, 444 analysed, moderate quality evidence). Where 300 per 1000 would develop severe oral mucositis, oral cryotherapy would reduce this to 120 (95% CI 81 to 183), NNTB 6 (95% CI 5 to 9). Adults receiving high-dose melphalan-based chemotherapy before haematopoietic stem cell transplantation (HSCT)Oral cryotherapy may reduce oral mucositis of any severity (RR 0.59, 95% CI 0.35 to 1.01, 5 studies, 270 analysed, low quality evidence). Where 824 per 1000 would develop oral mucositis, oral cryotherapy would reduce this to 486 (95% CI reduced to 289 to increased to 833). The NNTB is 3, although the uncertainty surrounding the effect estimate means that the 95% CI ranges from 2 NNTB, to 111 NNTH (number needed to treat in order to harm one additional person, i.e. for one additional person to develop oral mucositis).The results were similar for moderate to severe oral mucositis (RR 0.43, 95% CI 0.17 to 1.09, 5 studies, 270 analysed, low quality evidence). NNTB 3 (95% CI 2 NNTB to 17 NNTH).Severe oral mucositis is probably reduced (RR 0.38, 95% CI 0.20 to 0.72, 5 studies, 270 analysed, moderate quality evidence). Where 427 per 1000 would develop severe oral mucositis, oral cryotherapy would reduce this to 162 (95% CI 85 to 308), NNTB 4 (95% CI 3 to 9).Oral cryotherapy was shown to be safe, with very low rates of minor adverse effects, such as headaches, chills, nu. We are confident that oral cryotherapy leads to large reductions in oral mucositis of all severities in adults receiving 5FU for solid cancers. We are less confident in the ability of oral cryotherapy to reduce oral mucositis in adults receiving high-dose melphalan before HSCT. Evidence suggests that it does reduce oral mucositis in these adults, but we are less certain about the size of the reduction, which could be large or small. However, we are confident that there is an appreciable reduction in severe oral mucositis in these adults.This Cochrane review includes some very recent and currently unpublished data, and strengthens international guideline statements for adults receiving the above cancer treatments.

Topics: Adult; Antineoplastic Agents; Cryotherapy; Fluorouracil; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Mouth Diseases; Myeloablative Agonists; Neoplasms; Pain; Randomized Controlled Trials as Topic; Stomatitis

Of the 13 286 autologous haematopoietic cell transplant procedures reported in the US in 2010-2012 for plasma cell disorders, 10 557 used single agent, high-dose melphalan. Despite 30 years of clinical and pharmacokinetic (PK) experience with high-dose melphalan, and its continuing central role as cytoreductive therapy for large numbers of patients with myeloma, the pharmacodynamics and pharmacogenomics of melphalan are still in their infancy. The addition of protectant agents such as amifostine and palifermin allows dose escalation to 280 mg/m(2), but at these doses it is cardiac, rather than gut, toxicity that is dose-limiting. Although combination with additional alkylating agents is feasible, the additional TRM may not be justified when so many post-consolidation therapies are available for myeloma patients. Current research should optimise the delivery of this single-agent chemotherapy. This includes the use of newer formulations and real-time PKs. These strategies may allow a safe and effective platform for adding synergistic novel therapies and provide a window of lymphodepletion for the addition of immunotherapies.

Topics: Amifostine; Antineoplastic Agents, Alkylating; Fibroblast Growth Factor 7; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Melphalan; Multiple Myeloma; Neoplasms; Obesity; Reproducibility of Results

The introduction of molecular targeted agents (e.g., monoclonal antibodies or kinase inhibitors) and cancer vaccines has raised the question whether alternate clinical trial designs, including window trials, are better suited to evaluate such new molecular entities (NMEs) and improve their approval rates. In window trials, patients receive an NME for a window of time before starting standard treatment allowing the evaluation of an NME in tumors unperturbed by previous therapies.. A systematic literature search was conducted to identify window trials in adult and pediatric oncology.. Twenty-nine window trials were identified and reviewed, 13 in pediatric and 16 in adult oncology. Most of the trials (20/29) tested cytotoxics known to have activity in other clinical situations. In contrast to trials with pretreated patients, the window trials established the antitumor activity of melphalan, topotecan, epirubicin and etoposide in untreated patients with rhabdomyosarcoma or small-cell lung cancer. In window trials with ineffective or modestly active NMEs, we found no indication of a significant negative effect on overall survival for participating patients.. Provided close safety monitoring and careful patient selection, window trials are a safe option to investigate potential clinical activity of NMEs.

Topics: Adult; Antineoplastic Agents; Child; Clinical Trials as Topic; Epirubicin; Etoposide; Humans; Melphalan; Molecular Targeted Therapy; Neoplasms; Topotecan

Recombinant human tumour necrosis factor (TNF) has a selective effect on angiogenic vessels in tumours. Given that it induces vasoplegia, its clinical use has been limited to administration through isolated limb perfusion (ILP) for regionally advanced melanomas and soft tissue sarcomas of the limbs. When combined with the alkylating agent melphalan, a single ILP produces a very high objective response rate. In melanoma, the complete response (CR) rate is around 80% and the overall objective response rate greater than 90%. In soft tissue sarcomas that are inextirpable, ILP is a neoadjuvant treatment resulting in limb salvage in 80% of the cases. The CR rate averages 20% and the objective response rate is around 80%. The mode of action of TNF-based ILP involves two distinct and successive effects on the tumour-associated vasculature: first, an increase in endothelium permeability leading to improved chemotherapy penetration within the tumour tissue, and second, a selective killing of angiogenic endothelial cells resulting in tumour vessel destruction. The mechanism whereby these events occur involves rapid (of the order of minutes) perturbation of cell-cell adhesive junctions and inhibition of alphavbeta3 integrin signalling in tumour-associated vessels, followed by massive death of endothelial cells and tumour vascular collapse 24 hours later. New, promising approaches for the systemic use of TNF in cancer therapy include TNF targeting by means of single chain antibodies or endothelial cell ligands, or combined administration with drugs perturbing integrin-dependent signalling and sensitizing angiogenic endothelial cells to TNF-induced death.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Cell Adhesion; Cell Division; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Female; Humans; Inflammation; Integrin alphaVbeta3; Liver Neoplasms; Male; Melanoma; Melphalan; Mice; Mice, Nude; Models, Molecular; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Osteosarcoma; Protein Conformation; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Recombinant Proteins; Remission Induction; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor Decoy Receptors; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

Recombinant human TNF (rhTNF) has a selective effect on endothelial cells in tumour angiogenic vessels. Its clinical use has been limited because of its property to induce vascular collapsus. TNF administration through isolated limb perfusion (ILP) for regionally advanced melanomas and soft tissue sarcomas of the limbs was shown to be safe and efficient. When combined to the alkylating agent melphalan, a single ILP produces a very high objective response rate. ILP with TNF and melphalan provided the proof of concept that a vasculotoxic strategy combined to chemotherapy may produce a strong anti-tumour effect. The registered indication of TNF-based ILP is a regional therapy for regionally spread tumours. In soft tissue sarcomas, it is a limb sparing neoadjuvant treatment and, in melanoma in-transit metastases, a curative treatment. Despite its demonstrated regional efficiency TNF-based ILP is unlikely to have any impact on survival. High TNF dosages induce endothelial cells apoptosis, leading to vascular destruction. However, lower TNF dosage produces a very strong effect that is to increase the drug penetration into the tumour, presumably by decreasing the intratumoural hypertension resulting in better tumour uptake. TNF-ILP allowed the identification of the role of alphaVbeta3 integrin deactivation as an important mechanism of antiangiogenesis. Several recent studies have shown that TNF targeting is possible, paving the way to a new opportunity to administer TNF systemically for improving cancer drug penetration. TNF was the first agent registered for the treatment of cancer that improves drug penetration in tumours and selectively destroys angiogenic vessels.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Vessels; Chemotherapy, Cancer, Regional Perfusion; Humans; Interferon-gamma; Melanoma; Melphalan; Neoplasms; Pilot Projects; Recombinant Proteins; Sarcoma; Tumor Necrosis Factor-alpha

The interest in TNF, discovered at the interface between inflammation and cancer, as an anti-cancer agent, has phased out in recent years. Indeed, despite its profound cytostatic and cytotoxic effects in primary tumors, the cytokine's systemic toxicity in general and its hepatotoxic and pro-metastatic nature in particular, prevent its routine use in cancer patients. An elegant approach to circumvent these problems consists in the local application of TNF in an isolated limb or organ setting, preferentially in the presence of cytostatic and alkylating agents, such as melphalan. However, this treatment, when locally applied during the perfusion of liver tumors, results in hepatotoxicity in a significant number of the patients, by means of a still unknown mechanism. The hemorrhagic necrosis of the tumors induced by TNF seems to be predominantly mediated by an induction of apoptosis as well as by an anti-angiogenic effect in the endothelial cells of the microvasculature supplying the tumor. These cells therefore represent a prime target for the action of anti-cancer drugs. In this review, we discuss preclinical studies which elucidated the mechanism of melphalan- and TNF-associated hepatotoxicity and, as a consequence, provided insights for preventing the adverse reactions of the drug. Moreover, we review recent findings aimed at improving the TNF molecule by means of specific mutations, or searching for alternative factors lacking the systemic toxicity of TNF.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Humans; Liver; Melphalan; Neoplasm Regression, Spontaneous; Neoplasms; Protein Conformation; Recombinant Proteins; Tumor Necrosis Factor-alpha

Topics: Alkylation; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; DNA; DNA Repair; DNA Topoisomerases, Type I; DNA-Directed DNA Polymerase; Drug Resistance, Neoplasm; Glutathione; Glutathione Transferase; Humans; Melphalan; Neoplasms

Topics: Animals; Antineoplastic Agents, Alkylating; Female; Glutathione; Humans; Melphalan; Neoplasms

The greater affinity of electrophiles for thiol groups than for hydroxyl or amine groups provides a teleological basis for the evolution of this mechanism to assist in the maintenance of cellular homeostasis. As the most abundant cellular non-protein thiol, glutathione (GSH) is pivotal in the protection of cells from electrophiles created during normal respiration and protection after exposure to environmental mutagens. Mutagens and many anti-cancer drugs, e.g. cisplatin and alkylating agents, have the same target, i.e. DNA. This suggested that one mechanism by which cancer cells might circumvent the action of cancer chemotherapeutic agents would be by increasing their cellular GSH and/or enhanced conjugation of these drugs to this abundant tripeptide. This chapter describes the abundant preclinical data that support this mechanism of resistance to platinum drugs and alkylating agents. This data was the rationale for the development of pharmacologic strategies to lower GSH and inactivate the gluathione-S-transferases to make anti-cancer drugs more effective. The positive outcome of preclinical studies to lower GSH and enhance the activity of melaphalan are described as is the status of on going clinical trials built around this data.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Clinical Trials as Topic; Drug Resistance; Female; Glutathione; Humans; Male; Melphalan; Neoplasms

Glutathione (gamma-Glutamylcysteinyl glycine, GSH) exists in almost all cells in a millimolar order of concentration. GSH plays an important role in protecting cells against oxidative stress, maintaining a reducing environment within the cells, and inactivating many xenobiotics. Synthesis of GSH is regulated by gamma-glutamylcysteine synthetase (gamma-GCS). Increase in the activity of gamma-GCS has been found in many drug-resistant cancer cells. It is believed that GSH plays a role in the aquisition of resistance to anti-cancer drugs, such as a cisplatin, adriamycin, melphalan, or taxol. In this paper, the possible mechanism of GSH involvement in drug-resistance and new approach for the depletion of GSH by suppressing the expression of gamma-GCS are introduced.

Topics: Antineoplastic Agents; Cisplatin; Doxorubicin; Drug Resistance, Neoplasm; Glutathione; Humans; Melphalan; Neoplasms; Peptide Synthases; RNA, Catalytic; Tumor Cells, Cultured

Between June 1991 and January 1995 we performed 67 peripheral blood progenitor cell transplants (PBPCT). Ten patients (group 1) were mobilised with 7 gm/m2 of cyclophosphamide followed by daily G-CSF injections (5 micrograms/kg, subcutaneously). When the white cell count reached 1 x 10(9)/1 they were leukapheresed for 5 days. After stem cell infusion they received G-CSF (10 micrograms/kg/day) until the neutrophil count reached 1.5 x 10(9)/1. Fifty-six patients had PBPCs mobilised with 3 gm/m2 of cyclophosphamide followed by daily subcutaneous G-CSF (5 micrograms/kg) and PBPCs were harvested on 2 consecutive days, when the white cell count rose to 4 x 10(9)/1. After stem cell infusion this group did not receive G-CSF. In 47 of the 56 patients (group 2) adequate MNC (> or = 4 x 10(8)/kg) and/or CFU-GM (> or = 10 x 10(4)/kg) were obtained. Insufficient MNC and/or CFU-GM were obtained in 10 patients. They were therefore transplanted using a combination of bone marrow and peripheral blood progenitor cells (group 3). Overall 64 patients successfully engrafted. Median days to neutrophils > or = 0.5 x 10(9)/1 were 9 (range 8-13), 12 (range 8-25) and 11 (range 9-16) and to platelets > or = 50 x 10(9)/1 were 11 (range 9-23), 13 (range 9-90) and 16 (range 13-99) in groups 1, 2 and 3 respectively. Patients in group 1 had a faster neutrophil recovery than patients in group 2 (P = 0.0002). The three patients who failed to engraft all received a combination of autologous peripheral blood and bone marrow cells.

Topics: Adolescent; Adult; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carmustine; Cell Movement; Colony-Forming Units Assay; Cyclophosphamide; Cytarabine; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Kidney Diseases; Leukapheresis; Leukocyte Count; Male; Melphalan; Middle Aged; Neoplasms; Podophyllotoxin; Retrospective Studies; Thiotepa; Transplantation Conditioning

Topics: Animals; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Drug Screening Assays, Antitumor; Extremities; Humans; Immunologic Factors; Interferon-gamma; Melanoma; Melphalan; Mice; Mice, Inbred BALB C; Neoplasms; Sarcoma; Sarcoma, Experimental; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

Alkylating agents have been used for over 30 years in the treatment of malignant disease. Because of their very reactive nature, studies of their intermediate metabolism have been difficult. However, this is now possible with modern analytical techniques. Further understanding of their metabolism and pharmacokinetics should lead to a more rational use in the clinic.

Topics: Alkylating Agents; Carmustine; Chlorambucil; Cyclophosphamide; Humans; Ifosfamide; Lomustine; Melphalan; Neoplasms; Nitrosourea Compounds; Organophosphorus Compounds; Thiotepa

Topics: Antineoplastic Agents; Bone Marrow Transplantation; Child; Combined Modality Therapy; Humans; Melphalan; Neoplasms; Neuroblastoma; Randomized Controlled Trials as Topic; Rhabdomyosarcoma; Sarcoma, Ewing

All cancer chemotherapeutic agents, except altretamine, the nitrosoureas, and dactinomycin, have produced at least an isolated instance of a HSR. Certain drugs, such as L-asparaginase and mitomycin (administered intravesically), cause HSRs of significant degree in approximately 10% of patients. All four types of HSRs are represented in the reactions produced by antitumor drugs, although Type I is the most common. Some of the Type I reactions are IgE-mediated, and others are probably mediated by nonspecific release of vasoactive substances from targets such as mast cells. It is possible to continue therapy with some drugs, despite a prior HSR, if the prophylactic measures outlined in Table 2 are taken. An example of this is provided by taxol in which the lengthening of the infusion time and the administration of preventive medication allowed some patients to continue taxol therapy. The mechanisms of the HSRs have been carefully assessed in only a minority of patients who sustained such toxicity. Such evaluation would increase our understanding of this form of drug toxicity and perhaps lead to means of effectively reducing the risk and severity.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Asparaginase; Aziridines; Benzoquinones; Bleomycin; Chlorambucil; Cisplatin; Cyclophosphamide; Cytarabine; Dacarbazine; Drug Hypersensitivity; Etoposide; Fluorouracil; Humans; Ifosfamide; Melphalan; Methotrexate; Mitomycins; Neoplasms; Paclitaxel; Pentostatin; Procarbazine; Teniposide

Studies are described of high-dose therapy in metastatic breast cancer, early stage breast cancer, stage IV neuroblastoma, recurrent or bulky disease testicular cancer and Ewing's sarcoma. The outcome in these subgroups with conventional therapy is described for comparison. The results of these studies suggest that high-dose therapy with autologous marrow support increases the proportion of patients with long-term survival without evidence of disease. Newer supportive care and recurrent high-dose therapy cycles of non-cross resistant regimens may improve outcome further in these diseases and increase the application to more resistant tumors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Humans; Melphalan; Neoplasm Metastasis; Neoplasms; Neuroblastoma; Prednisone; Prognosis; Remission Induction; Survival Rate; Transplantation, Autologous; Treatment Outcome; Vincristine

Topics: Anemia, Aplastic; Antineoplastic Agents; Colony-Stimulating Factors; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Drug Evaluation; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Melphalan; Neoplasms; Radiotherapy

Melphalan (L-phenylalanine mustard) is a bifunctional alkylating agent that is commonly administered orally to treat a wide variety of malignancies, including cancers of the breast and ovary, as well as multiple myeloma. Although commercially available in Europe and Canada, intravenous (IV) melphalan remains investigational in the United States. The role of IV melphalan in cancer chemotherapy is not well defined, despite its manageable toxicity and higher and more predictable blood levels following IV administration compared with oral administration. In addition, unlike oral melphalan, an extensive phase I evaluation of IV melphalan has not been undertaken. At lower doses (eg, 30 to 70 mg/m2), both as a single agent and in combination, the activity of IV melphalan has been evaluated in only a limited number of diseases. However, striking activity has been observed in previously untreated patients with rhabdomyosarcoma, a disease not generally considered responsive to alkylating agents. When administered at high doses (greater than 140 mg/m2) requiring bone marrow reinfusion, melphalan effects a high response rate (but no improvement in survival) in a variety of nonhematologic tumor types, including resistant tumors such as melanoma and colon carcinoma. In contrast, in poor-prognosis patients with non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or neuroblastoma, high-dose melphalan-containing regimens have yielded both high response rates and improved survival, despite considerable toxicity. Additional clinical trials will be necessary to define the spectrum of activity of lower doses of IV melphalan and to define subgroups of patients most likely to benefit from high-dose melphalan.

Topics: Administration, Oral; Body Water; Bone Marrow; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Humans; Infusions, Intravenous; Melphalan; Neoplasms

Both in vitro and in vivo studies have demonstrated antiproliferative effects of interferon alfa-2b (Intron A; Schering-Plough) when tested with human tumor cells. A clonogenic assay has been widely used to determine its direct antiproliferative effects on human tumor cells in vitro using colony reduction as a reproducible endpoint. As a single agent, interferon alfa-2b shows maximum tumor cell colony reduction when used in high concentrations with continuous cell exposure. Short-term exposure to interferon alfa-2b does not produce significant tumor cell colony reduction. Clonogenic assays have also been used to test combinations of interferon alfa-2b with cytotoxic drugs. Variations in drug scheduling, sequencing and concentrations have indicated the best combinations which maximize tumor cell colony reduction. Combinations of interferon alfa-2b with doxorubicin, cisplatin, vinblastine, melphalan and cyclophosphamide have been shown to have at least additive and occasionally synergistic antiproliferative effects. In clinical trials, optimal pairs of agents have been identified frequently combining either doxorubicin, cisplatin or vinblastine with interferon alfa-2b. Pretreatment with interferon alfa-2b has been adopted from in vitro studies and applied to most clinical trials. One study has enrolled 135 patients having a variety of advanced or recurrent solid tumor types, using a schema which combines interferon alfa-2b and doxorubicin administration, both given on a weekly basis for three weeks, followed by treatments every two weeks in responding patients. Clinical responses have been seen using this regimen in patients with ovarian, cervical, colorectal and pancreatic carcinomas and in one lymphoma patient. Another study has been designed combining melphalan, prednisone and interferon alfa-2b for the treatment of patients with relapsing multiple myeloma. This is also based upon preclinical data. New methods of administration are being studied giving interferon alfa-2b as a single agent or in combination with cisplatin by the intraperitoneal route to patients with relapsing ovarian carcinomas limited to the peritoneal cavity. This method can maximize both the levels of interferon alfa-2b as well as the tumor cell exposure time.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Interferon Type I; Melphalan; Neoplasms; Vinblastine

The available evidence suggests that if benefit is to be obtained from high dose chemotherapy regimens, it will be in patients whose tumours are either untreated or still responding to conventional therapy. In each of the diseases discussed in this chapter the optimum timing of the treatment regimen has still to be determined. Effective regimens have been found but it is probable that further improvements can be made. In small cell lung cancer initial high dose therapy followed by non-cross-resistant regimens may prove effective. In glioma studies with high dose therapy before irradiation are awaited and may offer the best means of exploiting this approach to treatment. In breast cancer some impressive responses have occurred but the category of patient likely to benefit has not yet been defined. In melanoma high dose treatment is likely to benefit only those patients with probable minimal disease after surgery.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Breast Neoplasms; Carcinoma, Small Cell; Carmustine; Cell Separation; Cisplatin; Colonic Neoplasms; Cyclophosphamide; Etoposide; Glioma; Humans; Lung Neoplasms; Male; Melanoma; Melphalan; Neoplasms; Testicular Neoplasms; Whole-Body Irradiation

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Drug Evaluation; Drug Resistance; Etoposide; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Melphalan; Neoplasm Recurrence, Local; Neoplasms; Thioguanine; Transplantation, Autologous

There has been a striking improvement in the overall numbers of children and adolescents who become disease-free and remain disease-free as a result of intensive therapy as defined today, for the following cancers: acute nonlymphocytic leukemia (ANLL), non-Hodgkin's lymphoma (NHL), poor risk acute lymphocytic leukemia (ALL), osteosarcoma, and Ewing's sarcoma. The therapy for each of these tumors, with the exception of osteosarcoma, consisted of combination chemotherapy with or without radiotherapy and was started as soon after diagnosis as possible. Aggressive therapy of osteosarcoma has consisted of surgical removal of lung metastases and chemotherapy. Intensive chemotherapy recently has included the use of high doses of certain drugs such as cytosine arabinoside (Ara-C), methotrexate, VP-16-213 and melphalan in the treatment of patients with tumors that are currently difficult to treat.

Topics: Acute Disease; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Etoposide; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Melphalan; Methotrexate; Neoplasms; Osteosarcoma; Risk; Sarcoma, Ewing

Pharmacokinetic modeling has suggested, and clinical investigations have confirmed, that intracavitary drug administration can result in a much greater drug exposure for the cavity into which the agent is instilled compared to the plasma. Both the safety and the efficacy of several agents administered individually or in combination have now been demonstrated. Several malignancies, in particular ovarian carcinoma and malignant mesothelioma, which remain confined to body cavities for much of their natural history, might be most rationally treated by the intracavitary treatment approach. Early clinical trials have demonstrated significant activity of intracavitary chemotherapy in both of these malignancies. Optimal drugs and dosages as well as appropriate scheduling for the various tumors involving body cavities remain to be defined. Whether or not combination intracavitary chemotherapy will significantly improve survival of patients with malignant disease confined to body cavities must await carefully controlled clinical trials comparing this treatment approach to standard systemically administered chemotherapy.

Topics: Absorption; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ascitic Fluid; Bacterial Infections; Bleomycin; Cisplatin; Cytarabine; Diffusion; Doxorubicin; Drug Synergism; Female; Fluorouracil; Humans; Immunotherapy; Melphalan; Methotrexate; Mitomycins; Neoplasms; Ovarian Neoplasms; Peritoneal Cavity; Permeability; Pleura; Pleural Effusion; Radiation-Sensitizing Agents; Sclerosis; Streptozocin

Glutathione, as the chief nonprotein intracellular sulfhydryl, affects the efficacy and interactions of a variety of antineoplastic interventions, mainly through nucleophilic thioether formation or oxidation-reduction reactions. Thus, glutathione plays a role in the detoxification and repair of cellular injury by such diverse agents as mechlorethamine, melphalan, cyclophosphamide, nitrosoureas, 6-thiopurine, 4'-(9-acridinylamino)methanesulfon-m-anisidide, the quinone antibiotics (including Adriamycin, daunorubicin, and mitomycin C), the sesquiterpene lactones (such as vernolepin), and other sulfhydryl-reactive diterpenes (like jatrophone). Glutathione may play a similar role in host and tumor cell responses to radiation, hyperthermia, and the reactive reduction products of oxygen secreted by inflammatory cells. Further, glutathione participates in the formation of toxic metabolites of such chemotherapeutics as azathioprine and bleomycin and may affect the cellular uptake of other agents, such as methotrexate. It seems likely that alterations in glutathione metabolism of tumor or host as a result of one therapeutic intervention may affect the outcome of concurrent treatments. Knowledge of these interactions may be useful in designing combination therapy for neoplastic disease.

Topics: Aminoacridines; Amsacrine; Animals; Antineoplastic Agents; Biological Transport; Carmustine; Cyclophosphamide; Cytochrome P-450 Enzyme System; Glutathione; Humans; Mechlorethamine; Melphalan; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental

The potentiation of chemotherapeutic agents by radiation sensitizers has been extensively studied for several years. There is little doubt that the effectiveness of certain anti-cancer drugs, primarily alkylating agents, can readily be enhanced both in vitro and in vivo through the addition of a sensitizer. While enhanced effects have been observed in certain critical normal tissues, in general most animal model studies have demonstrated a therapeutic gain at large sensitizer doses. This approach to combination therapies therefore appears promising. Yet many questions concerning the interaction between chemotherapeutic agents and radiosensitizers, particularly in the area of mechanisms of action, still remain. This overview attempts to focus on some of these questions. Four aspects of modification of chemotherapy by nitroimidazoles are reviewed and discussed. These address the importance in chemopotentiation of i) hypoxia, ii) alterations in DNA damage and/or repair, iii) depletion of intracellular sulfhydryls and iv) modification of drug pharmacokinetics. It is concluded that: i) even though chemopotentiation can occur at intermediate oxygen levels, hypoxia ultimately plays a pivotal role, ii) no single unifying mechanism for chemopotentiation exists; alterations in drug pharmacokinetics, cellular SH levels and DNA damage/repair all are involved, the relative importance of each factor is dependent on the particular drug-sensitizer combination, iii) it is important to continue the evaluation of chemopotentiation under conditions mimicking clinically achievable sensitizer pharmacokinetics and iv) further investigations into more effective utilization of chemopotentiation are warranted.

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; DNA Repair; Drug Synergism; Glutathione; Lomustine; Melphalan; Mice; Misonidazole; Neoplasms; Nitroimidazoles; Oxygen; Radiation-Sensitizing Agents; Time Factors

Topics: Alkylating Agents; Busulfan; Carcinoma, Bronchogenic; Carmustine; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Mechlorethamine; Melphalan; Neoplasms; Ovarian Neoplasms; Testicular Neoplasms

The treatment of solid tumours with high-dose chemotherapy using alkylating agents either as single agents or in combination schedules has received increasing attention from clinical investigators in recent years. This has frequently been given in association with autologous bone marrow support, a technique which appears to ameliorate myelosuppression that might otherwise be dose-limiting, and which thus may allow dose escalation into a range previously not reached. Despite this ability, and in spite of much experimental evidence from drug-sensitive animal tumours that increasing doses result in increased response rates, no major impact has yet been made in the therapy of solid tumours using this form of therapy. In addition, the use of high-dose schedules has seen the emergence of extramedullary manifestations of drug toxicity which were not encountered at conventional doses. Nevertheless, there are some encouraging data from reports in certain tumours, including small cell lung cancer, testicular cancer, ovarian cancer, and lymphoma, and further studies are clearly indicated. These should probably be restricted to certain drug-sensitive tumours, and should include an examination of the role of high-dose chemotherapy as consolidation treatment, following conventional induction therapy for selected tumour types. This form of treatment may yet provide an important contribution to the control of human solid tumours, but much further work, probably with combination drug schedules, is required.

Topics: Antineoplastic Agents; Carmustine; Cyclophosphamide; Drug Administration Schedule; Drug Therapy, Combination; Etoposide; Forecasting; Humans; Melphalan; Neoplasms

Topics: Animals; Cell Line; Cell Survival; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Electrons; Humans; Melphalan; Mice; Misonidazole; Neoplasms; Oxygen; Radiation-Sensitizing Agents; Radiotherapy Dosage; Structure-Activity Relationship; Technology, Pharmaceutical

Considerable evidence has been accumulated to demonstrate that sensitive tumor cells in experimental animals take up and retain at least some effective anticancer drugs to a greater extent than normal tissues, thus providing a greater degree of exposure and accounting for the selective effect of the drugs. In sensitive cells, DNA synthesis is inhibited for prolonged periods, whereas in cells less sensitive the time of inhibition is shorter. In those cases examined where a metabolite, formed intracellularly, is the active form of the agent, the metabolite is produced and is retained to a greater extent than in normal tissues.

Topics: Animals; Antineoplastic Agents; Cytarabine; Doxorubicin; Floxuridine; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasms

Although cytotoxic immunosuppressive agents play an unquestionably useful role in treating many neoplastic and non-neoplastic disorders, there is accumulating evidence that the toxicity associated with their use is considerable. The therapeutic successes obtained with antitumor agents have led to increases in the life span of cancer patients, but have also provided the opportunity for this toxicity to become manifest. A search of the available literature was carried out, with emphasis on cases in which a malignancy developed in patients following chemotherapy for either neoplastic or non-neoplastic (e.g., renal transplantation, psoriasis) conditions; particular focus was given to the incidence of acute myelogenous leukemia in various groups of Hodgkin's disease and multiple myeloma patients. That patients with nonmalignant conditions treated with cytotoxic immunosuppressive agents are also at increased risk of developing a malignancy raises the possibility that these agents may have oncogenic potential. Therefore, one may be faced with the paradox that the patients benefiting most from chemotherapy may be at highest risk of suffering its consequences.

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Azathioprine; Burkitt Lymphoma; Choriocarcinoma; Cyclophosphamide; Dactinomycin; Female; Hodgkin Disease; Humans; Immunosuppressive Agents; Kidney Neoplasms; Leukemia, Myeloid, Acute; Lymphoma; Mechlorethamine; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Prednisone; Pregnancy; Procarbazine; Time Factors; Vincristine

Topics: Adult; Alkylating Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Child; Cyclophosphamide; Doxorubicin; Drug Combinations; Drug Therapy, Combination; Female; Fluorouracil; Humans; Immunotherapy; Leucovorin; Male; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasms; Osteosarcoma; Prednisone; Rhabdomyosarcoma; Testicular Neoplasms; Thiotepa; Vinblastine; Vincristine

Topics: Acute Disease; Adenofibroma; Animals; Carcinogens; Drug Evaluation, Preclinical; Female; Humans; Lethal Dose 50; Leukemia; Male; Mammary Neoplasms, Experimental; Melphalan; Mice; Neoplasms; Rats; Stereoisomerism

Topics: 2-Naphthylamine; Alkylating Agents; Antineoplastic Agents; Busulfan; Carcinogens; Cocarcinogenesis; Cyclophosphamide; Female; Hodgkin Disease; Humans; Leukemia; Male; Melphalan; Neoplasms; Nitrogen Mustard Compounds; Radiotherapy; Time Factors

Topics: Antineoplastic Agents; Asparaginase; Cell Division; Chlorambucil; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Fluorouracil; Folic Acid Antagonists; Humans; Melphalan; Mercaptopurine; Methotrexate; Neoplasms; Triaziquone; Triethylenephosphoramide; Vincristine

Topics: Alkylating Agents; Busulfan; Carcinogens; Chlorambucil; Melphalan; Mustard Compounds; Mutation; Neoplasms; Nitrogen Mustard Compounds; Triethylenemelamine

Topics: Animals; Busulfan; Chlorambucil; Cyclophosphamide; Female; Humans; Male; Mechlorethamine; Melphalan; Methotrexate; Mice; Neoplasms; Thiotepa

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Cell Division; Cyclophosphamide; Cytarabine; Female; Fluorouracil; Humans; Leukemia L1210; Leukemia, Lymphoid; Lymphoma; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Nitrogen Mustard Compounds; Prednisone; Pregnancy; Time Factors; Trophoblastic Neoplasms; Vinblastine

Topics: Alkylating Agents; Alkylation; Animals; Busulfan; Cell Division; Chemical Phenomena; Chemistry; Chlorambucil; Cyclophosphamide; DNA Viruses; Ethers, Cyclic; Ethoglucid; Ethylamines; Humans; Mannomustine; Melphalan; Neoplasms; Nitrogen Mustard Compounds; Thiotepa; Triaziquone

Topics: Abdominal Neoplasms; Alkylating Agents; Animals; Antimetabolites; Antineoplastic Agents; Carcinoma, Basal Cell; Choriocarcinoma; Cyclophosphamide; Dactinomycin; Dysgerminoma; Female; Fluorouracil; Head; Head and Neck Neoplasms; Hodgkin Disease; Humans; Injections, Intra-Arterial; Leg; Melanoma; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Nitrogen Mustard Compounds; Pregnancy; Sarcoma; Sarcoma, Ewing; Skin Neoplasms; Vinblastine; Wilms Tumor

Topics: Alkylating Agents; Antineoplastic Agents; Arsenicals; Cyclophosphamide; Dactinomycin; Fluorouracil; Humans; Mechlorethamine; Melphalan; Methotrexate; Mitomycin; Mitomycins; Neoplasms; Pharmacology; Steroids; Triethylenemelamine; Vinblastine; Vincristine

Topics: Antineoplastic Agents; Azaguanine; Aziridines; Chemotherapy, Cancer, Regional Perfusion; Cyclophosphamide; Female; Fluorouracil; Humans; Infusions, Parenteral; Melphalan; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Triaziquone; Uracil Mustard; Uterine Cervical Neoplasms; Vinblastine

Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models.. This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11).. In the dose-escalating phase I part of the study, seven patients were treated with increasing fixed doses of melflufen (25-130 mg) Q3W. In the subsequent phase IIa part, 38 patients received in total 115 cycles of therapy at doses of 30-75 mg. No dose-limiting toxicities (DLTs) were observed at 25 and 50 mg; at higher doses DLTs were reversible neutropenias and thrombocytopenias, particularly evident in heavily pretreated patients, and the recommended phase II dose (RPTD) was set to 50 mg. Response Evaluation Criteria In Solid Tumors (RECIST) evaluation after 3 cycles of therapy (27 patients) showed partial response in one (ovarian cancer), and stable disease in 18 patients. One NSCLC patient received nine cycles of melflufen and progressed after 7 months of therapy.. In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Alkylation; Antineoplastic Agents, Alkylating; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hematologic Diseases; Humans; Male; Melphalan; Middle Aged; Neoplasms; Peptide Hydrolases; Phenylalanine; Prospective Studies

To investigate a possible difference between true ovarian volume and ovarian volume estimated with two-dimensional (2D) transvaginal ultrasound.. Prospective clinical and laboratory study.. University hospital research laboratory.. Premenopausal girls and women from three Danish national fertility centers (A: n = 42; B: n = 6; C: n = 18), who had one entire ovary removed for cryopreservation of ovarian cortex.. Transvaginal 2D ultrasound measurement of ovarian volume before oophorectomy. True ovarian volume was obtained by weighing the ovary.. Ovarian volume estimated by weight and ultrasound.. Ovarian tissue density was 1.00 g/mL. Mean ovarian volume by ultrasound vs. weight in the three groups was as follows: A: 6.3 mL vs. 7.8 mL; B: 5.4 mL vs. 6.8 mL; and C: 2.8 mL vs. 6.1 ml. Ovarian volume obtained by ultrasound was at least 27% smaller than the true ovarian volume.. Ovarian volume was severely underestimated by transvaginal 2D ultrasound measurement.

Topics: Adult; Anti-Mullerian Hormone; Female; Humans; Immunoglobulin G; Infertility, Female; Melphalan; Menstrual Cycle; Neoplasms; Oocytes; Ovariectomy; Ovary; Prospective Studies; Ultrasonography; Vagina

Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability.. A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated.. Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16-23 kg; 0.95 mg/kg for >23-34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3-17.2 years (median 5.6 years).. No difference in AUC values was observed between weight strata (mean +/- SD 1248 +/- 205 micromol.min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900-1500 micromol.min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.

Topics: Adolescent; Age Factors; Antineoplastic Agents, Alkylating; Area Under Curve; Body Weight; Busulfan; Child; Child, Preschool; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Monitoring; Female; Hematologic Diseases; Humans; Infant; Infusions, Intravenous; Male; Melphalan; Models, Biological; Neoplasms; Prospective Studies; Stem Cell Transplantation

Limited information is available regarding the use of amifostine in pediatric hematopoietic stem cell transplant (HSCT) patients. Melphalan, carboplatin, etoposide +/- cyclophosphamide is a commonly used preparatory regimen in pediatric solid tumor HSCT. Therefore, we decided to determine the feasibility of the addition of amifostine (750 mg/m b.i.d. x 4 d) to melphalan (200 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) (level 1) and escalating doses of cyclophosphamide (3000 mg/m and 3800 mg/m, levels 2 and 3, respectively) followed by autologous HSCT. Thirty-two patients with a variety of pediatric solid tumors were studied. Seventeen patients were accrued at level 1, 9 at level 2, and 6 at level 3. Major toxicities during the administration of the preparatory regimen were hypocalcemia, emesis, and hypotension. Hypocalcemia required aggressive calcium supplementation during the conditioning phase. No dose limiting toxicities were encountered at level 3. Amifostine at 750 mg/m b.i.d. for 4 days can be administered with a double alkylator regimen consisting of melphalan (200 mg/m), cyclophosphamide (up to 3800 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) with manageable toxicities.

Topics: Adolescent; Adult; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Bone Neoplasms; Carboplatin; Central Nervous System Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Etoposide; Feasibility Studies; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Hypocalcemia; Kidney Neoplasms; Melphalan; Neoplasms; Neuroblastoma; Pilot Projects; Recurrence; Risk Factors; Sarcoma; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Wilms Tumor

Hepatic veno-occlusive disease (HVOD) is a frequent complication during hematopoietic stem-cell transplantation (HSCT). A strong relationship has been demonstrated between busulfan exposure and HVOD for busulfan-cyclophosphamide and allogeneic HSCT in adults. Busulfan disposition after the first intake was studied in 77 children treated for solid malignancies with high-dose busulfan-containing regimens and autologous HSCT. Busulfan was combined with cyclophosphamide and melphalan (n=30), melphalan (n=27), and thiotepa (n=20). No relationship was observed between busulfan exposure and HVOD. In contrast, plasma ferritin at baseline was higher in patients with HVOD (750 ng/ml (20-3,110)) compared with those without HVOD (189 ng/ml (8-3,967), P=0.012). Multivariate analysis showed that a ferritin level exceeding 300 ng/ml was the only risk factor for HVOD with an odds ratio of 4.0 (confidence interval 95% (1.5-11.2), P=0.0071). A high ferritin level at baseline was explained by the diagnosis of neuroblastoma, related treatments and transfusions.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Cyclophosphamide; Female; Ferritins; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Incidence; Infant; Iron; Male; Melphalan; Neoplasms; Odds Ratio; Prospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Thiotepa; Transferrin; Transplantation, Homologous; Treatment Outcome

The purpose of this trial was to define the maximum tolerated duration (MTD), dose-limiting toxicity (DLT), regimen-related toxicities (RRT), and pharmacokinetics of gemcitabine infused at a fixed dose rate (FDR) of 10 mg/m2/min, combined with docetaxel/melphalan/carboplatin, using autologous stem cell transplantation (ASCT). The duration of gemcitabine infusion was incrementally escalated as a single treatment on day -6 or as 4 daily infusions on days -5 to -2. Gemcitabine was followed by docetaxel (300 or 350 mg/m2) on day -5, and then melphalan (50 mg/m2/day) and carboplatin (333 mg/m2/day) on days -4 to -2. Fifty-two patients with refractory tumors were accrued with a median age of 40 (range: 6-66), a median of 3 (1-6) prior chemotherapy regimens, and 3 (1-7) organs involved. The gemcitabine MTD was defined at 20 hours (total dose 12,000 mg/m2) on both schedules. The DLT was enteritis. Three patients died from aspiration, catheter-related sepsis, and enteritis, respectively. The tumor response rate was 91%, with 50% complete responses. At current 2-year median follow-up, the event-free and overall survival (EFS, OS) rates are 54% (median 26 months) and 79% (median not reached), respectively. Gemcitabine area under the curve (AUC), but not clearance, increased linearly with infusion duration, and correlated with grade 3 RRT. Docetaxel showed a linear increase of its AUC and similar clearance compared with prior reports at lower doses. In conclusion, ASCT-supported infusions of gemcitabine at FDR could be prolonged up to 20 hours. The resulting gemcitabine/docetaxel/melphalan/carboplatin combination was highly active in refractory cancers and should be further tested in disease-specific trials.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Deoxycytidine; Disease-Free Survival; Docetaxel; Dose-Response Relationship, Drug; Female; Gemcitabine; Hematopoietic Stem Cell Transplantation; Humans; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Neoplasms; Taxoids; Transplantation, Autologous

This study was conducted to define a new maximum tolerated dose and the dose-limiting toxicity (DLT) of melphalan and autologous hematopoietic stem cell transplantation (AHSCT) when used with the cytoprotective agent amifostine. Fifty-eight patients with various types of malignancy who were ineligible for higher-priority AHSCT protocols were entered on a phase I study of escalating doses of melphalan beginning at 220 mg/m(2) and advancing by 20 mg/m(2) increments in planned cohorts of 4 to 8 patients until severe regimen-related toxicity (RRT) was encountered. In all patients, amifostine 740 mg/m(2) was given on 2 occasions before the first melphalan dose (ie, 24 hours before and again 15 minutes before). AHSCT was given 24 hours after the first melphalan dose. Melphalan was given in doses up to and including 300 mg/m(2). Hematologic depression was profound, although it was rapidly and equally reversible at all melphalan doses. Although mucosal RRT was substantial, it was not the DLT, and some patients given the highest melphalan doses (ie, 300 mg/m(2)) did not develop mucosal RRT. The DLT was not clearly defined. Cardiac toxicity in the form of atrial fibrillation occurred in 3 of 36 patients treated with melphalan doses >/=280 mg/m(2) and was deemed fatal in 1 patient given melphalan 300 mg/m(2). (Another patient with a known cardiomyopathy was given melphalan 220 mg/m(2) and died as a result of heart failure but did not have atrial fibrillation.) Another patient given melphalan 300 mg/m(2) died of hepatic necrosis. The maximum tolerated dose of melphalan in this setting was thus considered to be 280 mg/m(2), and 27 patients were given this dose without severe RRT. Moreover, 38 patients were evaluable for delayed toxicity related to RRT; none was noted. Tumor responses have been noted at all melphalan doses and in all diagnostic groups, and 21 patients are alive at median day +1121 (range, day +136 to day +1923), including 16 without evidence of disease progression at median day +1075 (range, day +509 to day +1638). Amifostine and AHSCT permit the safe use of melphalan 280 mg/m(2), an apparent increase over the dose of melphalan that can be safely administered with AHSCT but without amifostine. Further studies are needed not only to confirm these findings, but also to define the antitumor efficacy of this regimen. Finally, it may be possible to evaluate additional methods of further dose escalation of melphalan in this setting.

Topics: Adult; Aged; Amifostine; Cohort Studies; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Neoplasms; Transplantation, Autologous; Treatment Outcome

A strong relationship has been demonstrated between high systemic exposure to busulfan and the occurrence of hepatic veno-occlusive disease (HVOD) after a busulfan-cyclophosphamide regimen (BU CY). We report a prospective study aimed at exploring the pharmacodynamics of high-dose busulfan combined with either melphalan (BU MEL) or thiotepa (BU TTP) followed by autologous stem cell transplantation in children and adolescents with a malignant solid tumor. Busulfan was given orally at a total dose of 600 mg m(-2). In all, 45 patients with a median age of 6.3 years were included in the study: 25 received BU MEL and 20 received BU TTP. The incidence of HVOD was 44% (CI 95% [23-65%]) in the BU MEL group and 25% (CI95% [9-49%]) in the BU TTP group. In the BU TTP group, patients who developed HVOD had a significantly higher AUC 0-6 h after the 13th dose (6201+/-607 h ng ml(-1)) than those who did not (5024+/-978 h ng ml(-1)) (P<0.05). In the BU MEL group, there was no difference in terms of systemic exposure to busulfan between patients who developed HVOD and those who did not. In conclusion, the guidelines established for monitoring BU CY cannot be extrapolated when busulfan is combined with another drug.

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Busulfan; Child; Child, Preschool; Drug Interactions; Drug Monitoring; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Incidence; Infant; Male; Melphalan; Neoplasms; Pharmacokinetics; Thiotepa; Transplantation, Autologous

This study sought to use a microdialysis technique to relate clinical and biochemical responses to the time course of melphalan concentrations in the subcutaneous interstitial space and in tumour tissue (melanoma, malignant fibrous histiocytoma, Merkel cell tumour and osteosarcoma) in patients undergoing regional chemotherapy by Isolated Limb Infusion (ILI). 19 patients undergoing ILI for treatment of various limb malignancies were monitored for intra-operative melphalan concentrations in plasma and, using microdialysis, in subcutaneous and tumour tissues. Peak and mean concentrations of melphalan were significantly higher in plasma than in subcutaneous or tumour microdialysate. There was no significant difference between drug peak and mean concentrations in interstitial and tumour tissue, indicating that there was no preferential uptake of melphalan into the tumours. The time course of melphalan in the microdialysate could be described by a pharmacokinetic model which assumed melphalan distributed from the plasma into the interstitial space. The model also accounted for the vascular dispersion of melphalan in the limb. Tumour response in the whole group to treatment was partial response: 53.8% (n = 7); complete response: 33.3% (n = 5); no response: 6.7% (n = 1). There was a significant association between tumour response and melphalan concentrations measured over time in subcutaneous microdialysate (P< 0.01). No significant relationship existed between the severity of toxic reactions in the limb or peak plasma creatine phosphokinase levels and peak melphalan microdialysate or plasma concentrations. It is concluded that microdialysis is a technique well suited for measuring concentrations of cytotoxic drug during ILI. The possibility of predicting actual concentrations of cytotoxic drug in the limb during ILI using our model opens an opportunity for improved drug dose calculation. The combination of predicting tissue concentrations and monitoring in microdialysate of subcutaneous tissue could help optimise ILI with regard to post-operative limb morbidity and tumour response.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Extremities; Histiocytoma, Benign Fibrous; Humans; Melanoma; Melphalan; Microdialysis; Middle Aged; Neoplasms; Osteosarcoma; Treatment Outcome

The objectives of the present study were to determine the following: (a) the maximum tolerated dose (MTD) of melphalan using a 24-h continuous infusion; (b) the clinical toxicity; and (c) the pharmacokinetic characteristics of melphalan at each dose level. Twenty-one patients with refractory solid tumors were enrolled in the study. Melphalan, packaged in 3% sodium chloride, was administered i.v. over a 24-h period. Patients were assigned to one of three escalating dose levels of melphalan: (a) 20 mg/m2 (n = 5); (b) 30 mg/m2 (n = 7); and (c) 40 mg/m2 (n = 6). Each patient underwent pharmacokinetic evaluation during the first cycle of treatment. Melphalan concentrations in plasma were determined by high-performance liquid chromatography. Toxicity was evaluated after each course of chemotherapy. All of the patients were assessable for toxicity and pharmacokinetics, and 20 patients were assessable for response analysis. A total of 50 courses of melphalan was studied. The MTD was 30 mg/m2. The dose-limiting toxicity was neutropenia and thrombocytopenia. Hematotoxicity was reversible (nadir, 14-15 days; recovery, 3.5 and 12.5 days for 30 and 40 mg/m2, respectively), cumulative, and related to the administered dose and to the history of previous therapy. There were six episodes of neutropenic sepsis. Individual pharmacokinetic parameters were estimated using a Bayesian approach and linear elimination kinetics. Data were compatible with a one-compartment model. Relationships have been found between the area under the plasma concentration-time curve and doses and between Css and doses. Moreover, clearance, t1/2 elimination, and volume of distribution did not change statistically with dose, which suggests linear kinetics. Two partial responses were observed in patients with ovarian carcinoma or adenocarcinoma of unknown primary origin, and another patient had stabilization disease. In conclusion, melphalan MTD was determined to be 30 mg/m2 when administered as a 24-h infusion. Hematological toxicity was the dose-limiting toxicity. The most important nonhematological toxicity encountered was nausea and vomiting. The recommended dose for Phase II studies was 30 mg/m2.

Topics: Adolescent; Adult; Aged; Anemia; Antineoplastic Agents, Alkylating; Area Under Curve; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Melphalan; Middle Aged; Neoplasms; Neutropenia; Regression Analysis; Thrombocytopenia

The purpose of this study was to determine the maximum tolerated dose of carboplatin administered with 500 mg/m2 thiotepa and 100 mg/m2 melphalan followed by autologous peripheral blood stem cell (PBSC) infusion in patients with refractory malignancies. Twenty-eight patients with refractory malignancies received high-dose thiotepa (500 mg/m2, melphalan (100 mg/m2) and escalating doses of carboplatin 900-1500 mg/m2) followed by infusion of cryopreserved autologous PBSCs. The maximum tolerated doses were determined to be 500 mg/m2 thiotepa, 100 mg/m2 melphalan and 1350 mg/m2 carboplatin. Two consecutive patients receiving 1500 mg/m2 carboplatin experienced grade 3 mucositis and colitis. Ten patients were enrolled at the maximum tolerated dose and none had grade 3-4 regimen-related toxicity and mortality. All patients at this level experienced grade 1-2 mucositis, 90% grade 1-2 gastrointestinal toxicity, 30% grade 1-2 cardiac and renal toxicity, and 10% experienced grade 1 hepatic toxicity. The median time to achieve a granulocyte count of 0.5x10(9)/l was 9 days (range 7-12 days) and platelet count of 20x10(9)/l was 10 days (range 7-15 days). Of eight patients with stage IV refractory breast cancer, even were evaluable for response, one patient on day 75 will be evaluated soon. Five of seven (71.5%) evaluable patients achieved a complete remission (CR) and two had no response. Of seven patients with non-Hodgkin's lymphoma (n = 4) or Hodgkin's disease (n = 3), five achieved a CR (71.5%). Thiotepa, melphalan and carboplatin can be administered in high doses with tolerable mucositis as the major side-effect. This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy-sensitive malignancies are warranted.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Neoplasms; Thiotepa; Transplantation, Autologous

Between August 1998 and July 1999, 21 patients received a novel protocol of reduced conditioning with fludarabine, carmustine and melphalan (FBM) followed by matched-related allogeneic peripheral blood stem cell transplantation (PBSCT) in a prospective multi-center phase I/II study. Cyclosporin A and 'mini-methotrexate' were used for GVHD prophylaxis. Patients were included because of age, advanced disease, previous transplantation or co-morbidity. Hematopoietic engraftment after allogeneic transplantation was rapid with a median white blood count (WBC) >1 x 10(9)/l on day +11 (range 10-17) and a median platelet count >20 x 10(9)/l on day +13 (range 9-36). Donor chimerism was complete in 16/21 (76%) patients at all time points during follow-up and mixed at least on one occasion in 5/21 (24%) patients. The conditioning regimen was well tolerated with low toxicity even in previously transplanted patients. Thirteen patients (62%) developed acute GVHD grades II-IV. Nineteen out of 21 patients achieved complete (CR, n = 15) or partial remission (PR, n = 4) with a median patient follow-up of 354+ days (range 258-577) for patients alive. The reduced intensity protocol FBM is feasible with rapid engraftment, early achievement of complete donor chimerism, low toxicity, especially in heavily pretreated patients, and good response rates in advanced disease patients.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclosporine; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukapheresis; Male; Melphalan; Methotrexate; Middle Aged; Neoplasms; Prospective Studies; Survival Analysis; T-Lymphocytes; Transplantation Chimera; Transplantation Conditioning; Transplantation Tolerance; Vidarabine

We conducted a prospective pilot study to assess the feasibility and safety of high-dose busulfan/melphalan as conditioning therapy prior to autologous PBPC transplantation in pediatric patients with high-risk solid tumors. From January 1995 to January 1999, 30 patients aged 2-21 years (median 8) were entered into the study. There were 14 females and 16 males. Diagnoses included neuroblastoma in 10 patients; Ewing's sarcoma and peripheral neuroectodermal tumor (PNET) in 15 patients and rhabdomyosarcoma in five patients. Treatment consisted of busulfan 16 mg/kg, orally over 4 days (from days -5 to -2) in 6 hourly divided doses, and melphalan at a dose of 140 mg/m2 given by intravenous infusion over 5 min on day -1. G-CSF mobilized PBPC were used as autologous stem-cell rescue. One patient developed a single generalized convulsion during busulfan therapy. The most relevant non-hematologic toxicity was gastrointestinal, manifesting as grade 2-3 mucositis and diarrhea in 12 patients. Two patients died of procedure-related complications, one from veno-occlusive disease of liver and multiorgan failure and the other from adult respiratory distress syndrome. Probability of treatment-related mortality was 6.6 +/- 4.5%. With a median follow-up of 18 months (range, 1-48), 19 patients are alive and disease-free, the actuarial EFS at 4 years being 55 +/- 12% for the whole group. We conclude that high-dose busulfan/melphalan for autologous transplantation in children with solid tumors is feasible even in small patients. It is well-tolerated, with an acceptable transplant-related mortality and has proven antitumor activity.

Topics: Adolescent; Adult; Antigens, CD34; Antineoplastic Agents, Alkylating; Blood Cell Count; Bone Diseases; Bone Neoplasms; Busulfan; Child; Child, Preschool; Clonazepam; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Neoplasms; Neuroblastoma; Pilot Projects; Retrospective Studies; Rhabdomyosarcoma; Sarcoma, Ewing; Survival Rate; Transplantation Conditioning; Transplantation, Autologous

We examined the efficiency of disease-specific "standard" chemotherapies epirubicin, cyclophosphamide (EC); cyclophosphamide, vincristine, doxorubicin, etoposide, prednisolone (CHOEP); epirubicin, ifosfamide (EPI/IFOS) for peripheral blood progenitor cell (PBPC) mobilization in comparison to well-characterized mobilization protocols, i.e. etoposide, ifosfamide, cisplatin, epirubicin (VIPE) and dexamethasone, carmustine, etoposide, cytarabine, melphalan (DexaBEAM). Twenty-seven patients with various malignancies underwent 75 apheresis procedures for PBPC collection. Median cell yields from all 75 aphereses were 1.18 x 10(5) mononuclear cells/kg [range (0.28-3.7) x 10)8)], 1.4 x 10(5) granulocyte/macrophage-colony-forming units (CFU-GM)/kg [range (0.2-11) x 10(5)] and 3.3 x 10(6) CD34+cells/kg [range (0.35-17.7) x 10(6). CD34+/ CD90+ cells could be mobilized by all mobilization regimens used. The difference observed in the mobilization of CD34+ cells was only of low significance when the mobilization regimens were compared, whereas the mobilizations of MNC and CFU-GM were significantly different between the groups. Breast cancer patients treated with the VIPE regimen (including pretreated women) had a significantly higher CFU-GM rate than patients treated with EC (P=0.0005). Mobilized CD34+ PBPC were correlated with CFU-GM in all apheresis products. The linear correlation coefficients differed for the various mobilization groups: DexaBEAM (r=0.9, P < 0.0001), VIPE (r=0.68, P=0.0024), CHOEP (r=0.52, P=0.022), EPI/ IFOS (r=0.34, P=0.11) and EC (r=0.23, P=0.2). We conclude that clonogenic assays can provide additional information about the autotransplant quality, particularly when alternative or new mobilization regimens are being investigated.

Topics: Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Blood Component Removal; Carmustine; Cell Separation; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Epirubicin; Etoposide; Female; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Granulocytes; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Humans; Ifosfamide; Macrophages; Male; Melphalan; Neoplasms; Prednisolone; Vincristine

To evaluate the biologic interactions and toxicities of melphalan (L-PAM) combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes.. Sixteen patients with refractory cancer were treated (May 1992 to May 1995) with WBH alone during week 1) thereafter patients were randomized to receive either L-PAM alone on week 2 and L-PAM plus WBH on week 5, or the reverse sequence. Patients who demonstrated clinical improvement received WBH plus L-PAM monthly. Dose levels of L-PAM were 10 mg/m2 (n = 3), 15 mg/m2 (n = 3), 17.5 mg/m2 (n = 6), and 20 mg/m2 (n = 4). L-PAM was administered at target temperature; WBH was administered with an Aquatherm radiant-heat device (patent pending; Cancer Research Institute, New York, NY).. Comparisons of mean WBC count and platelet nadirs for L-PAM alone and L-PAM plus WBH demonstrated that the addition of WBH resulted in nadir counts that were, on average, 25% lower. There were no instances of febrile neutropenia or bleeding. Toxicities allowed for escalation of L-PAM to 20 mg/m2; all four patients at this level experienced grade 4 myelosuppression. No significant myelosuppression was observed at 10 and 15 mg/m2. Grade 3 myelosuppression was observed in two of six patients at 17.5 mg/m2. Responses included complete remission (CR) of pancreatic cancer (10 mg/m2), partial remission (PR) of malignant melanoma in two patients (20 mg/m2), and transient clinical and/or serologic improvement in five patients. The pharmacokinetics of L-PAM were not altered by WBH. Observed cytokine induction by WBH is also discussed in detail.. We conclude that L-PAM with 41.8 degrees C WBH is well tolerated. Clinical results are consistent with preclinical predictions and provide a foundation for second-generation trials now in progress.

Topics: Adult; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Combined Modality Therapy; Drug Administration Schedule; Female; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Nausea; Neoplasms; Temperature; Vomiting

Increased intracellular glutathione has long been associated with tumor cell resistance to various cytotoxic agents. An inhibitor of glutathione biosynthesis, L-S,R-buthionine sulfoximine (BSO), has been shown to enhance the cytotoxicity of chemotherapeutic agents in vitro and in vivo. We performed a phase I study of BSO administered with the anticancer drug melphalan to determine the combination's safety/tolerability and to determine clinically whether BSO produced the desired biochemical end point of glutathione depletion (<10% of pretreatment value).. Twenty-one patients with advanced cancers received an initial 30-minute infusion of BSO totaling 3.0 g/m2 and immediately received a continuous infusion of BSO on one of the following schedules: 1) 0.75 g/m2 per hour for 24 hours (four patients); 2) the same dose rate for 48 hours (four patients); 3) the same dose rate for 72 hours (10 patients); or 4) 1.5 g/m2 per hour for 48 hours (three patients). During week 1, the patients received BSO alone; during weeks 2 or 3, they received BSO plus melphalan (15 mg/m2); thereafter, the patients received BSO plus melphalan every 4 weeks. Glutathione concentrations in peripheral blood lymphocytes were determined for all patients; in 10 patients on three of the administration schedules, these measurements were made in multiple sections from tumor biopsy specimens taken before, during, and after continuous-infusion BSO.. Continuous-infusion BSO alone produced minimal toxic effects, although BSO plus melphalan produced occasional severe myelosuppression (grade 4) and frequent low-grade nausea/vomiting (grade 1-2). This treatment also produced consistent, profound glutathione depletion (<10% of pretreatment value). The degree of glutathione depletion in peripheral lymphocytes was considerably less than that observed in tumor sections.. Continuous-infusion BSO is relatively nontoxic and results in depletion of tumor glutathione.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Drug Administration Schedule; Female; Glutathione; Humans; Infusions, Intravenous; Lymphocytes; Male; Melphalan; Middle Aged; Neoplasms; Treatment Outcome

Between January 1993 and December 1996, 21 children with advanced solid tumors were entered in a dose-escalating study of high-dose sequential chemotherapy followed by autologous stem cell transplantation. The diagnoses included neuroblastoma (NB) for 13 patients; Ewing's sarcoma (ES) for six patients and osteosarcoma for two patients. Nine patients received therapy as consolidation for primary metastatic disease, and 12 patients had had previous relapses. Treatment consisted of CY given i.v. at a dose of 7 g/m2 on day 1, followed by G-CSF until myeloid recovery. After 3 weeks of rest, all patients were given thiotepa i.v. on days 22-24. The total dose of thiotepa was 450 mg/m2 in three patients, 600 mg/m2 in six patients, and 750 mg/m2 in 12 patients. Melphalan was given i.v. at a dose of 180 mg/m2 i.v. on day 27 followed by stem cell infusion on day 28. Major toxic reactions included stomatitis, esophagitis, diarrhea and dermatitis. Three patients died of treatment-related complications. Twelve patients have had a relapse. Six patients (five with NB and one with ES) are alive in continuous remission 5-50 months (median 36) after transplantation. The results of this study show that it is feasible to administer high-dose sequential chemotherapy to children with advanced solid tumors.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Digestive System Diseases; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Melphalan; Neoplasms; Neuroblastoma; Osteosarcoma; Remission Induction; Salvage Therapy; Sarcoma, Ewing; Survival Analysis; Thiotepa; Treatment Outcome

Resistance to alkylating agents and platinum compounds is associated with elevated levels of glutathione (GSH). Depletion of GSH by buthionine sulfoximine (BSO) restores the sensitivity of resistant tumors to melphalan in vitro and in vivo. In a phase I trial, each patient received two cycles as follows: BSO alone intravenously (i.v.) every 12 hours for six doses, and 1 week later the same BSO as cycle one with melphalan (L-PAM) 15 mg/m2 i.v. 1 hour after the fifth dose. BSO doses were escalated from 1.5 to 17 g/m2 in 41 patients.. The only toxicity attributable to BSO was grade I or II nausea/vomiting in 50% of patients. Dose-related neutropenia required an L-PAM dose reduction to 10 mg/m2 at BSO 7.5 g/m2. We measured GSH in peripheral mononuclear cells (PMN), and in tumor biopsies when available, at intervals following BSO dosing. In PMNs, GSH content decreased over 36 to 72 hours to reach a nadir on day 3; at the highest dose, recovery was delayed beyond day 7. The mean PMN GSH nadirs were approximately 10% of control at BSO doses > or = 7.5 g/m2; at 13 and 17 g/m2, all but two patients had nadir values in this range. GSH was depleted in sequential tumor biopsies to a variable extent, but with a similar time course. At BSO doses > or = 13 g/m2, tumor GSH was < or = 20% of starting values on day 3 in five of seven patients; recovery had not occurred by day 5. We measured plasma concentrations of R- and S-BSO by high-performance liquid chromatography (HPLC) in 22 patients throughout the dosing period. Total-body clearance (CLt) and volume of distribution at steady-state (Vss) for both isomers were dose-independent. The CLt of S-BSO was significantly less than that of R-BSO at all doses, but no significant differences in Vss were observed between the racemates. Harmonic mean half-lives were 1.39 hours and 1.89 hours for R-BSO and S-BSO, respectively.. A biochemically appropriate dose of BSO for use on this schedule is 13 g/m2, which will be used in phase II trials to be conducted in ovarian cancer and melanoma.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Buthionine Sulfoximine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Glutathione; Humans; Linear Models; Male; Melphalan; Methionine Sulfoximine; Middle Aged; Nausea; Neoplasm Recurrence, Local; Neoplasms; Neutropenia; Neutrophils; Radiography; Vomiting

To describe the postoperative course of patients who underwent hyperthermic isolated limb perfusion with recombinant tumor necrosis factor (TNF)-alpha and melphalan after pretreatment with recombinant interferon-gamma as treatment for recurrent melanoma, primary nonresectable soft-tissue tumors, planocellular carcinoma, or metastatic carcinoma. To measure systemic TNF-alpha concentrations and relate these values with indices of disease severity.. A 12-bed surgical intensive care unit (ICU) in a university referral hospital.. Prospective, descriptive study.. Consecutive patients (n=25) treated with hyperthermic isolated limb perfusion.. Blood samples were taken at regular intervals to determine TNF-alpha concentrations during and after hyperthermic isolated limb perfusion with recombinant TNF-alpha. Hemodynamic variables were obtained with a Swan-Ganz pulmonary artery catheter.. All patients developed features of sepsis syndrome and required intensive care treatment. Most patients recovered quickly, with a median ICU stay of 2 days (range 1 to 25). Maximum systemic TNF-alpha concentrations ranged from 2284 to 83,000 ng/L (median 25,409) and returned to baseline values within 8 hrs. Despite these high concentrations of TNF-alpha, no patient died in the ICU, although the patient with the highest TNF-alpha concentration developed multiple organ failure and required continuous venovenous hemofiltration for 16 days. Linear regression analysis showed positive correlations between maximum TNF-alpha concentrations and systemic vascular resistance (p < .01), cardiac index (p < .02), Lung Injury Score (p < .02), prothrombin time (p < .02), and activated partial thromboplastin time (p < .05).. Hyperthermic isolated limb perfusion with recombinant TNF-alpha leads to high systemic concentrations of TNF-alpha, probably due to leakage of recombinant TNF-alpha from the perfusion circuit, mainly through collateral blood flow. A sepsis-like syndrome is seen in all patients. Despite high concentrations of systemic TNF-alpha, this sepsis syndrome is short-lived and recovery is rapid and complete in most patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Hemodynamics; Humans; Hyperthermia, Induced; Interferon-gamma; Linear Models; Male; Melphalan; Middle Aged; Neoplasms; Prospective Studies; Recombinant Proteins; Severity of Illness Index; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

Between June 1991 and January 1995 we performed 67 peripheral blood progenitor cell transplants (PBPCT). Ten patients (group 1) were mobilised with 7 gm/m2 of cyclophosphamide followed by daily G-CSF injections (5 micrograms/kg, subcutaneously). When the white cell count reached 1 x 10(9)/1 they were leukapheresed for 5 days. After stem cell infusion they received G-CSF (10 micrograms/kg/day) until the neutrophil count reached 1.5 x 10(9)/1. Fifty-six patients had PBPCs mobilised with 3 gm/m2 of cyclophosphamide followed by daily subcutaneous G-CSF (5 micrograms/kg) and PBPCs were harvested on 2 consecutive days, when the white cell count rose to 4 x 10(9)/1. After stem cell infusion this group did not receive G-CSF. In 47 of the 56 patients (group 2) adequate MNC (> or = 4 x 10(8)/kg) and/or CFU-GM (> or = 10 x 10(4)/kg) were obtained. Insufficient MNC and/or CFU-GM were obtained in 10 patients. They were therefore transplanted using a combination of bone marrow and peripheral blood progenitor cells (group 3). Overall 64 patients successfully engrafted. Median days to neutrophils > or = 0.5 x 10(9)/1 were 9 (range 8-13), 12 (range 8-25) and 11 (range 9-16) and to platelets > or = 50 x 10(9)/1 were 11 (range 9-23), 13 (range 9-90) and 16 (range 13-99) in groups 1, 2 and 3 respectively. Patients in group 1 had a faster neutrophil recovery than patients in group 2 (P = 0.0002). The three patients who failed to engraft all received a combination of autologous peripheral blood and bone marrow cells.

Topics: Adolescent; Adult; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carmustine; Cell Movement; Colony-Forming Units Assay; Cyclophosphamide; Cytarabine; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Kidney Diseases; Leukapheresis; Leukocyte Count; Male; Melphalan; Middle Aged; Neoplasms; Podophyllotoxin; Retrospective Studies; Thiotepa; Transplantation Conditioning

This study was undertaken to determine the effects on systemic fibrinolysis of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor alpha (r-TNF-alpha) and melphalan, with or without pretreatment with recombinant IFN-gamma (r-IFN-gamma). Twenty patients were treated with r-TNF-alpha and melphalan; four patients, treated with melphalan only, served as controls. Of the twenty patients treated with both r-TNF-alpha and melphalan, eight received r-IFN-gamma for two days before the perfusion and as a bolus into the perfusion circuit. A significant leak of r-TNF-alpha from the perfusion circuit to the systemic circulation was observed in all r-TNF-alpha-treated patients (mean maximum TNF-alpha, 87,227 ng/liter versus 31 ng/liter in controls; P < 0.002). In these patients, but not in controls, there was an almost instantaneous rise in systemic tissue plasminogen activator activity (from 0.26 to 5.28 IU/ml in 90 min), causing activation of fibrinolysis. After a delay of 90 min, plasminogen activator inhibitor-1 (PAI-1) antigen rose to high levels in the r-TNF-alpha-treated group (mean maximum PAI-1, 1652 ng/ml versus 211 ng/ml in controls; P < 0.02), associated with a sharp decrease of tissue plasminogen activator activity and a slower decrease of plasminogen-antiplasminogen complexes (from 5.28 to 0.02 IU/ml in 2 h and from 1573 to 347 micrograms/liter in 22 h, respectively). No additional effect of IFN-gamma pretreatment on fibrinolysis could be demonstrated. These results suggest that in isolated limb perfusion with r-TNF-alpha and melphalan an initial activation of systemic fibrinolysis, induced by leakage of r-TNF-alpha from the perfusion circuit, is set off by a subsequent inhibition of the fibrinolytic system by PAI-1. This large increase in PAI-1 could place the patient at risk for deposition of microthrombi in the systemic circulation.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Hyperthermia, Induced; Interferon-gamma; Melphalan; Neoplasms; Plasminogen Activator Inhibitor 1; Recombinant Proteins; Tissue Plasminogen Activator; Tumor Necrosis Factor-alpha

The purpose of this study was to determine the toxicities and potential effectiveness of high-dose busulfan, melphalan and thiotepa (Bu/Mel/TT) followed by autologous peripheral blood stem cell (PBSC) infusion in patients with a variety of diseases. A phase II clinical trial of Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC infusion in 104 patients with breast cancer (n = 48), malignant lymphoma (n = 25), ovarian cancer (n = 13), multiple myeloma (n = 7) and other malignancies (n = 11) was performed. Sixty-two patients were treated in an academic medical center and 42 in a community cancer center. Grade 3-4 regimen-related toxicities occurred in 14% of patients, causing regimen-related mortality in six (6%) patients with an overall transplant-related mortality of 9%. Transplant-related deaths occurred in 6/62 patients (10%) treated in an academic medical center and in 3/42 (7%) treated in a community cancer center. Complete remissions (CR) were achieved in 1/17 (6%) patients with refractory stage IV breast cancer, 4/4 patients with responsive stage IV breast cancer, 6/13 (46%) with more-advanced lymphoma and 4/4 with less-advanced lymphoma. These patients are alive and disease-free a median of 712, 279, 461 and 404 days after transplant, respectively. Nineteen of 22 patients with stage II-III breast cancer remain alive and disease-free a median of 365 days after transplant. Complete remissions were also seen in 4/9 patients with ovarian cancer and 3/7 with multiple myeloma. The Bu/Mel/TT regimen followed by autologous PBSC infusion is associated with acceptable morbidity and mortality, appears to have significant activity in patients with breast cancer and is well tolerated in the adjuvant setting of stage II-III breast cancer. Bu/Mel/TT also appears to have significant activity in patients with lymphoma, multiple myeloma and possibly ovarian cancer. Further phase II-III studies are warranted in patients with these and other malignancies.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Busulfan; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Neoplasms; Ovarian Neoplasms; Thiotepa; Transplantation, Autologous

The development of time-dependent pharmacodynamic models in cancer chemotherapy has been extremely limited. A population approach was used to develop such a model to describe the effect of buthionine sulfoximine (BSO), via its active S-isomer (S-BSO), on glutathione (GSH) depletion in peripheral mononuclear cells. The Phase I trial utilized escalating doses of BSO, from 5 to 17 gm/m2, as a multiple infusion regimen. The population model consisted of a linear 2-compartment pharmacokinetic model coupled to an indirect response model. The indirect response model consisted of a GSH compartment with input and output rate processes that are modulated as a function of S-BSO and GSH concentrations. The model predicted the observed gradual depletion of GSH, a nadir at approximately 30 h after the last dose of BSO, and a return to baseline GSH levels. On the basis of an IC50 estimate of about 1.6 microM for inhibition of gamma-glutamylcysteine synthetase, the target enzyme of BSO, the population model predicted near identical GSH concentration time profiles over the dose range studied. Time-dependent pharmacodynamic models are seen as a powerful means to design dosing regimens and to provide a mathematical platform for mechanistic based models.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Enzyme Inhibitors; Glutathione; Humans; Melphalan; Methionine Sulfoximine; Neoplasms; Neutrophils

The matrix protein tenascin-C (TN-C) is present in the blood of healthy individuals at concentrations around 1 mg/l. Elevated serum levels have been reported in cancer patients. In this study we have measured the concentration of circulating TN-C in 40 patients with melanoma, soft-tissue sarcoma (STS) or squamous-cell carcinoma (SCC) of the limbs, and have found a minor increase in the mean concentration compared with healthy subjects. Only 10 patients had TN-C levels above the normal range. No correlation was observed between TN-C levels and tumor burden. Nineteen patients were treated by isolation limb perfusion (ILP) with TNF, IFN gamma, melphalan (11 melanoma, 2 SCC and I STS), melphalan alone (3 melanoma) or hyperthermia at 41.5 degrees C (2 melanoma). ILP with TNF, IFN gamma and melphalan induced a rapid increase in plasma TN-C levels, peaking in most patients between 24 or 48 hr after ILP. Two patients treated with hyperthermia only had a slow increase in TN-C concentration peaking at day 4, while the patients treated with melphalan alone had no significant change. In some cases elevated TN-C levels persisted for over 8 weeks after ILP. The early rise in TN-C concentration correlates with the increase in circulating C-reactive protein. Our findings suggest that circulating TN-C behaves, at least in part, as an acute-phase protein and that it may play a role in the inflammatory response.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; C-Reactive Protein; Carcinoma, Squamous Cell; Chemical and Drug Induced Liver Injury; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Extremities; Female; Humans; Interferon-gamma; Interleukin-6; Male; Melanoma; Melphalan; Middle Aged; Neoplasms; Recombinant Proteins; Sarcoma; Soft Tissue Neoplasms; Tenascin; Tumor Necrosis Factor-alpha

Melphalan has a steep dose-response curve, but the use of high doses results in unacceptable myelosuppression. Strategies to circumvent this dose-limiting myelosuppression would allow for the administration of higher, more effective doses of melphalan. Amifostine (WR-2721) has been shown in preclinical studies to protect the bone marrow from the myelotoxicity of melphalan, and in clinical trials, to protect from the myelotoxicity of other alkylating agents. A Phase I trial of the combination of amifostine and melphalan was performed in children with refractory cancers to: (a) define the acute toxicities of amifostine and its maximum tolerated dose (MTD); and (b) to determine whether the dose of melphalan could be safely escalated when administered in combination with amifostine. Amifostine was administered i.v. as a 15-min infusion 30 min before melphalan. The starting dose of amifostine was 750 mg/m2, with planned dose escalations in 30% increments. Melphalan was administered as a 5-min infusion using the previously defined MTD in heavily pretreated patients, 35 mg/m2, as the starting dose. The dose of melphalan was escalated by 30% increments. Nineteen patients, ranging in age from 3 to 24 years (median, 15 years), were entered on trial. The dose of amifostine was escalated to 2700 mg/m2, which is approximately 3-fold higher than the adult recommended dose, without reaching a MTD. Fifteen patients experienced nondose-limiting (< 25%), transient decreases in blood pressure after the amifostine infusion. Other nondose-limiting toxicities of amifostine included mild nausea and vomiting, flushing, anxiety, diarrhea, and urinary retention. Six patients, three each at the 2100 and 2700 mg/m2 amifostine dose levels were treated with an escalated dose of melphalan (45 mg/m2). All of these patients experienced grade 4 neutropenia (< 500/mm3), and five of six patients had grade 4 thrombocytopenia. The duration of this dose-limiting myelosuppression exceeded 7 days in four of six patients. Although no dose-limiting (grade 3 or 4) toxicity was attributed to amifostine, significant anxiety and reversible urinary retention occurred at the two highest amifostine dose levels. A dose of 1650 mg/m2 for pediatric Phase II trials is recommended. High doses of amifostine, however, do not appear to allow for escalation of melphalan beyond its single agent MTD of 35 mg/m2.

Topics: Adolescent; Adult; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Humans; Male; Melphalan; Neoplasms

The purpose of this study was to determine the maximal tolerated dose of thiotepa administered with busulfan 12 mg/kg and melphalan 100 mg/m2 followed by autologous stem cell transplantation in patients with refractory malignancies. Twenty-eight patients with refractory malignancies received high-dose busulfan 12 mg/kg, melphalan 100 mg/m2 and escalating doses of thiotepa 450-550 mg/m2 followed by infusion of cryopreserved autologous peripheral blood stem cells (n = 26) or marrow (n = 2). The maximum tolerated dose was determined to be busulfan 12 mg/kg, melphalan 100 mg/m2 and thiotepa 500 mg/m2. Two of three patients receiving thiotepa 550 mg/m2 experienced grade 3 colitis. Twenty patients were enrolled at the maximum tolerated dose and the incidence of grade 3-4 regimen-related toxicity and mortality was 10% and 5%, respectively. Ninety-five per cent of patients experienced grade 1-2 mucositis, 50% grade 1-2 gastrointestinal toxicity, 35% grade I hepatic toxicity and 20% experienced grade 1-2 skin toxicity. The median time to achieve a granulocyte count of 0.5 x 10(9)/I was 10 days (range 8-20 days) and platelet transfusion independence was 10 days (range 1-26 days). Five of ten patients with stage 4 refractory breast cancer achieved a complete and two a partial remission with a complete response rate of 50% and a overall response rate of 70%. In conclusion, busulfan, melphalan and thiotepa can be administered in high doses with tolerable mucositis as the major side-effect. This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy sensitive malignancies are warranted.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Busulfan; Combined Modality Therapy; Drug Tolerance; Female; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Neoplasms; Thiotepa; Transplantation, Autologous

The purpose of this work was to determine the maximum tolerated (phase II) dose of melphalan and etoposide that can be given in conjunction with autologous BM re-infusion in patients who have refractory or relapsed solid tumors. Twenty-six patients with refractory or relapsed breast cancer (n = 15), small cell lung cancer (n = 1), ovarian cancer (n = 3), colorectal cancer (n = 3) or malignant melanoma (n = 4) were enrolled and treated in this phase I study. Patients ranged in age from 31 to 60 years (median 44.5 years). Melphalan 180 mg/m2 (60 mg/m2/day for 3 consecutive days i.v. over 30 min) and etoposide 1200-3600 mg/m2 (400-1200 mg/m2/day for 3 consecutive days i.v. over 4 h) were given followed by autologous BM infusion 60-72 h after completion of chemotherapy. Ten patients received GM-CSF or G-CSF therapy after marrow re-infusion. Regimen-related toxicities included fever, pancytopenia, mucositis, nausea, vomiting, diarrhea, esophagitis, hepatic dysfunction and infection. Neutrophils recovered to > 500 x 10(6)/l and platelets recovered to > 20 x 10(9)/l (without transfusions) a median of 17 days and 20.5 days after marrow infusion, respectively. Dose-limiting toxicity occurred at an etoposide dose of 3600 mg/m2, since 4 of 6 patients treated at this dose level experienced grade 4 NCI Common Toxicity Criteria (mucositis (n = 3) and infection (n = 1)). Complete responses were noted in 7 patients (breast cancer (n = 5), colorectal cancer (n = 1) and melanoma (n = 1)); partial responses were observed in 5 patients. Melphalan 180 mg/m2 and etoposide 3000 mg/m2 is a potent high-dose chemotherapy regimen with significant antineoplastic activity, particularly for breast cancer, and has acceptable toxicity when administered in conjunction with autologous BM re-infusion.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Etoposide; Female; Follow-Up Studies; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Infusions, Intravenous; Melphalan; Middle Aged; Neoplasms; Retrospective Studies; Transplantation, Autologous

A phase I dose-escalation trial of intravenous (IV) L-buthionine-SR-sulfoximine (BSO) with melphalan (L-PAM) was performed to determine the toxicity and biologic activity of BSO, administered as a short infusion every 12 hours, and the combination of BSO plus L-PAM.. Twenty-eight patients with refractory malignancies received 30-minute infusions of BSO every 12 hours for 6 to 10 doses in week 1 followed in week 2 by either IV L-PAM (15 mg/m2) alone or BSO as in week 1 with L-PAM. Patients received the combination in week 5 (course no. 2) if they received L-PAM alone during week 2 and vice versa. BSO doses ranged from 1.5 g/m2 to 13.104 g/m2.. The only toxicity observed with BSO infusions was occasional nausea/vomiting. Evaluation of 23 paired courses (L-PAM plus BSO v L-PAM) showed significantly (P < .001) greater leukopenia and thrombocytopenia with L-PAM plus BSO. No other significant toxicity was noted. Measurement of intracellular glutathione (GSH) levels in peripheral mononuclear cells (PBLs) of all patients receiving BSO showed a consistent, non-dose-dependent, linear decrease in GSH with repeated BSO doses. Maximal GSH depletion (40% of baseline values, absolute values 200 to 250 ng/10(6) PBLs) was noted after the sixth BSO dose; extended BSO dosing schedules beyond six total BSO doses did not further deplete GSH. Evaluation of gamma-glutamylcysteine synthetase (GCS) activity showed marked inhibition near the end of each infusion with near complete recovery of GCS activity before the next BSO dose. The pattern of GCS inhibition mirrored the plasma BSO concentrations with peak values (level 6, 4 to 8 mmol/L L,R+L,S BSO) observed at the end of the infusion with a rapid decrease in plasma concentrations with an estimated half-life (t1/2) of less than 2 hours. Differential elimination of the R+S stereoisomers was observed. Analysis of L-PAM pharmacokinetics showed marked interpatient variability and a significant decrease in total-body clearance (P = .01) and volume of distribution (P = .03) in courses with L-PAM plus BSO as compared with L-PAM alone.. This study shows that BSO alone and in combination with L-PAM can be safely given to patients, but that a schedule of short infusions every 12 hours does not result in GSH depletion less than 30% of baseline values.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Female; Glutathione; Humans; Infusions, Intravenous; Male; Melphalan; Methionine Sulfoximine; Middle Aged; Neoplasms

High dose chemotherapy with autologous bone marrow support (ABMT) can achieve prolonged relapse-free survival in relapsed lymphomas, leukemias, and certain solid tumors. The principal morbidity and mortality relate to the infectious complications that occur during the 3-4 week aplasia until the marrow autograft recovers. Progenitor cells can be mobilized into the peripheral blood compartment by hematopoietic growth factors, used alone or after chemotherapy. We describe four trials using cytokine-mobilized peripheral blood progenitor cells (PBPC). In the first trial, PBPC collected after GM-CSF administration were used to augment marrow. Reconstitution of trilineage marrow function occurred promptly, resulting in short hospital stays and fewer platelet transfusions. In a second study, GM-CSF/chemotherapy-mobilized PBPC were used as the sole hematopoietic support during high dose chemotherapy. Granulocyte and platelet reconstitution was rapid. Time to hematopoietic recovery, transfusion requirements, and duration of hospital stay were all significantly improved for the patients receiving PBPC compared with similar patients receiving marrow alone. While most patients experienced prompt hematopoietic recovery they showed sluggish platelet engraftment. The next two trials built on the observation that a few PBPC alone could support both granulocyte and platelet recovery and were designed to test the feasibility of sequential high-dose therapies. In one trial, PBPC given with and without marrow made it possible to deliver two sequential cycles of high-dose therapy. The second trial utilized PBPC plus cytokines to deliver four cycles of dose-intensive chemotherapy at doses that could not be given with cytokine support alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Cells; Bone Marrow Transplantation; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Graft Survival; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leukapheresis; Male; Melphalan; Methotrexate; Middle Aged; Neoplasms; Neutropenia; Salvage Therapy; Treatment Outcome

A "priming" injection of cyclophosphamide (400 mg/m2 given i.v. on day -7) has been shown to reduce intestinal permeability and thus gut toxicity in patients receiving high-dose melphalan. To determine the optimal timing for this injection, patients receiving 200 mg/m2 melphalan with an autologous bone marrow transplant were randomly assigned to receive cyclophosphamide at 5, 7 or 9 days before the melphalan. The median percentage of [51Cr]-ethylenediaminetetraacetic acid excretion was similar (9.1% vs 7.1% vs 7.7%, respectively), with equivalent duration of WHO grade 2-4 mucositis and diarrhoea being recorded for each group. Thus, the timing of the cyclophosphamide prime is not critical, and the priming injection may be given between 5 and 9 days prior to high-dose melphalan.

Topics: Bone Marrow Transplantation; Chromium Radioisotopes; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Edetic Acid; Gastrointestinal Diseases; Humans; Melphalan; Neoplasms

Studies are described of high-dose therapy in metastatic breast cancer, early stage breast cancer, stage IV neuroblastoma, recurrent or bulky disease testicular cancer and Ewing's sarcoma. The outcome in these subgroups with conventional therapy is described for comparison. The results of these studies suggest that high-dose therapy with autologous marrow support increases the proportion of patients with long-term survival without evidence of disease. Newer supportive care and recurrent high-dose therapy cycles of non-cross resistant regimens may improve outcome further in these diseases and increase the application to more resistant tumors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Humans; Melphalan; Neoplasm Metastasis; Neoplasms; Neuroblastoma; Prednisone; Prognosis; Remission Induction; Survival Rate; Transplantation, Autologous; Treatment Outcome; Vincristine

Melphalan (L-phenylalanine mustard) is a bifunctional alkylating agent that is commonly administered orally to treat a wide variety of malignancies, including cancers of the breast and ovary, as well as multiple myeloma. Although commercially available in Europe and Canada, intravenous (IV) melphalan remains investigational in the United States. The role of IV melphalan in cancer chemotherapy is not well defined, despite its manageable toxicity and higher and more predictable blood levels following IV administration compared with oral administration. In addition, unlike oral melphalan, an extensive phase I evaluation of IV melphalan has not been undertaken. At lower doses (eg, 30 to 70 mg/m2), both as a single agent and in combination, the activity of IV melphalan has been evaluated in only a limited number of diseases. However, striking activity has been observed in previously untreated patients with rhabdomyosarcoma, a disease not generally considered responsive to alkylating agents. When administered at high doses (greater than 140 mg/m2) requiring bone marrow reinfusion, melphalan effects a high response rate (but no improvement in survival) in a variety of nonhematologic tumor types, including resistant tumors such as melanoma and colon carcinoma. In contrast, in poor-prognosis patients with non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or neuroblastoma, high-dose melphalan-containing regimens have yielded both high response rates and improved survival, despite considerable toxicity. Additional clinical trials will be necessary to define the spectrum of activity of lower doses of IV melphalan and to define subgroups of patients most likely to benefit from high-dose melphalan.

Topics: Administration, Oral; Body Water; Bone Marrow; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Humans; Infusions, Intravenous; Melphalan; Neoplasms

Both in vitro and in vivo studies have demonstrated antiproliferative effects of interferon alfa-2b (Intron A; Schering-Plough) when tested with human tumor cells. A clonogenic assay has been widely used to determine its direct antiproliferative effects on human tumor cells in vitro using colony reduction as a reproducible endpoint. As a single agent, interferon alfa-2b shows maximum tumor cell colony reduction when used in high concentrations with continuous cell exposure. Short-term exposure to interferon alfa-2b does not produce significant tumor cell colony reduction. Clonogenic assays have also been used to test combinations of interferon alfa-2b with cytotoxic drugs. Variations in drug scheduling, sequencing and concentrations have indicated the best combinations which maximize tumor cell colony reduction. Combinations of interferon alfa-2b with doxorubicin, cisplatin, vinblastine, melphalan and cyclophosphamide have been shown to have at least additive and occasionally synergistic antiproliferative effects. In clinical trials, optimal pairs of agents have been identified frequently combining either doxorubicin, cisplatin or vinblastine with interferon alfa-2b. Pretreatment with interferon alfa-2b has been adopted from in vitro studies and applied to most clinical trials. One study has enrolled 135 patients having a variety of advanced or recurrent solid tumor types, using a schema which combines interferon alfa-2b and doxorubicin administration, both given on a weekly basis for three weeks, followed by treatments every two weeks in responding patients. Clinical responses have been seen using this regimen in patients with ovarian, cervical, colorectal and pancreatic carcinomas and in one lymphoma patient. Another study has been designed combining melphalan, prednisone and interferon alfa-2b for the treatment of patients with relapsing multiple myeloma. This is also based upon preclinical data. New methods of administration are being studied giving interferon alfa-2b as a single agent or in combination with cisplatin by the intraperitoneal route to patients with relapsing ovarian carcinomas limited to the peritoneal cavity. This method can maximize both the levels of interferon alfa-2b as well as the tumor cell exposure time.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Interferon Type I; Melphalan; Neoplasms; Vinblastine

Melphalan uptake in the intestine has recently been shown to be an energy-dependent process which is affected by metabolic inhibitors. It is therefore theoretically possible that amino acids in food could reduce melphalan absorption by competing for uptake at the sites of absorption in the intestine. Since L-leucine has been shown to be the most potent inhibitor of melphalan transport into cells in vitro, this amino acid was chosen for the present study in patients. Oral melphalan (4.5 +/- 0.5 mg/m2) was given to ten fasting patients with and without a 2-g oral dose of L-leucine on separate randomized occasions at least 1 week apart. Melphalan plasma levels were measured by high-performance liquid chromatography (HPLC) for 5-h after dosing. L-Leucine plasma levels were measured by HPLC before and at 1 h after dosing. The area under the curve for melphalan was lower in seven of the patients after L-leucine. Plasma L-leucine levels 1 h after melphalan administration were 15.4 +/- 3.7 micrograms/ml fasting and 35.4 +/- 5.2 micrograms/ml after L-leucine. The results indicate that L-leucine can reduce plasma melphalan levels in some patients, probably through a reduction in absorption of the drug from the gastrointestinal tract. However, the effect, like that of food, is highly variable.

Topics: Administration, Oral; Aged; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Fasting; Female; Humans; Intestinal Absorption; Leucine; Male; Melphalan; Middle Aged; Neoplasms; Random Allocation; Time Factors

Topics: Anthraquinones; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carboplatin; Catheters, Indwelling; Cisplatin; Clinical Trials as Topic; Cytarabine; Doxorubicin; Etoposide; Fluorouracil; Humans; Immunotherapy; Infusions, Parenteral; Melphalan; Methotrexate; Mitomycins; Mitoxantrone; Neoplasms; Organoplatinum Compounds

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Drug Evaluation; Drug Resistance; Etoposide; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Melphalan; Neoplasm Recurrence, Local; Neoplasms; Thioguanine; Transplantation, Autologous

Topics: Administration, Oral; Adult; Aged; Female; Half-Life; Humans; Injections, Intravenous; Male; Melphalan; Middle Aged; Neoplasms; Time Factors

Fifty-one patients in the terminal stages of cancer have been treated with whole-body hyperthermia either alone (38 cases) or in combination with chemotherapy (13 cases). Altogether 227 treatment sessions were held averaging four hours each. The most sensitive tumours were those of the gastrointestinal tract and sarcomas. Breast and genitourinary tumours did not respond, and lung tumours and melanomas were only partially responsive. Major complications were remarkably few.

Topics: Adult; Body Temperature; Breast Neoplasms; Child; Colonic Neoplasms; Cyclophosphamide; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Hyperthermia, Induced; Injections, Intravenous; Male; Melphalan; Neoplasms; Time Factors; Vincristine

Topics: Adolescent; Adult; Child; Clinical Trials as Topic; Dysgerminoma; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Neoplasms; Osteosarcoma; Sarcoma, Kaposi

Topics: Clinical Trials as Topic; Cyclophosphamide; Hematopoiesis; Humans; Leukopenia; Melphalan; Neoplasms; Thrombocytopenia

The aim of this study was to analyze and identify documented infections and possible risk factors for Clostridioides difficile infections in children with cancer.. This is a retrospective case-control study, carried out in a pediatric cancer hospital, covering the years 2016-2019. Matching was performed by age and underlying disease, and for each case, the number of controls varied from 1 to 3. Logistic regression models were used to assess risk factors.. We analyzed 63 cases of documented infection by C. difficile and 125 controls. Diarrhea was present in all cases, accompanied by fever higher than 38°C in 52.4% of the patients. Mortality was similar among cases (n=4; 6.3%) and controls (n=6; 4.8%; p=0.7). In all, 71% of patients in the case group and 53% in the control group received broad-spectrum antibiotics prior to the infection. For previous use of vancomycin, the Odds Ratio for C. difficile infection was 5.4 (95% confidence interval [95%CI] 2.3-12.5); for meropenem, 4.41 (95%CI 2.1-9.2); and for cefepime, 2.6 (95%CI 1.3-5.1). For the antineoplastic agents, the Odds Ratio for carboplatin was 2.7 (95%CI 1.2-6.2), melphalan 9.04 (95%CI 1.9-42.3), busulfan 16.7 (95%CI 2.1-134.9), and asparaginase 8.97 (95%CI 1.9-42.9).. C. difficile symptomatic infection in children with cancer was associated with previous hospitalization and the use of common antibiotics in cancer patients, such as vancomycin, meropenem, and cefepime, in the last 3 months. Chemotherapy drugs, such as carboplatin, melphalan, busulfan, and asparaginase, were also risk factors.

Topics: Anti-Bacterial Agents; Asparaginase; Busulfan; Cancer Care Facilities; Carboplatin; Case-Control Studies; Cefepime; Child; Clostridioides difficile; Clostridium Infections; Cross Infection; Humans; Melphalan; Meropenem; Neoplasms; Retrospective Studies; Risk Factors; Vancomycin

In many stem cell transplant centres, BCNU, etoposide, cytarabine and melphalan (BEAM) high-dose chemotherapy (HDCT) has been replaced by the more economic and available bendamustine, etoposide, cytarabine, melphalan (BeEAM) regimen. However, there is a paucity of information on the efficacy and safety of BeEAM HDCT. We describe our experience with BeEAM HDCT in terms of safety, efficacy and cost-savings. We compare overall and progression-free survival to a cohort of patients previously transplanted at our institution with the older BEAM regimen. We performed a retrospective chart review of 41 lymphoma patients undergoing BeEAM HDCT at the Royal University Hospital in Saskatoon, Saskatchewan between 2015 and 2019 to elicit regimen safety in the first 100 days post-transplant. Furthermore, we calculated overall and progression-free survival and constructed corresponding Kaplan-Meier curves, comparing the results to a historical cohort of BEAM patients (n = 86). Finally, we conducted an economic analysis using the financials available at our centre's pharmacy. With regards to BeEAM HDCT, we report a 100-day transplant-related mortality of 2.4%. Additionally, we report acceptable rates of typhlitis (27%), grade III-IV mucositis (4.9%) and grade III-IV nephrotoxicity (2.4%). In terms of overall and progression-free survival, we found no statistical difference between BeEAM and BEAM (p = 0.296; 0.762, respectively). Finally, our economic analysis revealed a net savings of $21,200 CAD per transplant when BeEAM is used in replacement of BEAM. The acceptable safety profile of BeEAM and its comparable efficacy to BEAM are encouraging for the perseverance of this cost-effective HDCT regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Neoplasms; Outcome Assessment, Health Care; Podophyllotoxin; Transplantation Conditioning

Cryotherapy is a conventional method for preventing melphalan-induced oral mucositis (OM) in adult patients. We retrospectively examined the clinical benefits of cryotherapy in 41 pediatric patients undergoing autologous stem cell transplantation using a melphalan-etoposide-carboplatin regimen. Twenty-two patients received cryotherapy. The cumulative incidence of grade 3-4 OM was significantly lower in the cryotherapy group (57.1%) than in the noncryotherapy group (89.5%; P = .041). Multivariate analyses identified cryotherapy and the melphalan dose as independent factors for the lower occurrence of OM. The present study demonstrates the clinically significant efficacy of cryotherapy for preventing melphalan-induced OM in pediatric patients.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Cryotherapy; Dose-Response Relationship, Drug; Etoposide; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Melphalan; Neoplasms; Prognosis; Retrospective Studies; Stomatitis; Transplantation, Autologous; Young Adult

Cancer stem cells are responsible for the failure of a large number of cancer treatments and the re-emergence of cancer in patients. Parthenolide is a potent anticancer sesquiterpene lactone that is also able to kill cancer stem cells. The main problem with this compound is its poor solubility in water. To solve this problem, medicinal chemists have tried to prepare amino-derivatives of parthenolide, however, most amino-derivatives have less potency than that of parthenolide. In this paper, we proposed a new approach to synthesize parthenolide derivatives with better solubility and higher potency. We prepared novel parthenolide derivatives through the aza-Michael addition of nitrogen-containing anticancer drug molecules (cytarabine and melphalan) to the α-methylene-γ-lactone group of parthenolide. Different types of catalysts were used to catalyze the aza-Michael addition. Among all the used catalysts, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was found to have the highest catalytic activity. In addition, we examined the effects of parthenolide-anticancer drug hybrids on the growth and proliferation of three cancer cell lines (MCF-7, LNcaP, Hep G2) and CHO. The parthenolide prodrugs showed potent cytotoxic property with IC

Topics: Antineoplastic Agents; Apoptosis; Catalysis; Cell Line, Tumor; Chemistry Techniques, Synthetic; Cytarabine; Humans; Lactones; Melphalan; Neoplasms; Prodrugs; Sesquiterpenes

A series of 1-acyl-3,5-bis(benzylidene)-4-piperidones 3-7 were designed and synthesized as novel cytotoxic agents. These compounds displayed potent cytotoxic properties towards human Molt4/C8, CEM, HSC-2, HSC-3 and HSC-4 neoplasms and also to murine L1210 cells. The majority of the compounds have sub-micromolar or very low micromolar IC50 and CC50 values and are significantly more potent than the reference alkylating drug melphalan. Evaluation of these compounds against non-malignant HGF and HPLF cells revealed the tumour-specific toxicity. In particular, 3e emerged as a promising lead cytotoxic agent which caused apoptosis and PARP1 cleavage in HSC-2 cells.

Topics: Animals; Antineoplastic Agents; Cell Line; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Humans; Mice; Neoplasms; Piperidones; Structure-Activity Relationship

Mucositis is a common side effect of cancer therapies that causes painful, erythematous lesions to develop in the gastrointestinal tract. These lesions can lead to malnutrition, increased risk for serious infection, prolonged hospital stays, and reduced quality of life. Oral cryotherapy, or the use of ice chips to cool the mucous membranes during bolus chemotherapy infusions (e.g., 5-fluorouracil [Adrucil®] and melphalan [Alkeran®]), is the most readily accessible and cost-effective intervention available. Although many factors may contribute to the development of mucositis during cancer treatment, studies have found a reduction in the incidence and the severity of mucositis with the use of oral cryotherapy.


Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cryotherapy; Female; Fluorouracil; Humans; Ice; Male; Melphalan; Middle Aged; Mucositis; Neoplasms

Today due to improvements in cancer treatment there is an increasing number of long-term cancer survivors, many of whom suffer from infertility caused by malignancy itself and chemo- or radiotherapy. Also, anticancer therapy may cause myelosuppression. Presently granulocyte colony stimulating factor (G-CSF) is used for prevention and treatment of myelosuppression. Another treatment option used to decrease intoxication and ameliorate side effects of cancer therapy is sorption technology. The aim of our investigation was to study the efficiency of combined use of enterosorption and G-CSF to decrease gonadal toxicity of chemotherapy.. Melphalan (L-PAM) injected i.v. at a single dose of 4 mg/kg to white inbred rats was used as gonadotoxic and myelosuppressing agent. Carbon enterosorbent C2 was administered by intragastric route as a suspension in saline at a dose of 5 ml per 1 kg of rats' body weight (or 900 mg/kg of the dry mass of enterosorbent) daily for 3 days before and for 7 days after L-PAM injection. G-CSF was injected once a day for 4 days starting from the next day after L-PAM administration at a dose of 50 µg/kg. Histological preparations of testicular tissues were examined by light microscopy.. Our findings have shown that melphalan caused marked damage of testicular tissues and seminiferous, especially spermatogenic epithelium. The most expressed protection of the histological structure of testes was observed when enterosorbent and G-CSF were used in combination.. Gonadal toxicity of chemotherapy could be efficiently decreased by the combined use of enterosorption and G-CSF.

Topics: Animals; Antineoplastic Agents, Alkylating; Carbon; Enterosorption; Granulocyte Colony-Stimulating Factor; Male; Melphalan; Myeloablative Agonists; Neoplasms; Protective Agents; Rats; Testis

Acriflavine (ACF), a known antibacterial drug, has recently been recognized as a suitable candidate for cancer chemotherapy. However, the molecular target of ACF is not fully understood, which limits its application in cancer therapy. In this study, we established a structure-specific probe-based pull-down approach to comprehensively profile the potential target of ACF, and we identified DNA dependent protein kinase catalytic subunit (DNA-PKcs) as the direct target of ACF. Since DNA-PKcs facilitates the repair process following DNA double-strand breaks, we further developed a drug combination strategy that combined ACF with the bifunctional alkylating agent melphalan, which exerted a p53-dependent synergistic efficacy against human cancer cells both in vitro and in vivo. With these findings, our study demonstrated that structure-specific probe-based pull-down approaches can be used to identify new functional target of drug, and provided novel opportunities for the development of ACF-based antitumor chemotherapies.

Topics: Acriflavine; Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Comet Assay; DNA Breaks, Double-Stranded; DNA-Activated Protein Kinase; Dose-Response Relationship, Drug; Drug Synergism; HCT116 Cells; HeLa Cells; Humans; Melphalan; Mice, Nude; Molecular Docking Simulation; Neoplasms; Nuclear Proteins; Protein Binding; Protein Kinase Inhibitors; Signal Transduction; Time Factors; Tumor Burden; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) is a highly effective treatment for locally advanced tumours of the extremities. Previous research suggests an almost immediate disintegration of the blood supply of the tumour. The aim of the present study was to verify this hypothesis using non-invasive measurements of microvascular perfusion and tissue oxygenation.. A total of 11 patients were included in the study. TM-ILP was performed under mildly hyperthermic conditions (39 °C) in the extremities via proximal vascular access. Capillary-venous microvascular blood flow, haemoglobin level (Hb) and oxygen saturation (SO2) were determined using laser Doppler and white-light spectroscopy, respectively, before TM-ILP and at 30 min, 4 h, 1 day, 4 days, 1 week, 2 weeks and 6 weeks after TM-ILP from tumour and healthy muscle tissues.. Blood flow and Hb were mostly higher, whereas SO2 was lower, in tumour tissue compared with muscle tissue. In both tumour and muscle tissues, blood flow significantly increased immediately after TM-ILP and remained elevated for at least 2 weeks, followed by a return to the initial values 6 weeks after the procedure.. No signs were found of early destruction of the tumour vasculature. The observations suggest that an inflammatory reaction is one of the key elements of TM-ILP.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Hemoglobins; Humans; Hyperthermia, Induced; Melphalan; Middle Aged; Muscles; Neoplasms; Neovascularization, Pathologic; Oxygen; Regional Blood Flow; Tumor Necrosis Factor-alpha

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has become an option for peritoneal carcinomatosis (PC). Frequently, these patients have failed systemic chemotherapies and surgeries, including CRS/HIPEC with traditional regimens (mitomycin-C or platinum based). An alternative agent for failed or repeated CRS/HIPEC is unknown. We hypothesize that melphalan is an alternative agent in patients with PC from aggressive primaries, including recurrences following failed regional therapies.. A retrospective review of a prospective database of 247 patients revealed 25 patients (9 male and 16 female) who received intraperitoneal melphalan (50 mg/m(2)) in 31 CRS/HIPEC procedures, of which 19 were repeated. Primary malignancies included 17 appendiceal, one colorectal, two ovarian, two uterine sarcomas, two primary peritoneal and one mesentery sarcoma.. PC index (PCI) was ≥20 in 76 % of patients (19/25). 88 % of patients (22/25) had complete cytoreduction. Seventeen patients were alive, with mean survival of 63.6 months, and eight patients are deceased. Overall survival (OS) for the entire group since diagnosis was 95.8, 84.5, 50.9, and 38.2 % at 1, 3, 5, and 10 years, respectively; OS since melphalan HIPEC was 89.4, 45, and 30 % at 1, 3, and 5 years, respectively; and OS in patients with appendiceal malignancies was 91.7, 48.1 and 32.1 % at 1, 3 and 5 years, respectively. There was no postoperative mortality. Grade III-IV morbidity was 23 % (7/31). Nine patents had neutropenia, controlled with filgrastim.. Melphalan is an efficacious alternative agent in patients undergoing CRS/HIPEC for aggressive and recurrent peritoneal surface malignancies. Its postoperative significant myelosuppression effect should be addressed.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Neoplasm Staging; Neoplasms; Peritoneal Neoplasms; Prognosis; Prospective Studies; Retrospective Studies; Survival Rate

The efficacy of chemotherapeutic drugs is often offset by severe side effects attributable to poor selectivity and toxicity to normal cells. Recently, the enzyme dipeptidyl peptidase IV (DPPIV) was considered as a potential target for the delivery of chemotherapeutic drugs. The purpose of this study was to investigate the feasibility of targeting chemotherapeutic drugs to DPPIV as a strategy to enhance their specificity. The expression profile of DPPIV was obtained for seven cancer cell lines using DNA microarray data from the DTP database, and was validated by RT-PCR. A prodrug was then synthesized by linking the cytotoxic drug melphalan to a proline-glycine dipeptide moiety, followed by hydrolysis studies in the seven cell lines with a standard substrate, as well as the glycyl-prolyl-melphalan (GP-Mel). Lastly, cell proliferation studies were carried out to demonstrate enzyme-dependent activation of the candidate prodrug. The relative RT-PCR expression levels of DPPIV in the cancer cell lines exhibited linear correlation with U95Av2 Affymetrix data (r(2) = 0.94), and with specific activity of a standard substrate, glycine-proline-p-nitroanilide (r(2) = 0.96). The significantly higher antiproliferative activity of GP-Mel in Caco-2 cells (GI₅₀ = 261 μM) compared to that in SK-MEL-5 cells (GI₅₀ = 807 μM) was consistent with the 9-fold higher specific activity of the prodrug in Caco-2 cells (5.14 pmol/min/μg protein) compared to SK-MEL-5 cells (0.68 pmol/min/μg protein) and with DPPIV expression levels in these cells. Our results demonstrate the great potential to exploit DPPIV as a prodrug activating enzyme for efficient chemotherapeutic drug targeting.

Topics: Animals; Caco-2 Cells; Cell Line, Tumor; Cell Proliferation; Dipeptides; Dipeptidyl Peptidase 4; Humans; Melphalan; Neoplasms; Oligopeptides; Prodrugs; Proline; Swine

Heat shock protein 90 (Hsp90) has recently emerged as an attractive therapeutic target in cancer treatment because of its role in stabilizing the active form of a wide range of client oncoproteins. This study investigated the mechanism of apoptosis induced by the purine-scaffold Hsp90 inhibitor PU-H71 in different human cancer cell lines and examined the role of Bcl-2 and Bax in this process. We demonstrated that Hsp90 inhibition by PU-H71 generated endoplasmic reticulum (ER) stress and activated the Unfolded Protein Response (UPR) as evidenced by XBP1 mRNA splicing and up-regulation of Grp94, Grp78, ATF4 and CHOP. In response to PU-H71-induced ER stress, apoptosis was triggered in melanoma, cervix, colon, liver and lung cancer cells, but not in normal human fibroblasts. Apoptosis was executed through the mitochondrial pathway as shown by down-regulation of Bcl-2, up-regulation and activation of Bax, permeabilization of mitochondrial membranes, release of cytochrome c and activation of caspases. We also found that, in contrast to the ER stressor thapsigargin, PU-H71 induced apoptosis in cells overexpressing Bcl-2 and thus overcame the resistance conferred by this anti-apoptotic protein. In addition, although Bax deficiency rendered cells resistant to PU-H71, combined treatment with the anticancer drugs cisplatin or melphalan greatly sensitized these cells to PU-H71. Taken together, these data suggest that inhibition of Hsp90 by PU-H71 is a promising strategy for cancer treatment, particularly in the case of tumors resistant to conventional chemotherapy.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-2-Associated X Protein; Benzodioxoles; Blotting, Western; Caspases; Cell Proliferation; Cisplatin; Drug Resistance, Neoplasm; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Flow Cytometry; Fluorescent Antibody Technique; HSP90 Heat-Shock Proteins; Humans; Melphalan; Mitochondria; Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Purines; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thapsigargin; Tumor Cells, Cultured; Unfolded Protein Response

L19-tumor necrosis factor alpha (L19mTNF-α; L), a fusion protein consisting of mouse TNFα and the human antibody fragment L19 directed to the extra domain-B (ED-B) of fibronectin, is able to selectively target tumor vasculature and to exert a long-lasting therapeutic activity in combination with melphalan (M) in syngeneic mouse tumor models. We have studied the antitumor activity of single L19mTNF-α treatment in combination with melphalan and gemcitabine (G) using different administration protocols in two histologically different murine tumor models: WEHI-164 fibrosarcoma and K7M2 osteosarcoma. All responding mice showed significant reduction in myeloid-derived suppressor cells (MDSCs) and an increase in CD4(+) and CD8(+) T cells in the tumor infiltrates, as well as significant reduction in regulatory T cells (Treg) at the level of draining lymph nodes. What is important is that all cured mice rejected tumor challenge up to 1 year after therapy. Targeted delivery of L19mTNF-α synergistically increases the antitumor activity of melphalan and gemcitabine, but optimal administration schedules are required. This study provides information for designing clinical studies using L19mTNF-α in combination with chemotherapeutic drugs.

Topics: Adoptive Transfer; Animals; Antineoplastic Combined Chemotherapy Protocols; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Deoxycytidine; Disease Models, Animal; Drug Administration Schedule; Drug Synergism; Gemcitabine; Immunologic Memory; Lymphocyte Depletion; Lymphocytes, Tumor-Infiltrating; Melphalan; Mice; Myeloid Cells; Neoplasms; Recombinant Fusion Proteins; T-Lymphocytes, Regulatory

Carbonic anhydrase IX (CA IX) is a hypoxia-regulated enzyme, overexpressed in many types of human cancer. CA IX is involved in pH homeostasis, contributing to extracellular acidification and tumourigenesis. Acidification of the extracellular milieu can impact upon cellular uptake of chemotherapeutic drugs by favouring weak acids (e.g. melphalan), but limiting access of weak bases (e.g. doxorubicin). We investigated whether alterations of CA IX activity affected anti-cancer drug uptake and toxicity. CA inhibitor acetazolamide (AZM) enhanced doxorubicin toxicity but reduced melphalan toxicity in cell lines that highly expressed CA IX under anoxic conditions (HT29 and MDA435 CA9/18). The toxicity changes reflected modification of passive drug uptake. AZM did not alter toxicity or uptake in cells with low CA IX activity (HCT116 and MDA435 EV1). AZM lowered intracellular pH in HT29 and MDA435 CA9/18 cells under anoxic conditions. CA IX activity has chemomodulatory properties and is an attractive target for anti-cancer therapy.

Topics: Antineoplastic Agents; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Dose-Response Relationship, Drug; Doxorubicin; Drug Screening Assays, Antitumor; HCT116 Cells; HT29 Cells; Humans; Melphalan; Molecular Structure; Neoplasms; Protein Isoforms; Structure-Activity Relationship; Tumor Cells, Cultured

Poor distribution of anticancer drugs within solid tumors may limit their effectiveness. Here, we characterize the distribution within solid tumors of biomarkers of drug effect. γ-H2AX, cleaved-caspase-3 or -6, and Ki67 were quantified in tumor sections in relation to blood vessels (recognized by CD31) using monoclonal antibodies and immunohistochemistry. To validate their use, we compared their time-dependent distribution with that of (i) fluorescent doxorubicin and (ii) a monoclonal antibody that detects melphalan-induced DNA adducts. The biomarkers were then used to quantify the distribution of docetaxel in relation to tumor blood vessels. Activation of γ-H2AX was evaluated following in vitro exposure of tumor cells to multiple drugs. Distributions of doxorubicin in MDA-MB-231 and MCF-7 xenografts and of melphalan-induced DNA adducts in MCF-7 and EMT-6 tumors decreased with distance from blood vessels, similar to the distributions of (i) γ-H2AX at 10 minutes, (ii) cleaved caspase-3 or -6, and (iii) change in Ki67 at 24 hours following treatment. The distribution of these biomarkers following treatment with docetaxel also decreased with increasing distance from tumor blood vessels. Activation of γ-H2AX occurred within 1 hour after exposure to several drugs in culture. Multiple anticancer drugs show a decrease in activity with increasing distance from tumor blood vessels; poor drug distribution is an important cause of drug resistance. The above biomarkers may be used in designing strategies to overcome therapeutic resistance by modifying or complementing the limited spatial distribution of drug activity in solid tumors.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Caspase 3; Cell Line, Tumor; DNA Adducts; Doxorubicin; Female; Gene Expression; Histones; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Melphalan; Mice; Neoplasms; Time Factors; Transplantation, Heterologous

To evaluate the ability of a physiology-based pharmacokinetic (PBPK) model to predict the systemic drug exposure of high- and low-dose etoposide in children from a model developed with adult data.. Simulations were performed with PK-Sim(®) (Bayer Technology Services). Model development was done using data from adult patients receiving etoposide in a conventional and high-dose polychemotherapy regimen before stem cell transplantation. Michaelis-Menten parameters from in vitro experiments reported in the literature were applied to describe the metabolism and excretion processes by P450 enzymes and transporters. The model was scaled down to children and compared to etoposide plasma concentrations in this age group.. Simulated plasma concentration-time courses of protein-bound and free etoposide in adults for high- and low-dose schedules agreed with the observed data. Mean simulated total clearance of high- and low-dose etoposide was 0.70 ml/min/kg (Cl(observed): 0.70 ml/min/kg) versus 0.50 ml/min/kg (Cl(observed): 0.60 ml/min/kg), respectively. Integrated Michaelis-Menten kinetics was adequately transformed to age-related pharmacokinetics in children. Predictions of the pharmacokinetics in different age groups were also in good agreement with observed data. Drug interactions triggered by P-glycoprotein inhibitors or nephrotoxic drugs can also be elucidated.. The PBPK model matched the pharmacokinetics in different dosing regimens in adults. Furthermore, the scaling procedure from the adult model to children provides useful predictions for paediatric patients. Comedication with drugs influencing the metabolism and excretion has to be taken into account. This approach could be useful for planning pharmacokinetic studies in children.

Topics: Adolescent; Adult; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carboplatin; Child; Child, Preschool; Computer Simulation; Cyclophosphamide; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Etoposide; Female; Humans; Infant; Male; Melphalan; Metabolic Clearance Rate; Middle Aged; Models, Biological; Neoplasms; Protein Binding

To prospectively evaluate quality of life (QoL) evolution after a classic pulmonary metastasectomy or after an isolated lung perfusion (ILuP) metastasectomy.. QoL was prospectively recorded in 35 consecutive patients (27 classic metastasectomy; 8 ILuP) The European Organisation for Research and Treatment of Cancer C30 and lung cancer -13 QoL Questionnaires were administered before surgery and 1, 3, 6 and 12 months postoperatively (MPO).. After a classic metastasectomy, a temporary increase in dyspnea (1 MPO p = 0.03 3 MPO p = 0.01), coughing (3 MPO p = 0.01), fatigue (1 MPO p = 0.01, 3 MPO p = 0.02), thoracic pain (1 MPO, p = 0.02), shoulder dysfunction (1 MPO p = 0.03, 3 MPO p = 0.02) as well as an impaired physical (1 MPO p = 0.01, 3 MPO p = 0.04) and role functioning (1 MPO p = 0.01, 3 MPO p = 0.01) was reported the first 3 months after surgery. Six months after surgery, all domains returned to baseline. After ILuP metastasectomy, all QoL functioning and symptom scores, except for coughing complaints (1 MPO p = 0.03, 3 MPO p = 0.04) and shoulder dysfunction (1 MPO p = 0.04, 6 MPO p = 0.04), returned to baseline at 1 month after surgery. No significant differences were seen when QoL evolution was compared between classic and ILuP metastasectomy with the exception of a higher burden of thoracic pain (6 MPO p = 0.04, 12 MPO p = 0.01), shoulder dysfunction (6 MPO p = 0.04, 12 MPO p = 0.02), and dysphagia (6 MPO p = 0.04, 12 MPO p = 0.02) 6 and12 months after ILuP.. All QoL domains returned to baseline at 6 months after a classic metastasectomy. After ILuP, only increases in coughing and shoulder dysfunction were reported. In comparison classic metastasectomy patients, ILuP patients report more thoracic pain, shoulder dysfunction, and dysphagia.

Topics: Adult; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Melphalan; Metastasectomy; Middle Aged; Neoplasm Staging; Neoplasms; Pneumonectomy; Postoperative Period; Prognosis; Prospective Studies; Quality of Life; Risk Factors; Surveys and Questionnaires

A series of N-mustard-quinazoline conjugates was synthesized and subjected to antitumor studies. The N-mustard pharmacophore was attached at the C-6 of the 4-anilinoquinazolines via a urea linker. To study the structure-activity relationships of these conjugates, various substituents were introduced to the C-4 anilino moiety. The preliminary antitumor studies revealed that these agents exhibited significant antitumor activity in inhibiting various human tumor cell growths in vitro. Compounds 21b, 21g, and 21h were selected for further antitumor activity evaluation against human breast carcinoma MX-1 and prostate PC-3 xenograft in animal model. These agents showed 54-75% tumor suppression with low toxicity (5-7% body-weight changes). We also demonstrate that the newly synthesized compounds are able to induce DNA cross-linking through alkaline agarose gel shift assay and inhibited cell cycle arrest at G2/M phase.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Humans; Mice; Mice, Nude; Mustard Plant; Neoplasms; Quinazolines; Structure-Activity Relationship; Urea; Xenograft Model Antitumor Assays

A bioanalytical assay for the new poly(ADP-ribose) polymerase-1 inhibitor olaparib in combination with melphalan was developed and validated. For the quantitative assay, human plasma samples were pre-treated on ice using protein precipitation with 2% (v/v) acetic acid in acetonitrile containing erlotinib and melphalan-d₈ as internal standards. The extract was diluted with water and injected into the chromatographic system. This system consisted of a sub-2 μm particle, trifunctional bonded octadecyl silica column with an isocratic elution using 0.01% (v/v) of formic acid in a mixture of water and methanol. The eluate was transferred into the electrospray interface with positive ionization and the analyte was detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was validated in a 10-5000 ng/ml calibration range for both drugs. The lowest level of this range corresponded to the lower limit of quantification. Within day precisions were 3.0-9.3%, between day precisions 6.0-9.8% and accuracies were between 101 and 110% for the whole calibration range. After validation the assay was used to assess the pharmacokinetics of olaparib in a patient with metastatic breast carcinoma. In addition, systemic exposure of melphalan was monitored in patients subjected to isolated hepatic perfusion with this drug. Both applications show that the new assay can be applied for human pharmacokinetic studies for both drugs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chromatography, Liquid; Drug Stability; Female; Humans; Least-Squares Analysis; Melphalan; Middle Aged; Neoplasms; Phthalazines; Piperazines; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry

Immune reconstitution appears to be delayed following myeloablative conditioning (MAC) and umbilical cord blood transplantation (UCBT) in paediatric recipients. Although reduced toxicity conditioning (RTC) versus MAC prior to allogeneic stem cell transplantation is associated with decreased transplant-related mortality, the effects of RTC versus MAC prior to UCBT on immune reconstitution and risk of graft-versus-host disease (GVHD) are unknown. In 88 consecutive paediatric recipients of UCBT, we assessed immune cell recovery and immunoglobulin reconstitution at days +100, 180 and 365 and analysed risk factors associated with acute and chronic GVHD. Immune cell subset recovery, immunoglobulin reconstitution, and the incidence of opportunistic infections did not differ significantly between MAC versus RTC groups. In a Cox model, MAC versus RTC recipients had significantly higher risk of grade II-IV acute GVHD [Hazard Ratio (HR) 6·1, P = 0·002] as did recipients of 4/6 vs. 5-6/6 HLA-matched UCBT (HR 3·1, P = 0·03), who also had significantly increased risk of chronic GVHD (HR 18·5, P = 0·04). In multivariate analyses, MAC versus RTC was furthermore associated with significantly increased transplant-related (Odds Ratio 26·8, P = 0·008) and overall mortality (HR = 4·1, P = 0·0001). The use of adoptive cellular immunotherapy to accelerate immune reconstitution and prevent and treat opportunistic infections and malignant relapse following UCBT warrants further investigation.

Topics: Alemtuzumab; Antibiotic Prophylaxis; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antilymphocyte Serum; Busulfan; Child; Child, Preschool; Cord Blood Stem Cell Transplantation; Cyclophosphamide; Female; Genetic Diseases, Inborn; Graft Survival; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukocyte Count; Male; Melphalan; Myeloablative Agonists; Neoplasms; Neutrophils; Recombinant Proteins; Retrospective Studies; T-Lymphocytes; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

Topics: Animals; Antineoplastic Agents, Alkylating; Carcinogenicity Tests; Carcinogens, Environmental; Drug Labeling; Government Regulation; Guidelines as Topic; Humans; Leukemia; Melphalan; Mice; Molecular Structure; Neoplasms; Rats

Various 2-benzylidene-6-(nitrobenzylidene)cyclohexanones were prepared as candidate cytotoxins in which the nitro group was located in the ortho, meta and para positions leading to series 1-3, respectively. The CC(50) values towards human HSC-2 and HSC-4 oral squamous cell carcinomas as well as human HL-60 promyelocytic leukemic cells are in the low micromolar range in general. On the other hand, most of the compounds afforded clear evidence of being far less toxic towards human HGF gingival fibroblasts, HPC pulp cells and HPLF periodontal ligament fibroblasts which are non-malignant cells. Selectivity index (SI) figures were generated which are the ratios of the average CC(50) values towards normal cells and the CC(50) figure towards a malignant cell line. Huge SI values were obtained for many of the compounds. In particular 1c, 2f, 3c and 3g which have average SI values of >76, >38, 124 and 341, respectively, are clearly lead molecules affording direction for amplification of this area of study. A lead compound 1c caused internucleosomal DNA fragmentation and activation of caspase-3 in HL-60 cells but not in HSC-2 carcinomas. In a short-term toxicity study, doses up to and including 300 mg/kg of the majority of the compounds prepared in this study did not cause any mortalities to mice. Some guidelines for development of these tumor-selective cytotoxins are presented.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Crystallography, X-Ray; Cyclohexanones; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fibroblasts; HL-60 Cells; Humans; Mice; Models, Molecular; Neoplasms; Structure-Activity Relationship

Melphalan is an important cytotoxic drug. The empirical practice of body surface area-based (BSA) dosing (mg/m2) of melphalan has been critically analyzed in several observations. BSA-based dosing leads to significant variability in doses administered per kilogram of body weight (mg/kg), contributes to increased oral toxicity and probably does not have any significant effect on treatment results within equally BSA (mg/m2) dosed melphalan regimens.

Topics: Animals; Antineoplastic Agents, Alkylating; Body Weight; Humans; Melphalan; Neoplasms; Stem Cell Transplantation

A series of 2-(3-aryl-2-propenoyl)-3-methylquinoxaline-1,4-dioxides 3a-l were prepared by condensation of various aryl aldehydes with 2-acetyl-3-methylquinoxaline-1,4-dioxide 2. These compounds inhibit the growth of human Molt 4/C8 and CEM T-lymphocytes and the IC(50) values are mainly in the 5-30 microM range. The quinoxaline 1,4-dioxide 3j inhibited the growth of 58 human tumor cell lines, particularly leukemic and breast cancer neoplasms. All of the compounds 3a-l reversed the multidrug resistance (MDR) properties of murine L-5178Y leukemic cells which were transfected with the human MDR1 gene. The MDR-reversing effect may be due to the conjugated pi-electron system forming a weak electron charge transfer complex with the P-glycoprotein-mediated efflux pump. The compounds in series 2 and 3 were assessed against HL-60, HSC-2, HSC-3 and HSC-4 malignant cells as well as HGF, HPC and HPLF normal cell lines which revealed that the majority of the compounds displayed a greater toxicity to neoplastic than normal cells. Various ways in which the project may be expanded are presented.

Topics: Animals; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Inhibitory Concentration 50; Male; Mice; Molecular Structure; Neoplasms; Oxides; Quantitative Structure-Activity Relationship; Quinoxalines

The purpose of this study was to analyse our experience of early discharge 2 days after high-dose melphalan (HDM) (Day-1) followed by peripheral blood stem cell re-infusion (Day-0) and re-admission on Day +5 in patients with hematological diseases or solid tumors. From 2000 to November 2005, seven patients received tandem Melphalan 200 mg/m(2) HDM with peripheral blood stem cells transplantation (PBSC-T), 130 a single HDM, for a total of 144 procedures. In 123 of them, patients were discharged on Day +1 for re-admission on Day +5 or earlier in the event of complications. Antibiotic prophylaxis was not used. Patients were hospitalised in positive-pressure reverse isolation room during the neutropenic period. Of the 123 procedures eligible for our mixed inpatient-outpatient management regimen, six (5%) required early re-admission for complications. Full engraftment was achieved in all cases. Median time to neutrophil count >0.5 x 10(9)/microL and >1 x 10(9)/microL were 12 and 14 days, respectively. Median time to platelet recovery (>20 x 10(9)/microL) was 13 days. Severe extra-hematological toxicities occurred in 78 (63%) patients: all had oral mucositis and five had associated diarrhoea. During hospitalisation, 94/123 (76%) experienced febrile neutropenia, 20/94 (21%) had documented infection and 74/94 (79%) were considered fever of unknown origin. Median fever duration was 1 day (range 0-11). Median duration of antibiotic treatment was 6 days (range 3-26). Median time to discharge (from Day 0) was 16 days (range 11-57). There was no mortality by on Day +100. Our experience of early discharge after HDM and PBSC-T with re-admission on Day +5 is safe and feasible with acceptable frequency of hematological and extra-hematological toxicities. The regimen allows reduced hospital stay and hence cost savings.

Topics: Adolescent; Adult; Aged; Female; Hematologic Diseases; Humans; Infusions, Parenteral; Male; Melphalan; Middle Aged; Neoplasms; Patient Discharge; Peripheral Blood Stem Cell Transplantation; Time Factors

This study was done to evaluate the frequency and severity of mucositis in the early period of stem cell transplantation (SCT) and the relation of conditioning regimens with mucositis.. Patients with hematologic or solid tumors who underwent conditioning regimen were asked to score mucositis severity daily from the first day to the tenth day of reinfusion. Patient-reported scoring was performed according to a five-grade scale (0: no symptom; 1: mild; 2: moderate; 3: severe; 4: very severe). Total mucositis score (TMS) was defined as the addition of daily mucositis scores for 10 days. A total of 68 SCT (58 autologous and 10 allogeneic) patients, 48 men (71%) and 20 women (29%) were included to the study. Median age of patients was 32.5 (range 15-78) years. The most frequent three diagnosis were non-Hodgkin's lymphoma (37%, n = 25), Hodgkin's lymphoma (12%, n = 8), and multiple myeloma (12%, n = 8). BEAM (n = 27), ICE (n = 17), melphelan 200 mg/m(2) (M200)(n = 8), and TBI+C (total body irradiation + cyclophosphamide) (n = 16) were used as conditioning regimens.. All of the patients experienced mucositis at any grade. TMS in the sixth day was higher than TMS in the first day (p < 0.05). TMS was not related to the diagnosis or gender (p > 0.05). TMS at ICE regimen in the first 5 days after transplantation was more severe than BEAM regimen. TMS at TBI+C regimen was higher than TMS at BEAM regimen from day 4 to day 10 (p < 0.05). The mean percentages of patients who scored severe or very severe mucositis in 10 days was 7.4% in BEAM, 8.9% in ICE, 12.5% in M200, and 31.2% in TBI+C groups.. Patients experience mucositis frequently following conditioning regimen and SCT. The necessity and the timing of prophylaxis for mucositis change due to the type of conditioning regimens.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carmustine; Cyclophosphamide; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Ifosfamide; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Mucositis; Multiple Myeloma; Neoplasms; Severity of Illness Index; Whole-Body Irradiation; Young Adult

To investigate the significance and function of IFN-gamma on the changes of peripheral blood platelet count during tumor-rejection induced by a low dose of melphalan in C57BL/6 mice.. Mouse tumor rejection model induced by a single dose of melphalan was used in this experiment. Different gene-type tumor-bearing mice (IFN-gamma(+/-) and IFN-gamma(-/-)), which had the same genetic background of C57BL/6, were treated intraperitoneally with melphalan (7.5 mg/kg). Tumor size was observed and recorded every one to three days in these different gene-type mice subsequently. Blood samples were obtained from orbital venous sinus on different days before and after melphalan treatment, and then complete blood counts were performed. The function of IFN-gamma on the efficacy of chemotherapy and the changes of blood platelet count in IFN-gamma(+/-) and IFN-gamma(-/-) mice after melphalan treatment was analyzed.. There was no significant difference in tumor sizes and blood platelet count between IFN-gamma(-/-) and IFN-gamma(+/-) mice (P>0.05). On the first day after melphalan (7.5 mg/kg) treatment, there were no significant changes in tumor sizes between mice in these two groups (P>0.05). Tumors shrank a little in IFN-gamma(-/-) mice and then grew gradually. Tumors relapsed in 2 w after melphalan injection in all IFN-gamma(-/-) mice, while tumor volumes decreased progressively and tumor cured at last in IFN-gamma(+/-) mice. The number of blood PLT in IFN-gamma(+/-) mice increased to (1935+/-378) x 10(9)/L 6 h after melphalan treatment, significantly higher than before (P<0.01); While in IFN-gamma(-/-) mice it was (1183+/-186) x 10(9)/L 6 h after melphalan treatment, no obvious increase than before. There was significant difference in blood PLT 6 h after melphalan treatment between IFN-gamma(+/-) and IFN-gamma(-/-) mice (P<0.01). Later, the numbers of blood PLT in IFN-gamma(+/-) mice decreased gradually and it dropped to normal (1158+/-270) x 10(9)/L on 11th day after melphalan treatment (P>0.05); While it sustained in normal range in IFN-gamma(-/-) mice. There was no significant difference in blood platelet count between IFN-gamma(-/-) and IFN-gamma(+/-) mice.. Peripheral blood platelet count increased on the first day after melphalan treatment and tumors cured in IFN-gamma(+/-) mice; While tumors relapsed and there is no increase in blood platelet count on the first day after melphalan treatment in IFN-gamma(-/-) mice. These data indicated that the increase of blood PLT count was related to the function of IFN-gamma in tumor-bearing mice in vivo during tumor rejection induced by a low dose of melphalan.

Topics: Animals; Dose-Response Relationship, Drug; Interferon-gamma; Melphalan; Mice; Mice, Inbred C57BL; Neoplasms; Platelet Count; Tumor Burden

Various 6-aralkyl-9-substituted-6H-indolo[2,3-b]quinoxalines were synthesized by reaction of 1,5-disubstituted 2,3-dioxo-2,3-dihydroindole and orthophenylene diamine. Appreciable anticancer activity of compounds 5b, 5d, 5g and 5l at various cell lines among 59 human tumor cell panels was observed. All the synthesized compounds were evaluated for cytostatic activity against human Molt 4/C8 and CEM T-lymphocytes as well as for murine L1210 leukemia cells. Compound 5h exhibited an I C50 of 23 micromol L(-1) against Molt 4/C8 and 38 micromol L(-1) against CEM compared to melphalan 3.2 micromol L(-1) and 2.5 micromol L(-1), respectively. The IC(50) for compound 7i against L1210 was 7.2 micromol L(-1) compared to melphalan 2.1 micromol L(-1).

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cytostatic Agents; Humans; Indolequinones; Inhibitory Concentration 50; Leukemia L1210; Melphalan; Mice; Neoplasms; T-Lymphocytes

A series of 3,5-bis(benzylidene)piperidin-4-ones 1, 1-acryloyl-3,5-bis(benzylidene)piperidin-4-ones 2 and adducts of 2 with sodium 2-mercaptoethanesulfonate (mesna), namely series 3, were prepared as candidate cytotoxic agents. These compounds were examined against neoplastic HSC-2, HSC-4 and HL-60 cells as well as HGF, HPC and HPLF normal cell lines and many of the compounds displayed selective toxicity for malignant cells. The CC50 values of the analogs in series 2 towards the cancer cell lines were mainly submicromolar. The relative potencies, selectivity and logP values were in the order of 2>1>3. The sulfonic acid group of a representative compound in series 3 was replaced by a thiol function to produce 4 leading to substantial increases in cytotoxic potencies and hydrophobicity indicating that the presence of a hydrophilic sulfonic acid group was disadvantageous in terms of potency. Molecular modeling suggested that the superior cytotoxicity of various members of series 1-3 over an acyclic analog 5 may have been due to the greater torsion angles theta1 and theta2 created between the arylidene aryl rings and the adjacent olefinic groups in series 1-3.

Topics: Benzylidene Compounds; Cell Line, Tumor; Cell Survival; Cytotoxins; Humans; Hydrophobic and Hydrophilic Interactions; Models, Biological; Neoplasms; Piperidones; Sensitivity and Specificity

A series of 3-benzylidene-4-chromanones 1a-l were prepared and their cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 lymphoid leukemia cells were compared to the previously generated biodata in these three assays for the isosteric 2-benzylidene-1-tetralones 2a-l. Over 40% of the compounds in series 1 were more potent than their counterparts in series 2, while equipotency was noted in one-third of the comparisons made. In general the IC(50) values of 1a-l towards the human T-lymphocytes were in the low micromolar range. Molecular modelling revealed differences in shapes of representative molecules in series 1 and 2 which may contribute to the variation in cytotoxic potencies. Most of the compounds in series 1 displayed greater potencies towards HSC-2, HSC-3, HSC-4 and HL-60 neoplasms than HGF, HPC, and HPLF normal cells and were well tolerated in mice.

Topics: Animals; Antineoplastic Agents; Benzopyrans; Cell Survival; Drug Design; Drug Screening Assays, Antitumor; Fibroblasts; Humans; Injections, Intraperitoneal; Leukemia L1210; Mice; Models, Molecular; Molecular Structure; Neoplasms; Neurons; Structure-Activity Relationship; Survival Rate; T-Lymphocytes; Tumor Cells, Cultured

The dipeptide J1 acts as a prodrug of melphalan with a significant increased potency in vitro resulting from activation by cellular aminopeptidases. The current study was performed to evaluate the ex vivo profile of J1 using 176 primary tumor cell cultures from patients. In addition, the activity of J1 in combination with eight standard drugs, representing different mechanistic classes, was studied in nine different human tumor cell lines of different histopathological origin.. Ex vivo evaluation of tumor type selectivity, was performed using the established fluorometric microculture cytotoxicity assay (FMCA). Combinations between J1 and eight standard chemotherapeutic drugs were analyzed using the median-effect method.. The prodrug J1 expressed approximately 50- to 100-fold higher potency but similar activity profile as that of its metabolite, melphalan. The difference was greater in some diagnoses (e.g. breast cancer, NHL and AML), and exceptionally high in some breast cancer samples with aggressive phenotypes. Combination analysis of J1 and standard chemotherapeutics yielded several potentially additive and synergistic interactions, most striking for etoposide with significant synergism in all studied cell lines.. In conclusion, the ex vivo profile suggests that further evaluation of J1 as the alkylating agent in for example aggressive breast cancer might be of particular interest, preferentially in combination with DNA-topoisomerase II inhibitors like etoposide.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Dipeptides; Drug Screening Assays, Antitumor; Drug Synergism; Fluorometry; Humans; Melphalan; Neoplasms; Prodrugs

Topics: Antineoplastic Agents, Alkylating; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leukemia, Myeloid; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Myeloablative Agonists; Neoplasms; Neoplasms, Germ Cell and Embryonal; Neuroblastoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Topics: Animals; Cell Survival; Cells, Cultured; Mice; Molecular Structure; Neoplasms; Neurons; Pharmaceutical Preparations; Sensitivity and Specificity; Stem Cells

We have recently demonstrated that cytolysis of human melanoma cells by immune effectors (both NK and T cells) is associated with release of the nuclear chromatin protein, high mobility group box I (HMGB1). Extracellular HMGB1 mediates a number of important functions including endothelial cell activation, stromagenesis, recruitment and activation of innate immune cells, and also dendritic cell maturation that, in the setting of cancer, lead to a chronic inflammatory response. This reparative inflammatory response promotes tumor cell survival, expansion, and metastases. Release of HMGB1 after chemotherapy-induced cytotoxicity has not been well characterized. We measured the release of HMGB1 after chemotherapy or immune cytolysis and demonstrated that this did not correlate with conventional markers of apoptosis and necrosis in several human colorectal, pancreatic, and melanoma tumor cell lines. Rather, we observed that tumor cells incubated with the platinating agent oxaliplatin, retained HMGB1 within the nucleus for significantly longer periods than other agents used at comparable cytotoxic concentrations or even with potent cytolytic cells. Thus, release of HMGB1 from dying tumor cells treated with chemotherapy or cells with lymphokine activated killer cell activity is not dependent solely on the mode of cell death. Sequestration of the damage associated molecular pattern molecule, HMGB1, may play a role in the clinical efficacy of platinating agents and suggests this as a superior agent for coupling with immunotherapeutic strategies, possibly enhancing their effectiveness.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Nucleus; Colonic Neoplasms; Combined Modality Therapy; HMGB1 Protein; Humans; Immunotherapy; Killer Cells, Lymphokine-Activated; Melanoma; Melphalan; Microscopy, Confocal; Necrosis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

Patients with a central venous catheter (CVC) undergoing high-dose chemotherapy (HDC) followed by peripheral-blood stem-cell transplantation (PBSCT) for malignancies are at high risk of thrombosis, but the use of anti-coagulant prophylaxis remains debatable in this setting of patients. We analyzed the efficacy and the safety of minidose warfarin in 228 patients in whom CVCs had been placed and who had received 292 HDC courses of therapy. The catheters remained in place for a mean of 173 (range 40-298) days. All patients received prophylactic oral warfarin in the fixed dose of 1 mg/day starting on the day of CVC insertion. Prophylaxis was interrupted during aplasia when platelet counts fell below 50,000/dL. There were no toxic deaths related to the prophylaxis. Overall there were 4 thrombotic events. Three occurrences were directly related to the catheter, while the remaining event was a deep saphenous-vein thrombosis. A number of potential predictive factors were analyzed for their impact on thrombotic events without finding any significant correlation. Four episodes of bleeding occurred, with each of these individuals having a normal INR but a platelet count below 50,000/dL. Minidose warfarin is effective and safe to use for preventing thrombotic events in this setting of patients.

Topics: Administration, Oral; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Catheterization, Central Venous; Cytarabine; Female; Hemorrhage; Humans; Male; Melphalan; Neoplasms; Peripheral Blood Stem Cell Transplantation; Platelet Count; Podophyllotoxin; Retrospective Studies; Risk Factors; Transplantation, Homologous; Venous Thrombosis; Warfarin

Tumor response is strongly enhanced by addition of tumor necrosis factor (TNF)-alpha to chemotherapy in local-regional perfusion. TNF primarily targets the endothelial lining of the tumor-associated vasculature, thereby improving permeability of the vascular bed. This augments uptake of the coadministered chemotherapeutic drug in the tumor. In vitro, however the high dose of TNF did not directly affect endothelial cells, indicating that other factors, most likely TNF-induced, are involved in the antivascular activities observed in vivo. This is supported by in vivo studies in our laboratory in which depletion of leukocytes resulted in loss of the antivascular activity of TNF. The present study examined the role of peripheral blood mononuclear cells (PBMCs) on endothelial cells by exposing them to TNF, interferon (IFN)-gamma, and PBMCs. We observed morphological changes of the endothelial cells when exposed to TNF in combination with IFN. Endothelial cells became elongated. and gaps between the cells formed. Addition of PBMCs enhanced these alterations. The endothelial layer became disrupted with highly irregular-shaped cells displaying large gap formations. PBMCs also contributed to an increased permeability of the endothelial layer without augmenting apoptosis. Replacing PBMC by interleukin (IL)-1beta produced similar effect with regard to inhibition of cell growth, morphological changes, and induction of apoptosis. Blocking IL-1beta with a neutralizing antibody diminished the effects inflicted of PBMCs. These observations indicate that endogenously produced IL-1beta by primed PBMCs plays an important role in the antivascular effect of TNF.

Topics: Apoptosis; Capillary Permeability; Cell Membrane Permeability; Cell Shape; Cells, Cultured; Coculture Techniques; Cytokines; Cytoskeleton; Doxorubicin; Endothelial Cells; Humans; Interferon-gamma; Interleukin-1; Leukocytes, Mononuclear; Melphalan; Models, Biological; Neoplasms; Tumor Necrosis Factor-alpha

To analyse the pharmacokinetics of melphalan in 52 children (0.3-18 years) and determine whether any clinical factors affect the pharmacokinetic parameters Additionally, to examine whether a test melphalan dose can predict the pharmacokinetics of a full dose, when there are 5 intervening days of carboplatin therapy.. Melphalan concentrations were measured in 14 blood samples collected from each child following doses ranging from 30 to 180 mg m(-2). The pharmacokinetics were analysed with Kinetica 4.0.. Children who did not have carboplatin (n = 27) had median melphalan clearance (CL) of 15.5 l h(-1) m(-2) (interquartile range: 12.4-19.9 l h(-1) m(-2)) and steady state volume of distribution (Vss) of 14.9 l m(-2) (interquartile range: 12.7-18.3 l m(-2)). Children who had carboplatin (n = 25) had 34% lower median CL (10.2 l h(-1) m(-2)) and 18% lower median Vss (12.2 l m(-2)) (P < 0.001). Melphalan elimination was impaired in a separate group of three children given concomitant carboplatin and etoposide. Stepwise multiple linear regression indicated that weight, carboplatin, glomerular filtration rate (GFR) and total body irradiation (TBI) significantly affected CL, while weight and carboplatin influenced Vss. A test dose (10 mg m(-2)) tended to underpredict the area-under-the-concentration-vs.-time-curve for a full (180 mg m(-2)) dose in 19 individuals given carboplatin.. In children, melphalan CL is influenced by weight, carboplatin, TBI and GFR. Vss is influenced by weight and carboplatin.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Area Under Curve; Body Weight; Bone Marrow Transplantation; Carboplatin; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Interactions; Glomerular Filtration Rate; Humans; Infant; Kidney Diseases; Melphalan; Neoplasms; Time Factors; Whole-Body Irradiation

Topics: Antineoplastic Agents, Alkylating; Cryotherapy; Dose-Response Relationship, Drug; Humans; Melphalan; Neoplasms; Stomatitis

The objective of the present study was to characterize the population pharmacokinetics of melphalan infused over a 24-h period in patients with advanced malignancies.. Enrolled in the study were 64 patients (144 courses). The population pharmacokinetic analysis was performed using NONMEM through the graphical interface Visual-NM. Population characteristics were computed from an initial group of 43 patients (99 courses), and 21 additional patients (45 courses) were used for model validation. With the use of a one-compartment model, the influence of demographic and biological characteristics was examined. The basic parameters were total clearance (CL) and volume of distribution (V). The interoccasion variability was taken into account in the model. The drug exposure was estimated for each patient and correlated with markers of efficacy and toxicity.. Data analysis was performed using a three-step approach. In step 2, a close relationship was found between creatinine clearance, gender and melphalan CL. The inclusion of this second stage model significantly improved the fit. Melphalan CL was higher in male patients (14.3+/-4.5 l/h per m2) than in female patients (12.3+/-4.5 l/h per m2). CL was also reduced somewhat in patients with decreased creatinine clearance. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 4.4 to 30.6 l/h per m2). The percentage intrapatient variability in clearance between courses was 25.4%. For determining melphalan AUC in clinical routine from one sample drawn at steady state, Bayesian methodology allowed a more accurate estimation of CL than the classical formula. Neutropenia and thrombocytopenia were the main haematological toxicities encountered; grade 4 was observed in 34 and 22 courses over a total of 144 courses, respectively. No significant relationship between AUC and haematological toxicity was found. In patients with prostatic cancer a weak relationship was observed between the decrease in PSA levels and AUC (P=0.0457), while in patients with ovarian cancer no relationship was found between AUC and CA125 levels.. The population pharmacokinetic approach developed in this study should allow dosage to be individualized in order to decrease toxicity while maintaining good efficacy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Area Under Curve; Female; Humans; Infusions, Intravenous; Male; Melphalan; Metabolic Clearance Rate; Middle Aged; Neoplasms

Stop-flow perfusion (SFP) is a recently implemented locoregional treatment based on the vascular isolation of the tumor bearing body district through a radiointerventistic technique. SFP is currently under investigation as a palliative therapeutic option for patients with locally advanced tumors. This paper reports on the results of our prospective study of limb and pelvic SFP. Thirty-seven patients were treated with SFP. No postoperative deaths occurred. Locoregional and systemic toxicity were observed after 22 and 31 treatments, respectively; complete and partial response after 3 (6%) and 24 (51%) SFPs, respectively. The pharmacokinetic study showed that pelvic SFP was associated with a leakage rate higher than femoral SFP (38% vs 28%). In conclusion, SFP is a feasible procedure. Toxicity and tumor response rates strictly depend upon drug leakage control.

Topics: Adult; Aged; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melphalan; Middle Aged; Neoplasms; Prospective Studies

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Disease Management; Humans; Melphalan; Neoplasm Staging; Neoplasms; Prognosis; Risk Factors; Surgical Procedures, Operative

Recently, we presented a series of melphalan containing di- and tripeptides with high cytotoxic activity and J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester) was identified as one of the most interesting compounds. It was speculated that the increased activity compared to melphalan itself, demonstrated both in vitro and in vivo, resided in increased transport over the tumour cell membrane and/or hydrolytic cleavage and liberation of melphalan inside the cells. Indeed, overexpression of hydrolytic enzymes like peptidases, esterases and proteases has been described in several types of human malignancies, thus providing a target for selective chemotherapy. In this work, the details of the increased activity was further investigated and potential tumour selectivity is discussed. The intracellular delivery of melphalan is investigated in detail using peptidase resistant dipeptide derivatives, by enzyme inhibitors and probes for enzymatic activity and by studying the time dependency of drug effect as well as intracellular drug concentrations (cellular pharmacokinetics). The results show that the activity of the dipeptide mustards is highly dependent on intracellular hydrolysis, which result in rapid intracellular release of the alkylating unit (i.e. free melphalan) in cells with high enzymatic activity. The maximum intracellular melphalan concentration following J1 exposure was reached already after 15 min, thereafter declining with a half-life of approximately 1 h. This rapid intracellular loading resulted in less reduction of activity for J1 than for melphalan and six other standard drugs when human tumour cell lines were exposed to the drugs for a limited time (simulating short half-life in vivo). Peptidase inhibitors inhibited the activity and intracellular release of melphalan, and dipeptide derivatives designed to resist the action of peptidases was less active than the corresponding normal dipeptide.

Topics: Antineoplastic Agents, Alkylating; Cell Line, Tumor; Chromatography, High Pressure Liquid; Dipeptides; Fluorometry; Humans; Hydrolysis; Indicators and Reagents; Leucine; Melphalan; Neoplasms; Oligopeptides; Peptide Hydrolases; Prodrugs; Protease Inhibitors

The data are presented on polychemotherapy given to 17 children with advanced refractory malignant tumors using whole body hyperthermia and hyperglycemia. All patients suffered tumor progression throughout treatment and afterwards. Adjuvant Roncoleukin (interleukin-2) was administered in 5. Such salvage therapy was followed by overall tumor regression in 29.3%. Overall 4-year survival in such cases was 19%. Immunological monitoring of adjuvant whole body hyperthermia and interleukin-2 was carried out.

Topics: Adolescent; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Cyclophosphamide; Dactinomycin; Doxorubicin; Etoposide; Female; Humans; Hyperthermia, Induced; Interleukin-2; Male; Melphalan; Monitoring, Immunologic; Neoplasms; Neuroleptanalgesia; Salvage Therapy; Time Factors; Vincristine

A melphalan-resistant variant (Roswell Park Memorial Institute (RPMI)-2650Ml) and a paclitaxel-resistant variant (RPMI-2650Tx) of the drug-sensitive human nasal carcinoma cell line, RPMI-2650, were established. The multidrug resistance (MDR) phenotype in the RPMI-2650Tx appeared to be P-glycoprotein (PgP)-mediated. Overexpression of multidrug resistant protein (MRP) family members was observed in the RPMI-2650Ml cells, which were also much more invasive in vitro than the parental cell line or the paclitaxel-resistant variant. Increased expression of alpha(2), alpha(5), alpha(6), beta(1) and beta(4) integrin subunits, decreased expression of alpha(4) integrin subunit, stronger adhesion to collagen type IV, laminin, fibronectin and matrigel, increased expression of MMP-2 and MMP-9 and significant motility compared with the parental cells were observed, along with a high invasiveness in the RPMI-2650Ml cells. Decreased expression of the alpha(2) integrin subunit, decreased attachment to collagen type IV, absence of cytokeratin 18 expression, no detectable expression of gelatin-degrading proteases and poor motility may be associated with the non-invasiveness of the RPMI-2650Tx variant. These results suggest that melphalan exposure can result in not only a MDR phenotype, but could also make cancer cells more invasive, whereas paclitaxel exposure resulted in MDR without increasing the in vitro invasiveness in the RPMI-2650 cells.

Topics: Antigens, CD; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Blotting, Western; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Integrins; Melphalan; Membrane Glycoproteins; Neoplasm Invasiveness; Neoplasms; Paclitaxel; Reverse Transcriptase Polymerase Chain Reaction; Tetraspanin 29; Tumor Cells, Cultured

Glutathione (GSH) contents and activities of glutathione S-transferases (GST), glutathione reductase (GSH-RD), glutathione peroxidase (GSHpx) and glutathione conjugate export pump (GS-X pump) were determined in eight human tumour cell lines with different sensitivities to melphalan, a substrate of glutathione conjugation, and actinomycin D which has not been shown to be detoxified by glutathione-related mechanisms. Chang liver cells with highest GSH content and highest activities of GST, GSH-RD, GSHpx and GS-X pump were found to be most resistant to melphalan. Statistical analysis showed significant correlations between sensitivities of the human tumour cells to melphalan and the glutathione-related factors (r = 0.72-0.79; except for GST, r = 0.65, P = 0.08), while there were no significant correlations observed between sensitivities of the human tumour cells to actinomycin D and all the glutathione-related factors tested (r = -0.25-0.14). Significant correlations of the glutathione-related factors to resistance of human tumour cells to melphalan, a substrate of glutathione conjugation, but not to resistance of the human tumour cells to actinomycin D which has not been shown to be detoxified by glutathione-related mechanisms suggested that glutathione-related mechanisms contribute to drug resistance by increased detoxification of the drugs involved.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Dactinomycin; Drug Resistance, Microbial; Drug Resistance, Neoplasm; Glutathione; Humans; Melphalan; Neoplasms; Tumor Cells, Cultured

In an attempt to limit toxicities associated with dose-intensive therapy used for transplant regimens, we performed a pilot study using amifostine with high-dose busulfan (12 mg/kg), melphalan (100 mg/m2), and thiotepa (500 mg/m2) in 21 patients with a variety of malignancies. After 3 days of oral busulfan, amifostine was given at 910 mg/m2 IV for 10 minutes, preceding the infusion of each of 2 doses of melphalan and thiotepa given for 4 days. Antiemetic premedication for amifostine was given to all patients. The median patient age was 50 years (range: 32-65 years). Twenty-one patients received 82 separate amifostine infusions. One patient discontinued amifostine after the second dose because of severe nausea and emesis, and two infusions were temporarily held secondary to hypotension. Of these 82 cycles, there was a total of 37 episodes of nausea/vomiting, 28 episodes of sneezing, 11 episodes of flushing, and 1 episode of oral paresthesia. Systolic blood pressure and mean arterial pressure decreased by a mean of 8.4 mm Hg and 5.0 mm Hg, respectively. In general, the infusion was well tolerated. Patients were observed until discharge home (N = 15), until initiation of an additional tandem transplant procedure (N = 4), or until death (N = 2). All twenty-one patients experienced nonhematologic toxicities grade II or greater. Grade II toxicities included mucositis (N = 21), gastrointestinal (N = 3), skin (N = 1), and liver (N = 1), and grade III toxicities included liver (N = 1). Mucositis was also scored according to a detailed toxicity assessment. Mucositis did not appear to be improved with amifostine when compared with a control group of patients not receiving amifostine. Renal dysfunction after transplantation was decreased in the amifostine group, whereas there was no significant effect on posttransplant hepatic dysfunction. Although these data demonstrate the feasibility of delivering parenteral amifostine in conjunction with dose-intensive chemotherapy and autologous peripheral blood stem cell transplantation, there was no evidence of a significant reduction in nonmarrow toxicities.

Topics: Adult; Aged; Amifostine; Antiemetics; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Blood Pressure; Busulfan; Feasibility Studies; Female; Flushing; Hematopoietic Stem Cell Transplantation; Humans; Hypotension; Male; Melphalan; Middle Aged; Mucous Membrane; Neoplasms; Pilot Projects; Protective Agents; Sneezing; Thiotepa; Transplantation, Autologous; Vomiting

To evaluate the feasibilitv of sequencing (based on preclinical modeling) tumor necrosis factor-a (TNF) at two dose levels with melphalan (L-PAM) and 41.8 C whole-body hyperthermia (WBH) for 60 min.. Nine patients with refractory cancer were treated from October 1995 to June 1997. The study encompassed a total of 20 trimodality treatment courses. Three patients were treated at TNF dose level I (50 microg/m2) and six patients were treated at TNF dose level II (100 microg/m2). TNF was delivered as a 24-h intravenous infusion, 48 h prior to the combination of L-PAM and WBH; L-PAM was given over 10 min at target temperature at a dose of 17.5 mg/ m2 based on a previous phase I WBH/L-PAM trial. WBH was administered with an Aquatherm radiant heat device.. Myelosuppression was the major toxicity associated with therapy, but there were no instances of bleeding or neutropenic fevers. Grade 3 thrombocytopenia was seen with 15% of treatments. Regarding absolute neutrophil count, 15% of treatments were associated with grade 3 toxicity, and 45% with grade 4 toxicity, and regarding white blood cell count, 50% of treatments were associated with grade 3 toxicity and 10% with grade 4 toxicity. The myelosuppression observed was equivalent to that seen in our earlier phase I study of WBH and L-PAM (without TNF). Only mild toxicities (grade 1 or 2) were associated with TNF; these were seen with <25% of treatments and included nausea, vomiting, diarrhea, fevers, and headache. There were no instances of hypotension. There was no relationship between toxicities observed and the two TNF dose levels. Mild WBH toxicities were seen with less than 15% of treatments; these included nausea, vomiting, and herpes simplex I. Responses included two complete remissions (malignant melanoma, TNF dose level I; breast cancer, TNF dose level II), and two disease stabilizations (both malignant melanoma, TNF dose level I).. We conclude that the combination of TNF, L-PAM, and WBH is well tolerated at the dose levels studied. The clinical results justify further clinical investigation for this trimodality treatment approach.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Feasibility Studies; Female; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Neoplasms; Pilot Projects; Tumor Necrosis Factor-alpha

The objective of the present study was to investigate the effects of isolated limb perfusion (ILP) with tumour necrosis factor alpha (TNF-alpha) and melphalan on circulating T cells from cancer patients using two different methods.. Eight patients undergoing an ILP entered the study. At first, the number of T cells at several time points was determined using FACScan. Subsequently, production of interferon gamma (IFN-gamma) (T-helper 1) and interleukin (IL) 4 (T-helper 2) was measured at the intracytoplasmic level after stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin. IFN-gamma, IL-4 and IL-2 (also T-helper 1) production in the whole-blood cell culture system was then determined after stimulation with a combination of anti-CD3/anti-CD28 monoclonal antibodies.. An enormous decrease in the number of circulating T cells was observed. In the remaining T-cell population cytokine production (IL-2, IL-4, IFN-gamma) was depressed, showing the same pattern in both methods. No difference could be detected between the effect of TNF-alpha and melphalan on Th1 cells and Th2 cells.. The results demonstrate that TNF-alpha and melphalan reduce the number of circulating T cells and at the single-cell level decrease cytokine production in the remaining circulating T cells. No selective effect of TNF-alpha on Th1 or Th2 cells could be detected. If the impaired T-cell function is representative of all T cells remaining in the systemic circulation, this could help to explain the tolerability of high TNF concentrations after ILP, perhaps by decreasing the synthesis and production of T-cell-derived cytokines.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Cells, Cultured; Cytokines; Female; Humans; Lymphocyte Count; Male; Melphalan; Middle Aged; Neoplasms; T-Lymphocytes; Tumor Necrosis Factor-alpha

Time-related changes in apoptotic leukocyte numbers were studied in peripheral blood sampled from 12 cancer patients before and after myeloablative chemotherapy (MC); six of them received hemopoietic cell grafts. Apoptotic leukocytes were counted in fresh and ex vivo incubated blood samples. Nuclear chromatin autolysis was registered in supravital Acridin Orange-stained granulocytes and lymphocytes. The levels of apoptosis in fresh peripheral blood were under 1.5%. Incubation for another 3 h revealed considerable numbers of apoptosis-prone leukocytes both in untreated patients and healthy donors. High-dose chemotherapy with busulphan, cyclophosphamide or alkeran was followed by a sharp increase in apoptotic cell counts which peaked on days 7-9, before leukopenia started on days 13-15 at the earliest. It is suggested that apoptosis of mature leukocytes is a major cause of leukopenia development induced by chemotherapy. The simple technique of apoptosis-prone cell detection in whole blood may be effectively used in serial screening of hematological side-effects of chemotherapy.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Busulfan; Cyclophosphamide; Humans; Leukocytes; Leukopenia; Melphalan; Neoplasms

To assess hematologic recovery and procedure-related mortality in patients who received high-dose therapy with stem-cell support, in whom the peripheral-blood stem-cell (PBSC) collection fails (CD34+ cells < 1 x 10(6)/kg). The predictive value of granulocyte-monocyte colony-forming cell (GM-CFC) measurements and the value of bone marrow obtained after PBSC collection failure was assessed.. The study group comprised 324 consecutive patients mobilized with granulocyte colony-stimulating factor (G-CSF) and cyclophosphamide (273 patients), G-CSF with other chemotherapy (37 patients), and G-CSF alone (14 patients). Between one and four aphereses were performed.. In 51 of 324 patients, there was failure to obtain 1 x 10(6)/kg CD34+ cells. Twenty-three patients had greater than 1 x 10(5)/kg GM-CFC; 22 patients proceeded to high-dose therapy. Neutrophil recovery occurred within 21 days, but platelet independence was delayed (> 28 days) in eight patients. Of 28 patients with less than 1 x 10(5)/kg GM-CFC, six received high-dose therapy with PBSC alone and five had delayed engraftment. Twelve patients with less than 1 x 10(5)/kg GM-CFC received high-dose therapy supported by bone marrow collected after PBSC collection failure. Eleven patients were assessable for engraftment; four patients had slow (> 21 days) or delayed (> 28 days) neutrophil recovery and eight patients had delayed platelet recovery. In the group of patients who received less than 1 x 10(5)/kg GM-CFC, there were five procedure-related deaths.. This study shows that delayed hematologic recovery is frequent if less than 1 x 10(6)/kg CD34+ cells are infused after high-dose therapy, particularly with GM-CFC less than 1 x 10(5)/kg. The procedure-related mortality in this latter group is high. In most patients whose PBSC collection contains less than 1 x 10(5)/kg GM-CFC, the use of bone marrow cells does not improve engraftment, which suggests that poor PBSC mobilization usually indicates poor marrow function.

Topics: Adolescent; Adult; Aged; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Blood Transfusion; Bone Marrow; Carmustine; Combined Modality Therapy; Cryopreservation; Cyclophosphamide; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Neoplasms; Podophyllotoxin; Treatment Failure

TNF (tumour necrosis factor) is a new immunological anti-cancer agent which is too toxic for systemic use and relatively ineffective when used alone, but remarkably effective when used in closed circuit perfusion techniques together with other anti-cancer agents. Several studies have shown that when TNF is used with melphalan in closed circuit perfusion treatment for multiple melanoma metastases confined to a limb, a response rate of 80% can be achieved compared to a best response rate of 40% with melphalan alone. These findings confirm the difference in tumour responses which can be achieved with the appropriate use of regional chemotherapy in treatment of locally advanced tumours and the importance of surgical oncologists and vascular radiologists in maintaining and developing skills in integrated regional cancer treatment.

Topics: Chemotherapy, Cancer, Regional Perfusion; Humans; Melanoma; Melphalan; Neoplasms; Tumor Necrosis Factor-alpha

Major dose-limiting factors of high-dose thiotepa (TEPA) and melphalan are life-threatening mucositis and neurotoxicity. To administer a maximum dose of these drugs safely and to obtain a maximum anti-cancer effect, a double-conditioning regimen with a single grafting, two cycles of administration of a combination of TEPA (300-600 mg/m2) plus melphalan (70-150 mg/m2) with a 1-week interval was attempted in 20 patients with pediatric advanced or chemotherapy-resistant solid tumors (seven rhabdomyosarcoma, four hepatoblastoma, three neuroblastoma and four other malignancy). Combinations of TEPA plus melphalan/busulfan (Bu) (8-10 mg/kg) and TEPA plus Bu were given to four and two patients with brain tumors, respectively. In an additional two patients, three cycles of drug administration were performed. According to the results of the dose-escalating study, the maximum tolerable doses of TEPA and melphalan for children aged 2 years old or older were 1000 mg/m2 and 280 mg/m2, respectively. Mucositis was dose-limiting. Renal toxicity was also dose-limiting in young children (<2 years old). There were two treatment-related deaths (7%) (fungal pneumonia and renal tubular acidosis). Among 13 patients who received high-dose chemotherapy during CR, 10 are alive with no evidence of disease (15-59 months, median: 35 months) and in 13 evaluable patients without CR, six are alive without regrowth of the disease (14-59 months, median: 39 months). Thus, these novel conditioning regimens allowed us to increase the dose intensity to nearly the maximum for each drug and seemed to reduce adverse effects compared to previously reported regimens with these drugs. With regard to the effect on outcome, the results of this study seem to be encouraging, but a further study on a larger number of patients is required.

Topics: Adolescent; Adult; Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Hematopoietic Stem Cell Transplantation; Humans; Infant; Melphalan; Neoplasms; Thiotepa; Thrombocytopenia; Transplantation Conditioning

L-S,R-buthionine sulfoximine (L-S,R BSO) is a potent specific inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting step in glutathione (GSH) biosynthesis. GSH is an important component of tumor drug resistance based on a strong association and recent transfection studies. Depletion of intracellular GSH by BSO significantly enhances the cytotoxicity of many cytotoxic agents, principally alkylating agents and platinating compounds but also irradiation and anthracyclines. Phase I clinical trials of BSO + melphalan (L-PAM)have been carried out and observed little toxicity with BSO alone and increased myelosuppression with BSO + L-PAM. Consistent and profound (< 10% of control) GSH depletion was observed in serial determinations of tumor GSH levels in patients receiving continuous infusion (CI) BSO. Evidence of clinical activity has been observed in patients with alkylating or platinating agent-refractory tumors. Phase II evaluation of CI BSO with L-PAM is in progress.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Drug Resistance; Enzyme Inhibitors; Female; Glutamate-Cysteine Ligase; History, 20th Century; Humans; Male; Melphalan; Neoplasms

Following mobilising chemotherapy and myeloid growth factors, some heavily pretreated patients do not mobilise adequate numbers of peripheral blood progenitor cells (PBPC). It would be clinically useful to identify such patients in advance. A recent scoring system based on previous therapy may be useful in predicting CD34-positive cell yield. In this study we validated this scoring system on an independent group of 99 patients undergoing 103 harvesting episodes. In 61 patients mobilised with cyclophosphamide 1.5 g/m2 and G-CSF, those with treatment scores less than 21 yielded significantly more CD34-positive cells than patients with scores greater than 63 (P = 0.0012). Previous treatment with melphalan or carmustine was associated with a significantly lower yield of CD34-positive cells (P= 0.0001). No relationship was seen between the time from previous chemoradiotherapy and harvest outcome. Patients with treatment scores less than 21 required a shorter duration of G-CSF therapy (P = 0.05). Similar findings were seen in 42 further mobilisation cycles undertaken with alternative mobilisation schedules. The present data suggest that a score summarising previous treatment can be used to predict CD34 yields, and could be of clinical use to identify poor PBPC mobilisers in advance.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclophosphamide; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Neoplasms; Predictive Value of Tests; Transplantation, Autologous

We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m2) and melphalan (140 mg/m2) with or without cyclophosphamide (3.6 g/m2). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy.

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Estradiol; Female; Follicle Stimulating Hormone; Follow-Up Studies; Humans; Immunosuppressive Agents; Luteinizing Hormone; Melphalan; Neoplasms; Ovarian Function Tests; Ovary; Primary Ovarian Insufficiency; Puberty, Delayed; Survivors; Transplantation Conditioning; Transplantation, Autologous

DNA repair has been proposed to be an important determinant of cancer cell sensitivity to alkylating agents and cisplatin (DDP). Nucleotide excision repair (NER), which represents one of the most important cellular DNA repair processes able to remove a broad spectrum of DNA lesions, is involved in the recognition and repair of the crosslinks caused by DDP and melphalan (L-PAM). In this study, the mRNA levels of the different genes involved in NER (ERCC1, XPA, XPB, XPC, XPD, XPF) were examined in a panel of eight different human cancer cell lines, together with the overall DNA repair capacity using a host cell reactivation assay of a damaged plasmid. A statistically significant correlation was observed between the relative expression of XPA/XPC (P < 0.05) and ERCC1/XPC (P < 0.05) mRNAs. No correlation was found between the DDP and L-PAM IC50S and the relative mRNA expression of the tested NER genes. When the overall cellular DNA repair capacity was studied, carcinomas seemed to have a higher repair activity than leukaemias; but this repair DNA activity correlated neither with the mRNA expression of the different NER genes nor with DDP and L-PAM IC50S. These data seem to suggest that even if the NER pathway is an important determinant for the cytotoxicity of alkylating agents, as demonstrated by the extremely high sensitivity to alkylating agents in cells lacking this repair system, other factors have to play a role in regulating the cellular sensitivity/resistance to these antitumour drugs.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Blotting, Northern; Cisplatin; Colonic Neoplasms; DNA Repair; Female; Gene Expression; Humans; Leukemia; Melphalan; Neoplasms; Ovarian Neoplasms; Tumor Cells, Cultured

Hyperthermic isolated limb perfusion (HILP) with recombinant tumor necrosis factor-alpha (r-TNF alpha) and melphalan has been shown to result in a sepsis-like syndrome due to leakage of r-TNF alpha from the perfusion system to the systemic circulation. We have studied renal function parameters in 11 cancer patients, who underwent 12 perfusions. Three patients, perfused with melphalan only, served as controls. All patients treated with r-TNF alpha developed a sepsis syndrome and needed volume replacement and inotropes to remain normotensive; controls had an uneventful postoperative course. Creatinine clearance decreased transiently on the day of perfusion in both groups (mean preperfusion clearance 118 ml/min, mean post-perfusion clearance 68 ml/min, p < 0.02, n = 15). Follow-up measurements of renal plasma flow and glomerular filtration rate in 9 r-TNF alpha-treated patients did not suggest permanent damage. One patient became hypotensive and developed transient multiple organ dysfunction with renal failure needing hemofiltration. In r-TNF alpha-treated patients, but not in controls, a transient increase in clearance of beta2-microglobulin (0.05 vs. 8 ml/min, p < 0.001) and urinary excretion of phosphate (12 vs. 48 mmol/l, p < 0.05) was seen, compatible with proximal tubular dysfunction. These data suggest that HILP with melphalan decreases glomerular function, whether or not r-TNF alpha is added to the perfusion circuit. Extension of the treatment regimen with r-TNF alpha may result in additional proximal tubular dysfunction. If hypotension can be avoided, this deterioration in renal function seems to be transient, with full recovery within weeks.

Topics: Antineoplastic Agents, Alkylating; beta 2-Microglobulin; Blood Pressure; Chemotherapy, Cancer, Regional Perfusion; Creatinine; Glomerular Filtration Rate; Humans; Hyperthermia, Induced; Kidney; Melphalan; Neoplasms; Recombinant Proteins; Regional Blood Flow; Renal Circulation; Tumor Necrosis Factor-alpha

ID50 and ID90 values for L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester HCl (MF13), were determined in four murine (leukemia, lymphoma, melanoma, and lung) and eight human cancer cell lines (two leukemia, prostate, kidney, colon, two melanoma, and breast). Cytotoxic activity was 2-5 times higher than that of sarcolysin [(L-3-[bis(2-chloroethyl)amino]-L-phenylalanine] against all leukemias and lymphomas, ID50 0.5-0.9 microM, and against human solid tumors, ID50 0.4-2.1 microM. Sensitivities of L-phenylalanine mustard-resistant and methotrexate-resistant L1210 cells were the same as the naive lines, ID50 0.5 microM. Apoptosis was confirmed by: (a) morphology, revealing chromatin condensation and nuclear fragmentation; (b) flow cytometry, showing changes in cell size and DNA integrity; and (c) DNA electrophoresis, demonstrating multiples of 180-200-bp DNA units. MF13 had no cytotoxicity against human peripheral blood lymphocytes at concentrations lethal to tumor cells (ID50, 13.3 microM without and 11 microM with phytohemagglutinin stimulation) and failed to induce apoptosis. s.c. MF13 treatment of mice with advanced EL4 leukemic ascites yielded extensive apoptosis, with DNA degradation identical to that seen in vitro, and resulted in complete tumor regression in all treated mice. These results suggest MF13 as a potential chemotherapeutic agent.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Cell Survival; DNA Fragmentation; DNA, Neoplasm; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Flow Cytometry; Humans; Lethal Dose 50; Leukemia; Leukemia L1210; Lymphoma; Melphalan; Methotrexate; Mice; Neoplasms; Oligopeptides; Tumor Cells, Cultured

Glutathione(GSH) has been implicated as an important factor in the detoxification of many electrophilic xenobiotics, including agents used in cytotoxic chemotherapy. Maintenance of high levels of GSH in normal tissues is believed to be important in the prevention of drug-induced toxicity. Previous studies have indicated that exposure of cells to some toxic electrophiles both in vitro and in vivo can cause a temporary decrease in intracellular levels of GSH. In this paper we report that in a series of 22 children and young adults treated with high dose melphalan (ten courses studied, all 200 mg/m2), cisplatin (eight courses, 80-104 mg/m2) or carboplatin (seven courses, 507-750 mg/m2) there was no significant alteration in the level of plasma, erythrocyte or urine GSH in the period immediately following drug administration. Fluctuations in the level of GSH in mononuclear cells were observed in some patients but did not follow any consistent pattern and were similar to those observed in a series of nine normal adult controls over the same time course. These results suggest that for melphalan, cisplatin and carboplatin, drug-GSH adduct formation is insufficient to cause a measurable decrease in intracellular GSH levels in normal peripheral haematopoietic cells during the course of treatment.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Blood Cells; Carboplatin; Child; Child, Preschool; Cisplatin; Erythrocytes; Glutathione; Humans; Leukocytes, Mononuclear; Male; Melphalan; Neoplasms; Reference Values; Time Factors

The activities and the expression of 3-methyladenine glycosylase (3-meAde gly) and O6-alkylguanine-DNA-alkyltransferase (O6 ATase) were investigated in ten human cancer cell lines. Both 3-meAde gly and O6 ATase activities were variable among different cell lines. mRNA levels of the O6 ATase gene, appeared to be related to the content of O6 ATase in different cell lines, whereas no apparent correlation was found between mRNA of 3-meAde gly and the enzyme activity. No correlation was found between the activity of the two enzymes and the sensitivity to alkylating agents of different structures such as CC-1065, tallimustine, dimethylsulphate (DMSO), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), cis-diamminedichloroplatinum (cDDP) and melphalan (L-PAM). The most striking finding of this study is that a correlation exists between the activity of O6 ATase and 3-meAde gly in the various cell lines investigated (P<0.01), suggesting a common mechanism of regulation of two DNA repair enzymes.

Topics: Alkylating Agents; Antineoplastic Agents, Alkylating; Carcinogens; Cell Division; Cisplatin; Distamycins; DNA Glycosylases; Humans; Melphalan; Methylnitronitrosoguanidine; Methyltransferases; N-Glycosyl Hydrolases; Neoplasms; Nitrogen Mustard Compounds; O(6)-Methylguanine-DNA Methyltransferase; RNA, Messenger; Sensitivity and Specificity; Sulfuric Acid Esters; Tumor Cells, Cultured

We report our single institution's effort to standardize the method of collecting peripheral blood progenitor cells (PBPC) used for autologous transplantation. PBPC were mobilized by different types of chemotherapy followed by G-CSF (24 patients) or G-CSF alone (six patients) in 30 patients with various underlying neoplastic diseases. A median of three aphereses (range: 2-7), using the CS3000 cell separator was performed and a blood volume of 101 was processed. We studied the relationship between the absolute numbers of circulating leukocytes, mononuclear cells and CD34+ cells and the amount of PBPC collected during a single apheresis procedure. CD34+ cells were quantified by leukocyte subset analysis based on flow cytometry. Both CFU-GM and CD34+ cell contents of the apheresis products (69 procedures analyzed) correlated strongly: rho = 0.936, P = 0.0001). Regression analysis showed that the total number of CD34+ cells or CFU-GM content of the apheresis products could be predicted (r = 0.915, P = 0.0001) from the absolute number of CD34+ cells in the blood. A number of 10 circulating CD34+ cells per mm3 blood ensured a minimum of 0.5 x 10(6) CD34+ cells per kg, collected on the same day. Of the 30 patients, 17 received an autologous graft that contained only PBPC in 13. Long-term and complete hematological reconstitution was observed in all patients who had a minimum of 2 x 10(6) CD34+ cells per kg reinfused.

Topics: Adult; Aged; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Blood Component Removal; Bone Marrow; Cell Movement; Colony-Forming Units Assay; Cyclophosphamide; Female; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Male; Melphalan; Middle Aged; Neoplasms; Time Factors; Transplantation Conditioning

The time of stem cell harvest and the mobilization regimen may play important roles in terms of achieving adequate numbers of stem cells by leukapheresis. To optimize the timing of leukapheresis, we have determined simultaneously the number of CD34+ cells in the peripheral blood as well as in the leukapheresis product of 214 apheresis procedures performed in 66 unselected patients with malignant hematologic diseases and solid tumors. A significant correlation between the number of CD34+ cells in peripheral blood and the leukapheresis product (R = 0.8) was found. The presence of more than 20 x 10(3)/ml blood CD34+ cells gave a sufficient yield (> or = 1.0 x 10(6) CD34+ cells/kg) in 81% of the cases. In an attempt to compare two priming regimens, we performed leukapheresis twice in 12 patients with stable disease. In the first sequence, stem cells were mobilized with rhG-CSF (10 micrograms/kg/day) alone and, in the second sequence, with cyclophosphamide (4 g/m2) plus rhG-CSF. A significantly higher yield of CD34+ cells and a better correlation between CD34+ cells in the peripheral blood and the leukapheresis product were found after priming with high-dose cyclophosphamide plus rhG-CSF, compared with priming with rhG-CSF alone. In a multivariate analysis, three factors were found to correlate with the yield of CD34+ cells, namely prior chemotherapy, bone marrow function, and the mobilization regimen. The use of cyclophosphamide priming improves CD34+ mobilization, and the introduction of blood CD34+ level optimizes the timing for harvest of stem cells, which should be performed early during treatment of malignancies.

Topics: Adolescent; Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Blood Cells; Blood Transfusion, Autologous; Bone Marrow; Carmustine; Cyclophosphamide; Cytarabine; Drug Administration Schedule; Drug Synergism; Epirubicin; Etoposide; Female; Filgrastim; Fluorouracil; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic Stem Cells; Humans; Injections, Subcutaneous; Leukapheresis; Leukocyte Count; Male; Melphalan; Middle Aged; Neoplasms; Recombinant Proteins

To analyze the mechanism of vasodilation and circulatory shock occurring in patients who are treated with isolated limb perfusion with melphalan and recombinant tumor necrosis factor (TNF)-alpha for locally advanced malignant tumors. To determine the role of nitric oxide, if any, by measuring plasma nitrite and nitrate concentrations.. Observational survey.. A 12-bed surgical intensive care unit in a university referral hospital.. Eight patients treated with hyperthermic isolated limb perfusion.. Ninety minutes of hyperthermic isolated limb perfusion with recombinant TNF-alpha (3 or 4 mg) and melphalan (10 to 13 mg/L limb volume).. All patients developed sepsis syndrome due to leakage of recombinant TNF-alpha from the perfusion circuit to the systemic circulation. Despite the presence of very high systemic TNF-alpha concentrations during and immediately after perfusion, and despite definite signs of hyperdynamic circulatory shock (increased heart rate, increased cardiac index, decreased systemic vascular resistance), nitrite and nitrate concentrations, as measured in plasma at several time points, were not increased.. The hypothesis that in humans, TNF-alpha induces vasodilation and shock through activation of inducible nitric-oxide synthase and subsequent formation of excessive quantities of nitric oxide is not substantiated by our results. Normal nitric oxide metabolite concentrations were found in the presence of high TNF-alpha concentrations and shock. Other mechanisms that do not involve the nitric oxide pathway are likely to play a role in the generation of hypotension and septic shock in this setting.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Hemodynamics; Humans; Male; Melphalan; Middle Aged; Neoplasms; Nitrates; Nitric Oxide; Nitrites; Sepsis; Shock; Tumor Necrosis Factor-alpha

High-dose chemotherapy followed by autologous bone marrow transplantation (ABMT) enables dose escalation in the treatment of childhood malignancies. Here we report our experience of using peripheral blood progenitor cells (PBPC) to restore haematopoiesis in five children using a simple cell mobilising regime and non-cryopreservation of the harvests. Cells were mobilised using cyclophosphamide and granulocyte colony stimulating factor. Each patient underwent only two leukaphereses, the product being stored before use at 4 degrees C. Successful autologous PBPC transplantation was achieved with melphalan conditioning chemotherapy and re-infusion of the total progenitor cell product. No colony stimulating factors were administered after transplantation. The median numbers of mononuclear cells collected per patient was 10.0 x 10(8)/kg (range 8.13-19.44) and CFU-GM 57.6 x 10(4)/kg (range 10.4-178.85). All patients subsequently engrafted with the median number of days to a neutrophil count > 0.5 x 10(9)/l being 11 (range 10-16), and to a platelet count > 50 x 10(9)/l being 14 (range 12-31). The median number of in-patient days was only 20 (range 19-30). The median demand for blood was 2 units (range 1-2), and platelets 4 units (range 2-28). Usage of systemic antimicrobials and intravenous feeding was also low. Using this simple strategy, collection and transplantation of autologous progenitor cells can be a straightforward procedure in children. It is possible that this could enable dose escalation in some poor prognosis paediatric tumours.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Blood Transfusion, Autologous; Child; Child, Preschool; Cyclophosphamide; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukapheresis; Male; Melphalan; Neoplasms; Opportunistic Infections; Treatment Outcome

Carboplatin and melphalan are two drugs whose toxicity profile makes them suitable for use in high doses followed by stem cell rescue. We report the use of high-dose carboplatin, with the dose based on glomerular filtration rate (GFR), combined with melphalan followed by autologous stem cell rescue in children with advanced stage or chemoresistant solid tumours. Thirty children were treated. After multiagent induction chemotherapy before BMT, 13 were in CR, five in VGPR, 11 in PR and one had progressive disease. They received melphalan, 180 mg/m2 and carboplatin, followed by autologous stem cell rescue. The dose of carboplatin was varied by GFR rather than fixed by surface area. The dose given ranged from 0.7 to 2.6 g/m2. Haematological and gastrointestinal toxicities were severe. Life-threatening or fatal toxicity was attributable to opportunistic infection in two cases and regimen-related in two cases. Of the 30 patients, 15 are alive and 13 disease-free at 4-36 months post-BMT. This simple two-drug combination has been used as consolidation of initial remission for patients with high-risk tumours. The toxicity is severe but tolerable. Use of a carboplatin dose based on GFR should optimise effectiveness in patients with good renal function and avoid excessive toxicity where renal function is impaired.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Carboplatin; Child; Child, Preschool; Disease-Free Survival; Female; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infections; Kidney Diseases; Male; Melphalan; Neoplasms; Neuroblastoma; Treatment Outcome

We evaluated the efficacy, toxicity and feasibility of two cycles of high-dose chemotherapy (HDC), each supported with mobilized peripheral blood progenitor cells (PBPC). Ninety-six patients with metastatic or high-risk cancers received disease-specific HDC regimens. The first cycle consisted of cyclophosphamide 6000 mg/m2, thiotepa 500 mg/m2 and carboplatin 1200 mg/m2. Alternatively, some patients received etoposide 1800 mg/m2 substituted for thiotepa. A second cycle was planned 6-8 weeks later and consisted of mitoxantrone 60 mg/m2 with either melphalan 140 mg/m2 or thiotepa 600 mg/m2. PBPC were mobilized with either growth factor alone or cyclophosphamide followed by growth factor(s). Thirty-four of 96 enrolled patients (35%) did not receive the second cycle. The reasons were: patient refusal (15); insurance refusal (three); toxicities of cycle 1 (seven); no response to cycle 1 (four); and inadequate mobilization or poor engraftment, (five). Of the 33 patients who entered cycle 2 with measurable disease, 28 demonstrated further response after cycle 2 (including 10 who entered CR). One patient died of toxicity after each cycle. Hematologic recovery was rapid and complete in most patients. Tandem cycles of high-dose chemotherapy supported by PBPC are feasible and safe, although many patients fail to receive the second treatment. Preliminary evaluation shows evidence of further antitumor efficacy following cycle 2.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Carboplatin; Cyclophosphamide; Drug Administration Schedule; Etoposide; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukapheresis; Male; Melphalan; Middle Aged; Mitoxantrone; Neoplasms; Patient Acceptance of Health Care; Remission Induction; Salvage Therapy; Thiotepa; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Several investigators have reported that interferon-gamma (IFN gamma) can alter tumor necrosis factor alpha induced effects in vitro. We assessed in vivo effects of recombinant interferon-gamma (rIFN gamma) on recombinant tumor necrosis factor-alpha (rTNF alpha) induced activation of systemic blood coagulation in a non-randomized study in 20 consecutive cancer patients. Eight patients were treated with rIFN gamma prior to and during hyperthermic isolated limb perfusion with rTNF alpha and melphalan (IFN gamma group). They were compared with twelve patients who did not additionally receive rIFN gamma (non-IFN gamma group). Before start of perfusion, higher levels of TNF alpha, F1+2 and TAT levels were found in the IFN gamma group. Fibrinogen and ATIII levels tended to be lower in this group. High TNF alpha levels, due to leakage during perfusion, were associated with activation of coagulation in all patients, that became obvious after the end of perfusion, when heparin treatment had been antagonized. Activation, measured by increased F1+2 and TAT levels, was significantly stronger in the IFN gamma group. Monocytic TF remained low, possibly due to shedding of TF positive vesicles and/or sequestration of TF positive activated monocytes against the vessel wall. In both groups F1+2 and TAT levels declined 24 h after the perfusion, whereas monocytic TF increased to levels that were higher in the IFN gamma group. In conclusion, our data confirm a strong activation of coagulation induced by rTNF alpha in cancer patients. They suggest that rIFN gamma may lead to a slight activation of coagulation and augments TNF alpha induced procoagulant activity. These effects may be due to rIFN gamma induced sustained monocytic TF activity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Humans; Infusions, Intravenous; Interferon-gamma; Melphalan; Neoplasms; Recombinant Proteins; Tumor Necrosis Factor-alpha

Subungual melanoma is rare and experience in treating this condition with isolated limb perfusion is limited. Between 1985 and 1990, 24 patients were treated by digital amputation and isolated limb perfusion with melphalan and mild hyperthermia. The disease was staged according to the M.D. Anderson classification: stage I (17 patients), stage IIIA (one), stage IIIB (two) and stage IIIAB (four). Thirteen lesions were on the foot and 11 on the hand. Seven patients have developed locoregional recurrence. The estimated overall 2- and 5-year probabilities of survival were 77 and 46 per cent respectively, while for disease-free survival the rates were 58 and 51 per cent. When these results were compared retrospectively with those in 111 patients treated by amputation alone, no significant difference in survival was demonstrated. This experience suggests that isolated limb perfusion with melphalan and mild hyperthermia confers no additional survival benefit over appropriate surgery.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Nail Diseases; Neoplasm Recurrence, Local; Neoplasms; Proportional Hazards Models; Prospective Studies; Survival Rate

Adhesion molecules play a role in the migration of hematopoietic progenitor cells and regulation of hematopoiesis. To study whether the mobilization process is associated with changes in expression of adhesion molecules, the expression of CD31, CD44, L-selectin, sialyl Lewisx, beta 1 integrins very late antigen 4 (VLA-4) and VLA-5, and beta 2 integrins lymphocyte function-associated 1 and Mac-1 was measured on either bone marrow (BM) CD34+ cells or on peripheral blood CD34+ cells mobilized with a combination of granulocyte colony-stimulating factor (G-CSF) and chemotherapy. beta 1 integrin VLA-4 was expressed at a significantly lower concentration on peripheral blood progenitor cells than on BM CD34+ cells, procured either during steady-state hematopoiesis or at the time of leukocytapheresis. No differences in the level of expression were found for the other adhesion molecules. To obtain insight in which adhesion molecules may participate in the homing of peripheral blood stem cells (PBSCs), the number of CD34+ cells expressing these adhesion molecules present in leukocytapheresis material was quantified and correlated with hematopoietic recovery after intensive chemotherapy in 27 patients. The number of CD34+ cells in the subset defined by L-selectin expression correlated significantly better with time to platelet recovery after PBSC transplantation (r = -.86) than did the total number of CD34+ cells (r = -.55). Statistical analysis of the relationship between the number of CD34+L-selectin+ cells and platelet recovery resulted in a threshold value for rapid platelet recovery of 2.1 x 10(6) CD34+ L-selectin+ cells/kg. A rapid platelet recovery (< or = 14 days) was observed in 13 of 15 patients who received > or = 2.1 x 10(6) CD34+ L-selectin+ cells/kg (median, 11 days; range, 7 to 16 days), whereas 10 of 12 patients who received less double positive cells had a relative slow platelet recovery (median, 20 days; range, 13 to 37 days). The L-selectin+ subpopulation of CD34+ cells also correlated better with time to neutrophil recovery (r = -.70) than did the total number of reinfused CD34+ cells (r = -.51). However, this latter difference failed to reach statistical significance. This study suggests that L-selectin is involved in the homing of CD34+ cells after PBSC transplantation.

Topics: Adult; Antigens, CD; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bone Marrow; Bone Marrow Cells; Carboplatin; Carmustine; Cell Adhesion Molecules; Cell Movement; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Epirubicin; Etoposide; Female; Fluorouracil; Gene Expression; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Ifosfamide; L-Selectin; Leukocyte Count; Male; Melphalan; Middle Aged; Neoplasms; Neutrophils; Platelet Count; Podophyllotoxin; Receptors, Very Late Antigen; Thiotepa

Glutathione (GSH) transferases (GST), a family of detoxification enzyme proteins, are suggested to play an important role in tumor cell resistance to melphalan. The GST-activity inhibitor ethacrynic acid has been shown to increase the antitumor activity of melphalan in vitro as well as in vivo. In this study we determined the activity and toxicity of melphalan in combination with another GST-activity inhibitor, sulfasalazine, an agent used to treat ulcerative colitis. We entered 37 previously treated patients with advanced cancer of different histologies on sulfasalazine given at the individually calculated maximum tolerated dose (MTD) and melphalan given at doses beginning at 20 mg/m2. The main toxicity arising from this combination was nausea and vomiting, whereas increased myelosuppression was not observed. A partial response was seen in 2/4 of the ovarian cancer patients only. Plasma sulfasalazine levels varied between 2.5 and 47.1 micrograms/ml. Although reductions in GSH/GST levels were observed in peripheral mononuclear cells of certain patients following sulfasalazine treatment, there was no correlation between the extent of reduction and the plasma sulfasalazine level. A larger patient population must be studied to determine the usefulness of this combination.

Topics: Drug Administration Schedule; Drug Therapy, Combination; Female; Glutathione Transferase; Humans; Male; Melphalan; Neoplasms; Neutropenia; Sulfasalazine; Thrombocytopenia

Hematopoietic reconstitution has been studied in 180 patients after autologous bone marrow transplantation based on peripheral blood cell (PBC) recovery time and marrow progenitor counts sequentially tested for up to 4 years. Several factors that could influence hematopoietic reconstitution have been analyzed including sex, age, diagnosis, disease status, conditioning regimen, graft progenitor content, graft in vitro purging, and postgrafting administration of growth factors. Before transplantation, marrow progenitor values were normal only for colony-forming unit granulocyte macrophage (CFU-GM) in contrast to colony-forming unit-erythroid (CFU-E), burst-forming unit-erythroid (BFU-E), and colony-forming unit-megakaryocyte (CFU-Meg). After transplantation, as described with allogenic grafts, these values remained low for several years, although PBC counts were nearly normalized within a few weeks. Pregraft values were reached after 2 years for CFU-GM and BFU-E, and after 4 years for CFU-E, while CFU-Meg failed to reach pregraft values after this time. Normal levels were reached after 4 years only by CFU-GM. On univariate and multivariate analysis, the following factors appeared to delay both PBC and marrow progenitor reconstitution: underlying disease (particularly acute myeloid leukemias), graft characteristics such as low stem cell content and in vitro purging, conditioning regimens with total body irradiation or busulfan, and lack of postgraft administration of growth factors. In conclusion, high-dose therapy followed by bone marrow transplantation induces a deep and prolonged impairment of hematopoiesis irrespective of any alloimmune reaction or postgraft immunosuppressive therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Busulfan; Carmustine; Cell Count; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Etoposide; Female; Follow-Up Studies; Hematopoiesis; Hematopoietic Cell Growth Factors; Humans; Male; Melphalan; Methotrexate; Middle Aged; Mitoxantrone; Multivariate Analysis; Neoplasms; Prognosis; Radiation Injuries; Treatment Outcome; Vincristine; Whole-Body Irradiation

In order to perform melphalan dosage adjustment, the linearity of melphalan kinetics was studied, in the case of previous carboplatin administration. Eleven patients with various solid tumors entered the present study. Carboplatin was administered during 5 days over 1-hour infusions; the day after, the melphalan test-dose was administered and followed 24 hours after by the complement dose. Melphalan kinetics were determined from only three plasma samples by using bayesian estimation. The present study showed that previous carboplatin administrations induced wide variations of melphalan pharmacokinetic parameters between the two administrations. As part of this protocol, the order of drug administration should be taken into account, in order to perform melphalan dosage adjustment.

Topics: Adolescent; Adult; Carboplatin; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Melphalan; Neoplasms; Time Factors

Twenty-four patients with a variety of malignant diseases (13 lymphoma, 4 myeloma, 1 ALL, 6 solid tumours) were treated with the alkylating agents busulphan and melphalan as a preparative regimen for autologous BMT. Thirteen males and 11 females, aged 27-53 years (median 39.5 years) received oral busulphan 1 mg/kg q6 h on days -6 to -3, followed by i.v. melphalan 140 mg/m2 on day -2 and infusion of cryopreserved haemopoietic cells on day 0. The major toxicity seen was gastrointestinal with nausea, vomiting and diarrhoea in 17 patients and severe mucositis in 22. There was no evidence of cardiotoxicity, nephrotoxicity, haemorrhagic cystitis or clinical signs of hepatic veno-occlusive disease. Twenty-three patients engrafted with the median duration of neutropenia (< 0.05 x 10(9)/l) 10 days (range 5-63 days) and thrombocytopenia (< 50 x 10(9)/l) 43 days (range 5-350 days). Three patients died of transplant-related complications. Of 15 evaluable patients with active disease at BMT, 9 responded and 6 were refractory. Sixteen evaluable patients were in CR after BMT. Seven relapsed, 1 died in remission and 8 remain in CR 12-46 months (median 29 months) later. Of the group of 13 lymphomas, overall and relapse-free actuarial survival at 36 months was 64% and 58%, respectively, while for the entire group of 24 patients these values were 39% and 34%. Busulphan and melphalan is a safe and inexpensive conditioning regimen for autologous BMT with acceptable toxicity and substantial antitumour activity particularly against lymphomas.

Topics: Actuarial Analysis; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Busulfan; Combined Modality Therapy; Female; Gastrointestinal Diseases; Humans; Male; Melphalan; Middle Aged; Neoplasms; Neutropenia; Remission Induction; Stomatitis; Survival Analysis; Thrombocytopenia; Transplantation, Autologous; Treatment Outcome

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Female; Glutathione; Humans; Melphalan; Methionine Sulfoximine; Middle Aged; Neoplasms

Conventional chemotherapy results in high mortality rates in patients with solid tumors involving the bones or the bone marrow. High dose melphalan (MEL) with or without total body irradiation followed by bone marrow transplantation (BMT) has prolonged survival, but curative potential has remained disappointing. In order to improve survival 20 children with generalized or relapsed solid tumors (neuroblastoma, peripheral neuroectodermal tumor, Ewing's sarcoma, rhabdomyosarcoma) underwent autologous (n = 16) or allogeneic (n = 4) BMT. The myeloablative regimen consisted of 12 Gy fractionated total body irradiation (FTBI) and high dose MEL. In 12 of these patients this regimen was intensified by giving 60 mg/kg etoposide (1800 mg/m2 VP), and 1.5 g/m2 carboplatin (CBDCA) was added in seven of these 12 patients. The intensification of FTBI and MEL by adding VP and CBDCA was followed by acceptable toxicity. Acute liver toxicity in 15/20 patients (75%) and acute renal toxicity in 17/20 patients (85%) did not exceed WHO grade 1. The use of the conditioning regimen FTBI-MEL-VP-CBDCA during first chemotherapy response is a promising approach in treatment of children suffering from generalized solid tumors.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Etoposide; Humans; Infant; Melphalan; Neoplasms

To evaluate the long-term renal toxicity of cisplatin, 40 children who had been without treatment at least 18 months (range 18 months to 7 years) were observed. In all the children, glomerular filtration rate (GFR) was estimated from the plasma clearance of chromium 51-labeled ethylenediaminetetraacetic acid, both at the end of treatment and at a median follow-up of 2 years 6 months after treatment was stopped (range 18 months to 7 years). In 21 children, serum magnesium level was also measured at follow-up. Median age at diagnosis was 15 months (range 13 days to 13 years 8 months), and median cumulative doses of cisplatin was 500 mg/m2 (range 120 to 1860 mg/m2). In 22 of 24 children with an end-of-treatment GFR of less than 80 ml/min per 1.73 m2, the median improvement in GFR at follow-up was 22 ml/min per 1.73 m2 (range 2 to 56 ml/min per 1.73 m2). Hypomagnesemia was found in 6 of 21 children and was independent of GFR. No significant correlation was found between improvement in renal function and total cisplatin dose, age, gender, tumor type, or associated nephrotoxic medication. We conclude that most children have some recovery from cisplatin glomerular toxicity, especially if damage is not severe, but that hypomagnesemia may persist.

Topics: Adolescent; Blood Pressure; Child; Child, Preschool; Cisplatin; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Infant; Infant, Newborn; Kidney; Kidney Tubules; Male; Melphalan; Neoplasms

We have studied 60 pediatric patients with different neoplastic diseases, treated with anthracyclines. We have followed them clinically and echocardiographically to detect the cardiotoxicity due to anthracyclines and the enhanced factors promptly. We have detected a more important incidence of cardiomyopathy in patients with non-Hodgkin's lymphoma, osteosarcoma and neuroblastoma despite cumulative doses under 550 mg/m2 of anthracyclines. The 2 first groups were treated with high doses of cyclophosphamide and methotrexate, and neuroblastomas with melphalan. The anthracyclines cardiotoxicity is evaluated around 5% in patients treated with doses under 550 mg/m2, and is increased in case of previous or simultaneous aggressive therapy. Continued echocardiography enables a premature detection of cardiotoxicity in these high risk patients.

Topics: Antibiotics, Antineoplastic; Cardiomyopathies; Child; Cyclophosphamide; Doxorubicin; Drug Synergism; Echocardiography; Heart; Humans; Melphalan; Methotrexate; Neoplasms

Topics: Humans; Melphalan; Neoplasms

A group of potential alkylating agents have been synthesized that are structurally related to the oligopeptide antiviral antibiotic distamycin. All derivatives form complexes with native calf-thymus DNA but compounds 2, 3, and 6 give rise to covalent adducts. Cytostatic activity against both human and murine tumor cell lines in vitro is displayed by the new compounds. Compounds 3 and 4 are active on melphalan-resistant L1210 leukemia in mice.

Topics: Alkylating Agents; Animals; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Circular Dichroism; Distamycins; DNA; Humans; Leukemia L1210; Leukemia, Experimental; Mice; Neoplasms; Pyrroles; Structure-Activity Relationship; Tumor Cells, Cultured

As the dose-limiting toxicity of mitoxantrone is hematological, the drug is suitable for dose escalation and use in intensive chemotherapy followed by autologous bone marrow rescue. Adult patients with therapy-resistant solid tumors received a regimen of high-dose cyclophosphamide (7 g/m2) and escalating doses of mitoxantrone in dose steps of 30, 45, 60, and 75 mg/m2. Both drugs were given i.v. on 3 consecutive days. Despite the addition of mesnum (3.5 to 7 g/m2), hemorrhagic cystitis occurred on the second day in four of eight patients, irrespective of the mesnum or mitoxantrone dose. Therefore, the cyclophosphamide in the combination regimen was replaced by high-dose melphalan (180 mg/m2). Mucositis was dose limiting at 75 mg/m2 of mitoxantrone. Responses were seen in eight of ten evaluable patients with four complete responses. Three responders received, after the autologous bone marrow transplantation program, radiotherapy or surgery on pretreatment bulky tumor localizations. Five patients still have disease-free survival after 9 to 36 mo. Pharmacokinetic studies of mitoxantrone were performed by high-performance liquid chromatography with UV detection. The plasma disappearance of mitoxantrone fitted into a three-compartment model with a mean t1/2 alpha of 10 min, a mean t1/2 beta of 96 min, and a slow elimination phase of 172 h. The mean distribution volume was 4294 +/- 3836 liters. We conclude that the high-dose cyclophosphamide-mitoxantrone regimen led to unexpected bladder toxicity, but the combination of melphalan (180 mg/m2) and mitoxantrone (60 mg/m2) can probably be given without major extramedullary toxicity. However, more patients should be evaluated at this dose before definite conclusions can be drawn about toxicity.

Topics: Adult; Bone Marrow Transplantation; Breast Neoplasms; Cyclophosphamide; Female; Humans; Male; Melphalan; Middle Aged; Mitoxantrone; Neoplasms; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Stomach Neoplasms

236 patients with various advanced malignant solid tumors treated by combined chemotherapy with routine doses of cisplatin (DDP) from 1980 to 1986 are presented. According to different doses of cisplatin everyday, the patients were divided into 4 groups: 1. 20 mg/day x4-5, 80 cases; 2. 30 mg/day x3-5, 91 cases; 3. 40 mg/day x3-4, 37 cases; 4. 50 mg/day x2-3, 28 cases. Each group was repeated for 3 weeks. The effect and toxicity were analysed and compared with 22 cases treated by single DDP in 1975. The response (CR + PR) rate was 39.2% in 194 evaluated patients. The response rate was similar in group 20 mg and single DDP (29.2% and 27.3%). The response rate was lower than that of group 30 mg, 40 mg, and 50 mg (43.4%, 42.4%, and 50%) (P less than 0.05). The remissions in various groups were not significantly different. The toxicity of combined chemotherapy was not severe. 91.1% of patients had nausea and vomiting. There was no statistical difference in the various groups. Bone marrow suppression was less in single DDP group than that of combined chemotherapy group, (P less than 0.05). DDP 30 mg-50 mg 1/d x5-3 was better than HD-DDP in some patients.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Humans; Lomustine; Lung Neoplasms; Male; Melanoma; Melphalan; Methotrexate; Middle Aged; Neoplasms; Procarbazine; Testicular Neoplasms; Vincristine

The pharmacokinetics of melphalan following high-dose p.o. administration were determined in 17 patients with various malignancies for the purpose of assessing interpatient and intrapatient pharmacokinetic variability. All patients underwent bone marrow harvest on day -8 (relative to bone marrow reinfusion). On days -7, -6, and -5, melphalan was given p.o. and the dose was escalated on each cohort consisting of at least 3 patients (beginning at 0.75 mg/kg). On days -6, -4, and -2, cyclophosphamide at 2.5 g/m2 and thiotepa at 225 mg/m2 were given i.v. On day -7 the peak melphalan concentration was 1.64 +/- 0.89 (SD) microM with a terminal half-life of 1.56 +/- 0.86 h. The area under the plasma concentration time curve (AUC) and oral clearance were 217.9 +/- 115.1 microM/min and 30.2 +/- 14.2 ml/min/kg. There was only a moderate correlation between the melphalan dose and both the peak concentration (r = 0.50, P less than 0.05) and AUC (r = 0.64, P less than 0.01) over the dosage range of 0.75-2.5 mg/kg. There was a trend towards greater interpatient variability in peak concentration, AUC, and oral clearance observed at the higher doses of melphalan. Analysis of intrapatient pharmacokinetic variability in 8 patients showed a significant difference between the doses given on days -7 and -5 in the peak concentration (2.09 versus 1.07 microM, P = 0.02), AUC (264.9 versus 134.8 microM/min, P = 0.01), and oral clearance (25.1 versus 53.1 ml/min/kg, P = 0.05) but no significant difference in the time to peak and terminal half-life. We conclude that there is marked interpatient and intrapatient variability in melphalan pharmacokinetics following high-dose p.o. administration. The data are consistent with saturable absorptive pathways for melphalan, which might be especially sensitive to concurrent high-dose chemotherapy.

Topics: Absorption; Administration, Oral; Adult; Bone Marrow Transplantation; Female; Food; Humans; Male; Melphalan; Middle Aged; Neoplasms; Prospective Studies

A total of 23 patients were treated at five dose escalations with high-dose combination cyclophosphamide, cisplatin, and melphalan with autologous bone marrow support. The maximum tolerated doses of cyclophosphamide, cisplatin, and melphalan were 5,625, 180, and 80 mg/m2, respectively. The dose-limiting toxicity was cardiac toxicity. Objective tumor regression occurred in 14 of 18 evaluable cases, with a median duration of 3.5 months. Pharmacokinetic evaluation of melphalan in 20 patients revealed a dose-related increase in maximum plasma concentration (Cmax) and area under the curve (AUC). Perturbation of the melphalan plasma half-life and AUC, associated with severe toxicity, resulted when renal insufficiency occurred. The results suggest that high-dose combination cyclophosphamide, cisplatin, and melphalan produces frequent, rapid responses in breast cancer, melanoma, and sarcoma, although with significant extramedullary toxicity. The pharmacokinetics suggest that modification of the treatment schedule may result in a reduction of treatment-related toxicity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasms; Sarcoma; Transplantation, Autologous

In patients who have not received extensive prior chemotherapy or radiotherapy, it has been previously demonstrated that granulocyte colony-stimulating factor (G-CSF) abrogated the leukopenia following administration of melphalan (25 mg/m2). This study examined the necessity of a prechemotherapy period of G-CSF administration and the effect of varying the timing and duration of postchemotherapy G-CSF. Initially, patients received 0.3, 1.0, 3.0, and 10 micrograms/kg/d subcutaneously on days 1 to 5 and days 10 to 18. Melphalan was given on day 9. In the next portion of the study melphalan was administered on day 1 and G-CSF, 10 micrograms/kg/d, was administered by subcutaneous infusion on five schedules: (1) days 2 to 13; (2) days 8 to 13; (3) days 2 to 18; (4) days 8 to 18; (5) days -9 to -2 and 2 to 13. G-CSF produced a rapid and sustained elevation in neutrophil levels within 24 hours even when started 8 days after melphalan. This treatment was sufficient to abrogate the neutropenia in patients who had received no prior chemotherapy. It was not necessary to continue G-CSF for more than 7 days. G-CSF did not consistently alter the course of the thrombocytopenia that followed this dose of melphalan. G-CSF was well tolerated, although mild bone pain occurred and was reduced with acetaminophen. One of 22 patients developed cellulitis at an infusion site. We conclude that after melphalan chemotherapy, G-CSF may need to be given for only a short period to prevent chemotherapy-induced neutropenia, and that G-CSF induces a rapid rise in neutrophil levels even when started 8 days after melphalan administration.

Topics: Adult; Aged; Aged, 80 and over; Agranulocytosis; Colony-Stimulating Factors; Drug Evaluation; Female; Humans; Leukocyte Count; Male; Melphalan; Middle Aged; Neoplasms; Neutropenia; Neutrophils

Previous pharmacokinetic studies of i.v. high-dose melphalan (HDM) have demonstrated large interindividual variations in the pharmacokinetic parameters. We therefore studied the possibility of using a test dose of the drug to determine the level of a subsequent therapeutic dose. This study was undertaken to establish whether the pharmacokinetics of melphalan were linear and reproducible within the same patient and determine whether a linear extrapolation could be carried out from the test dose. The first eight patients were studied on two occasions separated by 2 hours (repeatability stage). Although reasonable evidence for linear pharmacokinetics was obtained from these patients, the data suggested a number of factors that might have introduced errors. Therefore, the second group of ten patients were treated on a slightly different protocol on two occasions 24 h apart (linearity stage). The ratios of the two doses ranged from 1 to 8 (repeatability stage) and from 2.6 to 10 (linearity stage). During both stages there was a good correlation between the AUC measured for the second infusion and that predicted from the first (r = 0.929 and r = 0.943, respectively). We conclude that a test dose can be used to determine the subsequent dose of melphalan necessary to produce a desired AUC.

Topics: Adolescent; Adult; Child; Child, Preschool; Furosemide; Humans; Melphalan; Metabolic Clearance Rate; Middle Aged; Neoplasms

Topics: Antineoplastic Agents; Chlorambucil; Hodgkin Disease; Humans; Leukemia; Melphalan; Neoplasms; Risk Factors

Adding Fluosol-DA and carbogen breathing to treatment with various anticancer drugs can result in a significant enhancement of tumor growth delay compared to the drug and air breathing. The optimal conditions for tumor response depend upon the drug, oxygenation level and duration, and perfluorochemical emulsion dosage. In this study, representative chemotherapeutic agents from several classes were tested in a tumor growth delay assay in combination with various doses of Fluosol-DA under conditions of normal aeration, carbogen breathing either for 1-2 hours or 6 hours, or with hyperbaric 100% oxygen (3 atmospheres) breathing for 1 hour to determine whether the antitumor activity of these drugs would be improved.

Topics: Animals; Antineoplastic Agents; Bleomycin; Breast Neoplasms; Carbon Dioxide; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Drug Combinations; Fibrosarcoma; Fluorocarbons; Fluorouracil; Humans; Hydroxyethyl Starch Derivatives; Male; Melphalan; Methotrexate; Mice; Mice, Inbred C3H; Mice, Nude; Neoplasm Transplantation; Neoplasms; Organoplatinum Compounds; Oxygen; Tumor Cells, Cultured

Bacterially synthesised human granulocyte colony-stimulating factor (G-CSF) was administered to patients with advanced cancer. The immediate effect of G-CSF was a fall in the level of circulating neutrophils followed by a rise after 4 hours that was sustained during G-CSF administration. The rise in neutrophil level was less in patients who had been treated previously with chemotherapy and/or radiotherapy. G-CSF was also administered to patients following melphalan and this resulted in a reduction in the duration of the neutropenia that invariably follows melphalan. G-CSF was well tolerated and did not have to be stopped in any patient.

Topics: Colony-Stimulating Factors; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Humans; Melphalan; Models, Theoretical; Neoplasms; Neutrophils; Recombinant Proteins

Hematopoietic progenitor cell levels were monitored in the peripheral blood and bone marrow of 30 cancer patients receiving recombinant human granulocyte-colony stimulating-factor (rG-CSF) in a phase I/II clinical trial. The absolute number of circulating progenitor cells of granulocyte-macrophage, erythroid, and megakaryocyte lineages showed a dose-related increase up to 100-fold after four days of treatment with rG-CSF and often remained elevated two days after the cessation of therapy. The relative frequency of different types of progenitor cells in peripheral blood remained unchanged. The frequency of progenitor cells in the marrow was variable after rG-CSF treatment but in most patients was slightly decreased. The responsiveness of bone marrow progenitor cells to stimulation in vitro by rG-CSF and granulocyte-macrophage colony-stimulating factor did not change significantly during rG-CSF treatment. In patients nine days after treatment with melphalan and then rG-CSF, progenitor cell levels were very low with doses of rG-CSF at or below 10 micrograms/kg/d, but equaled or exceeded pretreatment values when 30 or 60 micrograms/kg/d of rG-CSF was given.

Topics: Bone Marrow; Cell Differentiation; Cells, Cultured; Colony-Stimulating Factors; Granulocytes; Hematopoiesis; Hematopoietic Stem Cells; Humans; Leukocyte Count; Leukocytes, Mononuclear; Macrophages; Melphalan; Neoplasms; Recombinant Proteins

A multiinstitutional Phase I study using i.v. melphalan was conducted in dogs with spontaneously occurring neoplasia. Melphalan was administered at 7.5, 10, 11.25, 12.5, and 20 mg/m2 of body surface area. Disproportionately greater toxicity was observed in small dogs. Seven of the eight dogs (88%) weighing less than 14 kg experienced severe myelosuppression (neutropenia, less than 1500/mm3; and/or thrombocytopenia, less than 80,000/mm3), whereas only three of 13 dogs (23%) weighing greater than 14 kg developed severe myelosuppression (P = 0.016). We concluded that small dogs are at greater risk of developing bone marrow toxicity from i.v. melphalan than large dogs if body surface area is used to calculate the dose. Although both body surface area and weight were found to be significantly correlated with severity of toxicity, melphalan-induced toxicity in dogs can be more accurately estimated by body weight than by surface area, P = 0.008 versus P = 0.022, respectively. It may be necessary to prescribe antineoplastic agents that are eliminated by processes not primarily under metabolic influence or that produce side effects on tissue not correlated to basal metabolic rate on a parameter other than body surface area. In dogs, melphalan should be dosed on a weight basis, and treatment groups should be stratified by weight in randomized clinical studies, particularly when the weight range of treated subjects is great.

Topics: Animals; Body Surface Area; Bone Marrow; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Female; Male; Melphalan; Neoplasms; Regression Analysis

Cisplatin and melphalan given ip exert a synergistic therapeutic effect against ascitic P388 leukemia in mice and have different dose-limiting toxic effects as well as favorable pharmacokinetic characteristics in ip phase I studies. We gave a total of 98 courses of cisplatin (escalated from 40 to 120 mg/m2) and melphalan (escalated from 12 to 30 mg/m2) to 30 patients with ip tumors, most of whom had residual ovarian cancer following iv cisplatin-containing regimens. Treatment was delivered in 2 L of 0.9% NaCl through a Tenckhoff catheter with or without a Port-a-Cath system every 28 days for one to nine cycles. Myelosuppression was dose-related and leukopenia was dose-limiting. The maximum tolerated dose was 120 mg of cisplatin/m2 and 20 mg of melphalan/m2. With the exception of treatment-induced nausea and vomiting, nonhematologic toxic effects were mild and no (or very little) local toxicity occurred. Pharmacokinetic analyses showed that the areas under the peritoneal concentration versus time curve averaged 16-fold and 17-fold more than the area under the plasma curve for cisplatin and melphalan, respectively. Objective responses were documented by third-look laparotomy in ovarian cancer patients with minimal (less than 2 cm) residual disease.

Topics: Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Evaluation; Female; Humans; Injections, Intraperitoneal; Leukemia P388; Male; Melphalan; Mice; Middle Aged; Neoplasms; Random Allocation

Topics: Antineoplastic Agents; Body Weight; Chromatography, High Pressure Liquid; Extremities; Humans; Infusion Pumps; Melphalan; Neoplasms; Regional Blood Flow

Fifty-five ovarian cancer patients treated with melphalan during 1968-1978 were followed during 309 person years and studied with cytogenetic analyses. During the clinical follow-up 7 patients developed a new primary solid tumour. The excess risk of developing new primary solid tumours in patients treated with melphalan was statistically significant (p less than 0.05) and the relative risk corresponded to 3.0. Patients developing a new solid tumour showed a similar pattern of chromosome aberrations in the peripheral lymphocytes to that previously shown for the whole cohort.

Topics: Cells, Cultured; Chromosome Aberrations; Female; Humans; Lymphocytes; Melphalan; Neoplasm Staging; Neoplasms; Ovarian Neoplasms; Sister Chromatid Exchange

A small pre-treatment 'priming' dose of cyclophosphamide will reduce gut damage due to high dose i.v. melphalan in mice and sheep but efforts to demonstrate this effect in man have been hampered by difficulty in the measurement of gut damage. We have evaluated the 51CR EDTA absorption test, a new method for measuring intestinal permeability, as a means of assessing damage due to high dose melphalan. The test was reliable, with a narrow normal range, easy to use and well tolerated. It detected an increase in intestinal permeability after high dose melphalan with a maximum occurring between 9 and 15 days after treatment and subsequently returning to normal. It was shown in 19 patients that a pre-treatment dose of cyclophosphamide was capable of significantly reducing the abnormalities in intestinal permeability which resulted from high dose melphalan.

Topics: Adult; Bone Marrow Transplantation; Chromium Radioisotopes; Cyclophosphamide; Dose-Response Relationship, Drug; Edetic Acid; Female; Humans; Intestinal Absorption; Intestinal Diseases; Intestinal Mucosa; Male; Melphalan; Middle Aged; Neoplasms; Time Factors

CFU-GEMM, multipotent progenitor cells, give rise to erythroid, granulocyte-macrophage and megakaryocytic cells. We have examined the utility of this assay for predicting hematologic recovery in patients treated with high-dose chemotherapy and autologous marrow rescue with cryopreserved marrow. In marrow samples from 50 patients CFU-E, BFU-E and CFU-GEMM significantly decreased following cryopreservation. The median value for CFU-E declined from 132,659 to 10,648, BFU-E decreased from 36,112 to 3345 and CFU-GEMM decreased from 3242 to 260 colonies per ml of marrow frozen. Once cryopreserved, the number of CFU-E, BFU-E and CFU-GEMM remained stable with prolonged storage in liquid nitrogen. In 48 patients uniformly treated with high-dose melphalan (180 mg/m2) and rescued with cryopreserved autologous marrow, univariate analyses showed that the time to platelet recovery (greater than 50 x 10(9)/l) was correlated with the number of CFU-E, BFU-E and CFU-GEMM infused (p less than 0.05). The time to neutrophil recovery was only correlated with the number of BFU-E and CFU-GEMM infused (p less than 0.01). However, by multivariate analyses, only the number of CFU-GEMM, and not CFU-E and BFU-E, infused correlated both with the time to neutrophil and platelet recovery. These data indicate that the CFU-GEMM assay may be useful for determining the repopulating ability of cryopreserved bone marrow.

Topics: Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Colony-Forming Units Assay; Erythropoiesis; Freezing; Granulocytes; Hematopoiesis; Macrophages; Megakaryocytes; Melphalan; Neoplasms; Time Factors; Tissue Preservation; Transplantation, Autologous

Fifty-nine patients received 61 courses of cyclophosphamide, cisplatin, and carmustine combined. The phase I study consisted of seven dose escalations. Dose levels 5 and 6 also included the attempted addition of melphalan at 40 and 80 mg/m2. The maximum tolerated dose for the three-drug combination was 5620 mg/m2 of cyclophosphamide, 165 mg/m2 of cisplatin, and 600 mg/m2 of carmustine. The dose-limiting toxic effect was fatal veno-occlusive disease of the liver in two of five patients treated at the highest dose level. Veno-occlusive disease of the liver was fatal in two of 40 patients treated at Dose level 4, the maximum tolerated dose. The median time to recovery of polymorphonuclear leukocyte counts to greater than 500/microliters and platelet counts to transfusion independence greater than 20,000/microliters was 19 and 22 days, respectively, after marrow reinfusion. Other toxic effects observed included postdischarge pulmonary toxicity, which appeared to respond to prednisone therapy. Thus, this combination of alkylating agents can be combined at close to the transplant dose of each individual agent. The response rate was high despite considerable prior treatment in most patients. Of 16 evaluable patients with breast cancer, 15 responded (six complete responses). Of six evaluable patients with sarcoma, six responded (one complete response). While patients with melanoma had had no prior treatment, 11 of 17 patients responded (65%). There are currently three patients who are disease-free. Two patients with melanoma were rendered disease-free by excisional biopsy of the only remaining nodule after good partial response, and a patient with metastatic breast cancer remains disease-free after a complete response at 36+ months.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Drug Evaluation; Female; Hematologic Diseases; Humans; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasms; Statistics as Topic

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Colonic Neoplasms; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Levamisole; Lung Neoplasms; Melphalan; Neoplasms; Postoperative Care; Stomach Neoplasms

Forty children with multiply relapsed cancers received iv melphalan at three doses: 30 mg/m2, 45 mg/m2, and 60 mg/m2. The hematologic toxicity was severe and protracted at all dose levels, whether or not the bone marrow was involved with tumor. Of 39 evaluable patients, 37 had grade 3 or 4 hematologic toxicity. Nonhematologic toxic effects were infrequent and not severe. Two complete responses (Hodgkin's disease, rhabdomyosarcoma), eight partial responses, and 30 failures were seen. There appeared to be a very narrow margin between efficacy and toxicity. Further study of melphalan in pediatric tumors may be warranted in special circumstances: in higher doses (greater than 100 mg/m2) as cytoreduction therapy for specific cancers with marrow rescue, or as part of combination therapy in certain cancers (eg, lymphoma, sarcoma), possibly at doses of 20 to 30 mg/m2 every 4 weeks.

Topics: Child; Dose-Response Relationship, Drug; Humans; Melphalan; Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Demecolcine; Evaluation Studies as Topic; Humans; Hyperthermia, Induced; Melphalan; Neoplasms; Radiotherapy Dosage

Cellular glutathione (GSH) levels were found to be 7-fold higher in a human lung adenocarcinoma cell line (A549) than in a normal human lung fibroblast line (CCL-210). Differential modulation of cellular GSH was explored in these cell lines by (a) stimulation of GSH synthesis by oxothiazolidine-4-carboxylate (OTZ) and (b) inhibition of GSH synthesis by buthionine sulfoximine (BSO). In the tumor cell line, OTZ treatment had no effect; however, GSH levels of 140-170% of control were achieved in the normal fibroblast line. With BSO, the normal cell line was depleted of GSH at a faster relative rate than with the tumor line. Within 7 h, 5% GSH remained in the CCL-210 line while approximately 40% GSH remained in the A549 line. Survival response of normal versus tumor cell lines to selected chemotherapy drugs was compared following modulation of GSH levels. OTZ pretreatment of the A549 line provided no protection to a 1-h exposure to melphalan, cisplatin, or bleomycin; however, OTZ pretreatment of CCL-210 elevated GSH and provided protection to melphalan, cisplatin, and bleomycin (protection ratios at 5% survival of 1.2, 1.4, and 1.4, respectively). Neocarzinostatin toxicity in the normal CCL-210 line pretreated with BSO was greatly reduced (protection ratio at 50% survival = 5.0). The same BSO treatment to A549 cells (40% GSH remaining) yielded a similar survival curve to control cells. These studies demonstrate that selective differential chemotherapy responses of normal versus tumor cells is possible by manipulating the GSH synthetic cycle. Should basic phenotypic differences with regard to reductive capacity exist in vivo, such manipulation in GSH levels might yield a therapeutic gain for carefully selected chemotherapy drugs.

Topics: Antineoplastic Agents; Bleomycin; Buthionine Sulfoximine; Cell Survival; Cells, Cultured; Cisplatin; Glutathione; Humans; Lung; Lung Neoplasms; Melphalan; Methionine Sulfoximine; Neoplasms; Pyrrolidonecarboxylic Acid; Thiazoles; Thiazolidines; Zinostatin

Several preclinical and clinical studies have documented that dose or dose intensity of chemotherapeutic agents are important factors for response of patients' tumors. This finding has prompted empiric trials of certain chemotherapeutic agents in high-dose or regional administration treatment regimens. The present study was performed to identify agents that would be particularly good candidates for high-dose or regional administration regimens against particular types of tumors. Using a human tumor cloning technique, we constructed dose in vitro response lines for ten different chemotherapeutic agents against seven different histologic types of malignancies. Slopes of the lines indicated the agents with the greatest increases of in vitro response per increment in dose of the agent. Tumors against which the agents gave the steepest dose response lines included lymphoma, head and neck cancer, ovarian cancer, and small-cell lung cancer, while the dose response lines for non-small-cell lung cancer, breast cancer, and colon cancer were quite flat. Suggestions for clinical trials based on these findings include the use of high-dose melphalan for patients with lymphoma, head and neck, and ovarian cancer; the use of mitoxantrone in high-dose regimens for patients with breast cancer; high-dose cisplatin regimens for patients with small-cell lung cancer; high-dose bleomycin regimens for patients with non-small-cell lung and head and neck cancer; and regional perfusion of liver metastases from colorectal cancer with cisplatin. Prospective testing of high-dose or regional administration regimens suggested by this new model should indicate its use for prediction of the best agent to use in high-dose regimens against a particular tumor type.

Topics: Antineoplastic Agents; Bleomycin; Cisplatin; Colony-Forming Units Assay; Dose-Response Relationship, Drug; Female; Humans; Melphalan; Mitoxantrone; Models, Biological; Neoplasms; Statistics as Topic; Tumor Stem Cell Assay

A review of the development of regional chemotherapy by perfusion is presented. Techniques have been developed for most regions of the body. Early response rates ranged from 48% for glioblastoma and 55% with carcinoma to 67% with soft tissue sarcoma and 84% with melanoma. By 1984, 1325 patients had been perfused 1509 times. The best responses have occurred with melanoma and soft tissue sarcoma of the limbs. Thus, at 10 years, the cumulative overall survival for Stage I melanoma of the limbs, combining regional perfusion and conservative excisional surgery, was 77%. The best results occurred in female patients with upper-limb disease (83%), and the poorest results were in male patients with lower-limb disease (53%). The overall 10-year survival for regional melanoma was 41%, ranging from 23% for in-transit metastases to 51% for patients with positive regional nodes treated by perfusion and regional lymph node dissection. The 10-year survival for perfusion and limb-sparing excision for soft tissue sarcoma was 65%. Advantages and complications are presented and discussed. Questions and plans for the future are reviewed.

Topics: Animals; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Costs and Cost Analysis; Extremities; Female; Humans; Lymph Node Excision; Male; Melanoma; Melphalan; Neoplasms; Sarcoma; Thiotepa

Topics: Antineoplastic Agents; Cells, Cultured; DNA, Neoplasm; Doxorubicin; Humans; Immunoglobulin G; Melphalan; Mitomycin; Mitomycins; Neoplasms

Chemotherapeutic agents are used in increasingly high dosages to treat patients with refractory cancers. An in vitro clonogenic assay was used to investigate the effects of melphalan on cultures of human neuroblastoma, Ewing's sarcoma, and osteosarcoma cells, as well as on normal bone marrow cells. A 1-hr incubation with 10(-5) M melphalan significantly inhibited tumor colony growth of both fresh neuroblastoma and osteosarcoma cells (p less than 0.01) while Ewing's sarcoma cells and normal bone marrow appeared resistant to melphalan even at a 100-fold higher concentration. Incubation with melphalan for 8 hr did not significantly increase the sensitivity of neuroblastoma and osteosarcoma or the relative resistance of Ewing's sarcoma cells; however, normal bone marrow which had remained resistant to melphalan after 1 hr of incubation, showed significant inhibition of colony growth after an 8-hr incubation with the agent. Repeated exposure to melphalan increased the degree of inhibition of both tumor and normal marrow colonies. Fresh neuroblastoma cells were significantly more sensitive than long-term cultured neuroblastoma cells at all drug doses tested. HPLC studies demonstrated that the loss of melphalan followed first-order kinetics with a half-life of 69 min, and that in addition to the 2 known breakdown products, mono- and dihydroxy-melphalan, several other peaks were present which were not attributable to the tissue culture medium or the buffer solutions.

Topics: Bone Marrow; Cells, Cultured; Chromatography, High Pressure Liquid; Humans; Melphalan; Neoplasms; Neuroblastoma; Osteosarcoma; Sarcoma, Ewing; Tumor Stem Cell Assay

We investigated if high dose melphalan and total body irradiation could be administered to adult patients with acceptable toxicity. Nineteen adult patients with relapsed disease, 15 of them having hematologic malignancies, were treated with high-dose melphalan (100 mg/m2-140 mg/m2) divided over 2 consecutive days followed by a rest period of 4 days before receiving total body irradiation, 850 rad administered in five fractionated doses over 3 days. Subsequently 11 patients received autologous, seven allogeneic and one syngeneic, bone marrow transplantation. All patients had severe myelosuppression and the major extramedullary toxicity was mucositis. There were three early deaths, two related to septicemia and one to graft-versus-host disease with associated cytomegalovirus pneumonitis. All patients were heavily pretreated, and 16 were demonstrating progressive disease on alternative salvage therapies at the time of bone marrow transplantation. Two of the 16 evaluable patients (12.5%) achieved complete remissions, and 10 (63%) achieved partial remissions for a total response rate of 75%. One patient is a long-term disease-free survivor (over 1 yr). An occasional patient may be cured by this approach. The combination of melphalan, an alternative alkylating agent to cyclophosphamide and total body irradiation are associated with moderate gastrointestinal toxicity in heavily pretreated adult patients. The combination warrants further investigation in a less heavily pretreated population to determine more accurately the complete response rate.

Topics: Adult; Bone Marrow Transplantation; Combined Modality Therapy; Female; Graft vs Host Disease; Humans; Lymphoma; Male; Melphalan; Middle Aged; Neoplasms; Platelet Count; Whole-Body Irradiation

Cytogenetic studies were carried out on peripheral lymphocytes from cancer patients at different times after therapy with melphalan. The frequency of sister chromatid exchange (SCE) was increased markedly shortly after treatment, and then declined to near pretreatment levels over a four-week period. In-vitro studies showed that the SCE frequency induced by melphalan is reduced slowly in resting G0 lymphocytes and considerably faster in mitogen-stimulated G1 cells. The results demonstrate that measurement of SCE is useful for the study of newly-induced chromosome damage in melphalan-treated cells, but is less suitable for the detection of persistent, cytogenetic alterations long after therapy. The frequency of chromosomal aberrations in a cohort of 50 patients with ovarian carcinoma was increased for up to ten years after melphalan therapy. The predominant aberrations were chromosomal translocations, marker chromosomes and cells with multiple, complex rearrangements. The frequency distribution of chromosomes involved in aberrations was studied in cells from some of the patients. An overrepresentation of chromosomes 8 and 9 was found in these cells, whereas the X chromosome was overrepresented in cells from control subjects. An increased frequency of chromosomal rearrangements was found in long-term cultures of T-lymphocytes from three of the patients, indicating that these aberrations are compatible with cell survival and proliferation. Seven patients in the cohort developed a second, primary tumour during the observation time. The frequencies and types of aberrations in these patients were similar to those of the other patients in the cohort.

Topics: Carcinoma; Cell Division; Cell Survival; Chromosome Aberrations; Chromosomes; DNA Damage; Female; Humans; In Vitro Techniques; Karyotyping; Lymphocytes; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Sister Chromatid Exchange; Thrombocytopenia; Time Factors

The glutathione (GSH) synthesis inhibitor, buthionine sulfoximine (BSO) was tested for cytotoxicity and thiol depletion in murine and human tumor cells in vitro, and for its antitumor activity and toxicity in vivo. The cell lines used in these studies included murine L-1210 leukemia, human RPMI 8226 myeloma, MCF-7 breast cancer and WiDr colon carcinoma. Soft agar colony forming assays showed that BSO was most effective at reducing tumor colony formation when exposed continuously to cells in vitro. Drug concentrations which inhibited colony formation to 50% of control levels ranged from 2.0-6.2 mM (for 1 hour exposures), 2-100 mM for 24 hour exposures and 0.4-1.40 microM (for continuous BSO exposures). Human myeloma cells proved most sensitive to BSO. In vitro cytotoxicity correlated with depletion of intracellular nonprotein sulfhydryls to less than or equal to 10% of control values in both L-1210 and 8226 cells. This was routinely achieved with prolonged exposures to mM BSO concentrations for greater than 24 hours. Normal mice tolerated high BSO doses (up to 5.0 g/kg) without evidence of acute toxicity. BSO was not active against L-1210 leukemia-bearing DBA/2 mice. When tested in vivo against MOPC-315 plasmacytoma-bearing BALB/c mice, BSO was not active at doses up to 4.0 g/kg. In contrast, the bifunctional alkylating agent melphalan (L-PAM) was active against MOPC-315 and this activity was enhanced by a 24 hour pretreatment of mice with 50 mg/kg of L-BSO.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antineoplastic Agents; Buthionine Sulfoximine; Cell Line; Cell Survival; Female; Glutathione; Humans; Male; Melphalan; Methionine Sulfoximine; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Neoplasms; Sulfhydryl Compounds

It is well-known that second primary tumours occur at elevated levels in patients undergoing cancer treatment with cytotoxic drugs. While this is clearly an undesirable outcome, it represents one of the few situations where the relationship between dose and effect of a carcinogen can be studied in humans. Current epidemiological methods for studying this relationship are described, as well as some of the issues involved in the quantification of risk from human data. Finally, the possibility of measuring biochemical markers and other parameters of DNA damage in patients undergoing treatment with antineoplastic agents is discussed.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; DNA Damage; Dose-Response Relationship, Drug; Humans; Melphalan; Neoplasms; Time Factors

Melphalan pharmacokinetics were studied in 20 children with stage IV neuroblastomas or Ewing's sarcomas and in 10 adults with AML, ALL, or small cell lung carcinomas, after IV administration of high doses (140 mg/m2 with furosemide-induced diuresis and 180 mg/m2 without induced diuresis) and high fluid intake (3000 ml/m2/day). Unchanged melphalan was assayed in plasma and cerebrospinal fluid by means of a high-performance liquid chromatographic procedure. The elimination half-life (t1/2 less than 80 min) allows autologous bone marrow transplantation 24 h after the drug administration. In some children we were able to detect melphalan in cerebrospinal fluid samples.

Topics: Adolescent; Adult; Carmustine; Child; Child, Preschool; Diuresis; Dose-Response Relationship, Drug; Furosemide; Half-Life; Humans; Kinetics; Melphalan; Middle Aged; Neoplasms; Podophyllotoxin; Procarbazine

Fifteen patients receiving oral melphalan (4.2-5.3 mg/m2) for a variety of neoplastic disorders were studied. Ten patients received the drug on separate occasions, with and without a standardized breakfast. Eight of these patients also received an IV bolus dose (5 mg/m2) to determine bioavailability. Serial melphalan plasma samples were taken over 5 h after administration and assayed by high-performance liquid chromatography. The median area under the curve (AUC) when taken fasting was 179 (range 95-336) ng X h X ml-1, and when taken with food, 122 (47-227) ng X h X ml-1, the median reduction being 39% (P less than 0.01). In one patient, who died before completing the study, the drug was not detectable at all after being taken with food. In the eight patients who were also given IV melphalan, the median terminal melphalan half-life (57 min, range 38-71) was no different from its oral half-life [55 (27-104) min fasting; 55 (30-72) min with food] (P greater than 0.1). In these patients bioavailability was 85% (26-96)% when the drug was taken fasting and 58% (7-99)% when taken with food (P less than 0.025). Median clearance following IV administration was 362 ml/min/m2 (range 104-694). It was found that the melphalan level in a single plasma sample drawn 1.5 h after administration was highly predictive of oral melphalan AUC (rs = 0.915, P less than 0.1). This study suggests that to ensure optimum absorption of the drug, melphalan should not be taken with food.

Topics: Absorption; Administration, Oral; Aged; Biological Availability; Chromatography, High Pressure Liquid; Fasting; Female; Food; Humans; Injections, Intravenous; Kinetics; Male; Melphalan; Middle Aged; Neoplasms

Twenty-nine patients were treated with single or combined high-dose melphalan therapy followed by autologous bone marrow transplantation. Hematopoietic recovery from these treatments was studied. No correlation was found between the number of GM-CFC infused and the time required for hematopoietic recovery. It is suggested that this correlation is only demonstrable for low 'doses' of infused bone marrow cell and/or GM-CFCs. The role of bone marrow cell preservation techniques was examined and results were similar for fresh and cryopreserved bone marrow. The erythrocyte, lymphocyte and granulocyte levels of the patients reported here reached a normal or subnormal hematological steady state 3 months after autograft. Our results confirm the value of cryopreservation techniques. Hematopoietic recovery was short and of the same duration whether the patients were given single or combined high-dose melphalan before autologous bone marrow transplantation. These results also demonstrate the value of such transplantation in shortening the myelosuppression caused by high-dose chemotherapy.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Cell Count; Child; Child, Preschool; Combined Modality Therapy; Erythrocyte Count; Female; Freezing; Hematopoiesis; Hematopoietic Stem Cells; Humans; Infant; Leukocyte Count; Lymphocytes; Male; Melphalan; Neoplasms

Melphalan is now being investigated as an intravenous (IV) bolus chemotherapeutic agent in children with resistant tumors involving the bone marrow. Two patients received 2 mg/kg melphalan, IV bolus; 10 patients received 1 mg/kg. Seven of the ten patients receiving 1 mg/kg had noticeable downward trends in the serum sodium concentrations, whereas both patients receiving 2 mg/kg developed hyponatremia (serum sodium concentration [SNa], mEq/l = 124-125) and inappropriate urinary sodium losses. Syndrome of inappropriate antidiuretic hormone (SiADH) is a previously unreported complication of high dose bolus melphalan therapy.

Topics: Adolescent; Child; Female; Humans; Inappropriate ADH Syndrome; Injections, Intravenous; Male; Melphalan; Neoplasms; Sodium

In human tumor cells freshly obtained from patients with breast cancer, ovarian cancer, or adenocarcinoma of unknown etiology and in normal human bone marrow cells, the cell-to-medium ratio (intracellular/extracellular concentration) in vitro of 5.42 microM melphalan rose rapidly to levels of 6-17 after 35 min at 37 degrees C in Dulbecco's phosphate-buffered saline containing bovine serum albumin and glucose. Only patient C (breast cancer) had received chemotherapy. In all cells studied, L amino acids (1 mM) such as leucine, glutamine, tyrosine, and methionine reduced the cell-to-medium ratio of melphalan at 3 and 35 min. There was a good correlation between the reduction of melphalan transport at 35 min in the heterogeneous nucleated bone marrow cell population by amino acids and their effect on melphalan cytotoxicity in the CFU-C system. Aminoisobutyric acid (A1B), a specific substrate of the A system of amino acid transport, at a concentration between 1 and 50 mM had no significant effect on melphalan uptake at 3 min in any of the human cells studied except those of patient C. At 35 min A1B (10 or 50 mM) significantly reduced the intracellular melphalan concentration in normal bone marrow cells and tumor cells from patients B and C. At 2 mM, 2-aminobicyclo-(2, 2,1)-heptane-2-carboxylic acid (BCH), a specific substrate of the L system of amino acid transport, reduced the cell-to-medium ratio to 70% of control at 3 and 35 min in human bone marrow cells. In tumor cells from patients A, B, D, and F, 2 mM BCH had no significant effect on melphalan uptake at 3 min; it slightly decreased uptake in tumor cells from patient C. At 35 min, 2 mM BCH significantly reduced melphalan transport in tumor cells from patients C and F only. The lack of a BCH-suppressible component to melphalan uptake into human tumor cells freshly obtained from previously untreated patients contrasts with the presence of this component in murine L1210 leukemia cells, murine P388 leukemia cells, and human tumor cell lines. This suggests that minor differences in melphalan transport may exist amongst species and also between human tumor cells which are freshly obtained and cell lines maintained in culture.

Topics: Adenocarcinoma; Amino Acids; Amino Acids, Cyclic; Animals; Biological Transport; Bone Marrow; Breast Neoplasms; Cell Line; Cell Survival; Chromatography, Thin Layer; Colony-Forming Units Assay; Culture Media; Female; Humans; Kinetics; Melphalan; Mice; Neoplasms

Previous studies using cultured Chinese hamster cells indicated that pretreatment of the cells with the trace elements copper, selenium, and/or zinc resulted in increased survival of the metal-induced cultures following subsequent exposure to mono- and bifunctional alkylating agents. To ascertain whether a comparable protective response could be activated in human-derived material, a series of human normal and tumor cells was treated with these trace elements and later challenged with the alkylating agent melphalan, prior to determination of the surviving fraction via colony formation. Normal human cells derived from either newborn infants or adults exhibited an increase in survival of 7- to 9-fold when pretreated with zinc alone that increased to approximately 16-fold when these normal cells were induced with all three trace elements. In contrast, comparable pretreatment of tumor cell populations resulted in an increase in survival of 1.7-fold or less, with most types of tumors exhibiting no induced protection. These observations describing a differential inducibility of normal and tumor cells raise the possibility of a novel approach for selectively sparing normal tissue in patients undergoing treatment with alkylating agents. Possible ramifications to cancer chemotherapy are discussed.

Topics: Cell Survival; Cells, Cultured; Cisplatin; Copper; Drug Resistance; Humans; Melphalan; Neoplasms; Selenium; Trace Elements; Zinc

Topics: Animals; Cell Line; Cell Survival; Cisplatin; Clone Cells; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Humans; Melphalan; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Neoplasms; Ovarian Neoplasms; Thymidine; Time Factors; Vinblastine

The human tumor colony-forming assay was used to compare chemosensitivity among tumor cells within a primary tumor, between primary tumor and metastases, and between different metastases. No significant differences in cloning efficiency were found in any of the three comparison studies. However, considerable differences in chemosensitivities were observed between different parts of the same tumor and between the primary tumor and metastases. Two different parts of the same tumor were comparably assayed for nine primary tumors. In nine paired samples which allowed in vitro drug sensitivity testing, there was no satisfactory correlation of sensitivity to cytostatic drugs. Cell suspensions were prepared from 28 primary tumors and from metastases taken from the same patient. In 14 paired samples which formed sufficient colonies for determination of drug effect, the data showed no satisfactory correlation of chemosensitivity between a primary tumor and its metastases. Both tumor samples from different metastatic sites of the same patient formed sufficient colonies in seven of eight instances. In the seven paired samples, there was strong association of chemosensitivity (p less than 0.005). The results indicate that the reported discrepancies of in vitro and in vivo results in clinical trials using the tumor colony-forming assay for predicting resistance or sensitivity to cytostatic drugs may be due to therapeutic heterogeneity among tumor colony-forming units within a primary tumor and between a primary tumor and its metastases.

Topics: Antineoplastic Agents; Bleomycin; Cell Division; Cell Survival; Cells, Cultured; Cisplatin; Doxorubicin; Fluorouracil; Humans; Kinetics; Male; Melphalan; Mitomycin; Mitomycins; Neoplasm Metastasis; Neoplasms

Since 1981 we have received 50 tumor samples from 10 different sites; over half were breast or ovary. Of the 27 that were considered suitable for cloning, 11 produced colony formation and 6 of these were drug tested. One ovarian granulosa cell tumor and its xenograft (V7) were tested against several cytotoxic agents. During a period of 16 months, sensitivity to cisplatin was relatively stable but sensitivity to vinblastine was markedly changed when the original tumor cells and original cells stored in liquid nitrogen were compared with xenograft cells. These changes may be related to patient treatments prior to tumor sample collection. This xenograft V7 exhibited chromosome karyotype and iso-enzyme Glucose-6-phosphate dehydrogenase consistent with it being of human origin. Gross histology of original tumor and xenograft were similar. Chemosensitization in vivo of a breast xenograft (Hx99) to melphalan by misonidazole was investigated. Misonidazole at a total dose of 0.5 g/kg given prior to melphalan (14 mg/kg) was an effective chemosensitizer.

Topics: Animals; Antineoplastic Agents; Bleomycin; Cisplatin; Colony-Forming Units Assay; Drug Synergism; Etoposide; Female; Granulosa Cell Tumor; Humans; Melphalan; Methotrexate; Mice; Misonidazole; Neoplasm Transplantation; Neoplasms; Ovarian Neoplasms; Transplantation, Heterologous; Tumor Stem Cell Assay; Vinblastine

High-dose melphalan followed by "rescue" with autologous marrow stored for 12-24 hours at room temperature was used in the treatment of 14 patients with advanced tumors refractory to conventional treatment. Twelve patients were evaluable, with three complete responses (25%), five partial responses (42%), and two minimal responses (16%). Response durations ranged from 4 to 38 weeks (median, 7). There were two treatment-related deaths and one patient developed acute nonlymphocytic leukemia 3 months after a second course of high-dose melphalan.

Topics: Adult; Bone Marrow Transplantation; Combined Modality Therapy; Drug Evaluation; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Neoplasms; Neutropenia

Topics: Bone Marrow Transplantation; Carmustine; Humans; Melphalan; Neoplasms; Transplantation, Autologous

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cyclophosphamide; Drug Evaluation; Etoposide; Humans; Melphalan; Neoplasms; Whole-Body Irradiation

Autologous bone marrow rescue circumvents the major toxicity of most cancer chemotherapeutic agents. Melphalan is a particularly well suited agent for use with autologous bone marrow rescue and produces response in chemo-resistant tumours. Thirteen patients have been treated with high dose melphalan with autologous bone marrow rescue in this department. The aims of treatment were palliation, debulking of non-resectable tumours and curative adjuvant therapy. Three patients died of melphalan related toxicity. Of the remaining ten patients there were five partial remissions, one objective response, one complete remission, one with no response and two patients in whom the response is not yet assessable (adjuvant therapy). In our experience high dose melphalan is an effective means of killing tumour cells which are not sensitive to chemotherapy at conventional doses. It is recommended in young patients who have not had extensive previous radio- or chemotherapy, in the early stages of disease, with cure or prolonged remission the aim. High dose melphalan is not recommended in the older patient or in those with massive diseases and is no longer used with palliative intent.

Topics: Adenocarcinoma; Adolescent; Adult; Bone Marrow Transplantation; Female; Humans; Lung Neoplasms; Male; Melphalan; Middle Aged; Neoplasms; Osteosarcoma; Pelvic Neoplasms; Teratoma

Topics: Adult; Bone Marrow Transplantation; Combined Modality Therapy; Humans; Infant; Leukemia; Male; Melphalan; Neoplasms

During a 5 year period, 64 children with advanced stage malignant solid tumours have been treated with high dose melphalan (140-220 mg/m2) combined with non-cryopreserved autologous marrow transplantation. All children developed a profound neutropenia and thrombocytopenia following high dose melphalan. Both the duration of neutropenia (median 11 d) and the duration of thrombocytopenia (median 18 d) were related to the nucleated cell count of the reinfused marrow but neither appeared to be affected by the dose of melphalan. This suggests that the initial recovery of the peripheral blood count results from the engrafted autologous marrow. We conclude that autologous marrow transplantation accelerates haemopoietic recovery in children with solid tumours treated with high dose melphalan.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Humans; Infant; Leukocyte Count; Melphalan; Neoplasms; Neutropenia; Neutrophils; Platelet Count; Thrombocytopenia; Time Factors; Transplantation, Autologous

Topics: Agar; Animals; Biopsy; Breast Neoplasms; Cell Survival; Colonic Neoplasms; Colony-Forming Units Assay; Culture Techniques; Female; Humans; Male; Melanoma; Melphalan; Mice; Neoplasms; Ovarian Neoplasms; Rectal Neoplasms; Tumor Stem Cell Assay

We administered melphalan by the intraperitoneal route to investigate its toxicity and pharmacokinetics. The drug was instilled with 2 litres of fluid and allowed to dwell in the peritoneal cavity for 4 hours. No local toxicity was detected by clinical examination, laboratory tests, or histologic examination. The intraperitoneal route allowed the dose to be increased to approximately three times the maximum dose tolerated intravenously before drug leaking into the systemic circulation produced dose-limiting myelosuppression. The peak peritoneal concentration averaged 93-fold greater than the plasma concentration, and total drug exposure for the peritoneal cavity averaged 63-fold greater than that for plasma. Tumor regressions were observed in patients with ovarian carcinoma and gastrointestinal adenocarcinomas. This study shows that from the pharmacologic point of view, if any portion of the tumor can be reached by intraperitoneal instillation, then there is a very strong rationale for the administration of melphalan by the intraperitoneal route, rather than the oral or intravenous route, for the treatment of tumors confined to the peritoneal cavity.

Topics: Adult; Aged; Ascites; Ascitic Fluid; Bone Marrow Diseases; Colonic Neoplasms; Female; Humans; Infusions, Parenteral; Kinetics; Laparotomy; Male; Melphalan; Middle Aged; Models, Biological; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Peritoneal Cavity; Stomach Neoplasms

Dissociated cancer cells are exposed to antineoplastic drugs (5 X 10(4) viable cells/drug for 1 hr or continuously) and cultured for 4 to 6 days in liquid medium. Cells are then stained with Fast green dye, sedimented onto slides with a Cytospin centrifuge, and counterstained with a modified hematoxylin and eosin technique. Dead cells stain with Fast green, and living cells stain with hematoxylin and eosin. Cell kill is calculated as percentage of control based on the relative numbers of living tumor cells, living non-tumor cells, and dead cells. Drug sensitivity could be assayed in 125 of 162 specimens of human neoplasms obtained from malignant effusions (16 of 18), excisional biopsies (31 of 44), needle biopsies (34 of 47), endoscopic biopsies (18 of 23), peripheral blood samples (19 of 20), and bone marrow aspirates (five of seven). The assays were successful (median of ten drugs tested) in: 46 of 64 adenocarcinomas; four of 11 squamous cell carcinomas; five of seven lymphomas; six of seven melanomas; two of four sarcomas; 18 of 20 transitional-cell carcinomas; 14 of 15 small-cell carcinomas; seven of eight myelomas; 12 of 12 chronic lymphocytic leukemias; seven of nine acute leukemias, and four of five "undifferentiated" carcinomas. The assay results demonstrated a strong correlation between the in vitro chemosensitivity of different types of tumors and the known clinical response patterns of these tumors. This assay can be used to determine which specific cells are killed in a heterogeneous cell population. Further work is needed to determine if this assay may be useful in blind screening trials for antineoplastic agents or if it may be of clinical use in predicting response to agents which are not cycle specific.

Topics: Antineoplastic Agents; Cell Line; Cell Survival; Doxorubicin; Drug Evaluation, Preclinical; Eosine Yellowish-(YS); Etoposide; Fluorouracil; Hematoxylin; Humans; Leukemia, Myeloid, Acute; Mechlorethamine; Melphalan; Neoplasms; Staining and Labeling

Seventeen patients were treated with high-dose melphalan with autologous bone marrow transplant (ABMT) and cyclophosphamide pretreatment. All of the patients had marrow reconstitution. Although there was one death caused by infection, high-dose melphalan with ABMT causes toxicity that is generally acceptable, and can achieve a high-response rate, but with responses of short duration in tumors resistant to standard-dose combination chemotherapy. In other poor-prognosis tumors that are sensitive to chemotherapy, or can be debulked surgically, or locally irradiated, high-dose melphalan with ABMT given as late intensification therapy may significantly prolong time to relapse, and ultimately prolong survival.

Topics: Adult; Bacterial Infections; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Male; Melphalan; Middle Aged; Myeloproliferative Disorders; Neoplasms; Prognosis; Vomiting

Tissue distribution following subcutaneous injection of liposomes containing melphalan (MPL) was studied in rats using 14C-MPL and 3H-phosphatidylcholine. Two types of liposomes, prepared by either a brief or a prolonged sonication, were compared. Brief sonication formed large liposomes of various sizes, while liposomes obtained after a prolonged sonication were small and relatively uniform in size (34 nm in mean diameter). Subcutaneous injection of small liposomes produced a strikingly high and sustained concentration of MPL equivalents in regional lymph nodes. In contrast, most liposomes prepared by a brief sonication appeared to remain at the injection site, and there was only a slight increase in the lymph node concentration of MPL equivalents over the plasma level during the 24-hour experiments.

Topics: Animals; Female; Liposomes; Lymph Nodes; Lymphatic Metastasis; Melphalan; Neoplasms; Rats; Rats, Inbred F344; Sonication; Tissue Distribution

Misonidazole (MISO), a hypoxic cell radiosensitizer, has been shown in vivo to enhance tumor cell killing by melphalan (LPAM) with little or no enhancement of normal tissue injury. A Phase I trial was conducted using MISO p.o. 2 hr before i.v. LPAM. The highest doses used were the single maximum tolerated doses of MISO, 4 g/sq m, and LPAM, 0.6 mg/kg. Thirty-five patients were entered; 30 were evaluable for assessment of hematological toxicity, which was predicted to be the dose-limiting toxicity. The median age was 60 years (range, 28 to 72 years). Mild to moderate nausea and vomiting occurred in 80% of patients. Five developed serious hematological toxicity defined as nadir white blood cell count less than 1000/cu mm, platelets less than 20,000/cu mm or 4-week posttreatment white blood cell count less than 2000/cu mm, platelets less than 50,000/cu mm. Four of the toxicities occurred at the LPAM dose of 0.6 mg/kg but were independent of MISO dose. One patient died of infection. Two patients whose tumor demonstrated an objective response to therapy and 10 others with disease stabilization received additional courses. Four patients developed mild MISO neuropathy. Pharmacokinetic studies demonstrated that MISO did not appear to affect the pharmacokinetics of LPAM in plasma. Both LPAM and MISO can be given safely at their individual maximum tolerated dose. This combination will proceed to Phase II trials.

Topics: Adult; Aged; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Misonidazole; Neoplasms; Nitroimidazoles

Topics: Animals; Cyclophosphamide; Dogs; Drug Therapy, Combination; Etanidazole; Humans; Melphalan; Mice; Misonidazole; Neoplasms; Nitroimidazoles; Oxygen; Radiation-Sensitizing Agents; Solubility

Tumour cells from 7 patients with ovarian carcinoma and from 22 different human tumour xenografts representing a wide range of histological sub-types have been examined for multicellular spheroid forming ability. Spheroid formation was limited to cells derived from xenografts. Of the 22 lines tested, 5 formed spheroids capable of growth in isolation. There was no clear relationship between histological type and spheroid-forming ability. The plating efficiency of tumour cells obtained from spheroids was always greater than for the cells obtained from the dissociated tumour of origin and was in some cases as much as 6-fold greater. Spheroid growth was nearly exponential for 4 cell lines. Volume growth delay was used to investigate the activity of melphalan, adriamycin, the Vinca alkaloids, CCNU and cisplatin. Differences between lines in drug response broadly reflected patient and in vivo xenograft response.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Aggregation; Cell Division; Cell Line; Cisplatin; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Lomustine; Lung Neoplasms; Melphalan; Mice; Neoplasm Transplantation; Neoplasms; Ovarian Neoplasms; Transplantation, Heterologous; Vinca Alkaloids

Over a period of 4 years, 241 patients with advanced cancer were treated with mecaphane alone in 11 hospitals. Effective objective responses were obtained in 100 patients (41.4%). The response was most conspicuous in chronic granulocytic leukemia, with remission in 37 of 40 patients; in Hodgkin's disease and lymphosarcoma response rates were 60% and 47.3%, respectively. Mecaphane had an analgesic action in metastatic osteolytic bone cancer, and two patients with such metastases even attained recalcification of the osteolytic destructive lesions. The common toxic manifestations of mecaphane were leukopenia (33.6%), gastrointestinal upsets (28.2%), and thrombocytopenia (12.8%). It is concluded, therefore, that mecaphane could be a good antitumor agent in clinical use. It is less expensive and can be taken orally. Further trials of this drug are recommended.

Topics: Adult; Aged; Antineoplastic Agents; Drug Evaluation; Female; Humans; Male; Melphalan; Middle Aged; Neoplasms

We have studied the disposition of bleomycin, melphalan, or vinblastine after intraperitoneal (IP) instillation in 14 cancer patients. Although IP bleomycin had a somewhat longer terminal-phase plasma half-life than after intravenous (IV) administration (5.5 vs 4.0 h, respectively), its systemic absorption averaged only 44%-52% of the administered dose. IP melphalan's mean terminal-phase half-life of 1.3 h was similar to that seen after IV drug administration. Melphalan's systemic absorption form the IP space averaged only 39% of the administered dose. In contrast, vinblastine plasma levels remained elevated for longer than 24 h after IP instillation. Its use was associated with life-threatening adynamic ileus in two patients. Bleomycin's and melphalan's reduced systemic availability after IP dosing suggests that their dose could be increased safely by a factor of two over their standard IV doses.

Topics: Adult; Aged; Biological Availability; Bleomycin; Female; Humans; Male; Melphalan; Middle Aged; Neoplasms; Vinblastine

Effect of different antitumor drugs on the hemostasis system in oncological patients is shown to have many features in common. The differences mainly consist in the degree and duration of disorders, a shift of the balance toward hyper- or hypocoagulation, which was due to drugs toxicity with relation to the chains of the hemostasis system, individual susceptibility, the state of essential thrombocytopoiesis, etc.

Topics: Antibiotics, Antineoplastic; Blood Coagulation Tests; Female; Hemostasis; Humans; Melphalan; Neoplasms; Platelet Count; Time Factors

Topics: Adult; Antineoplastic Agents; Bone Marrow; Burns; Creatine Kinase; Electroencephalography; Etoposide; Female; Humans; Hyperthermia, Induced; L-Lactate Dehydrogenase; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasms; Peripheral Nervous System Diseases; Remission, Spontaneous; Tachycardia

An approach to increasing the selectivity of cancer chemotherapeutic agents is presented in which noncytotoxic competitive substrates are used to discern the differences in structural requirements for transport of cytotoxic agents between tumor cells and a sensitive host tissue, the hematopoietic precursor cells of the bone marrow. Examples are given for two such systems, one responsible for the transport of nucleosides and another for the transport of amino acids. Cytidine is twice as effective in reducing the toxicity of showdomycin for murine bone marrow cells in culture as it is for murine L1210 leukemia cella. Conversely, homoleucine is twice as effective in reducing the toxicity of melphalan for L1210 cells as it is for bone marrow cells. These observations can serve as a basis for the development of bone marrow protective agents and for the design of cytotoxic agents that may be preferentially transported into tumor cells.

Topics: Animals; Antibiotics, Antineoplastic; Biological Transport; Bone Marrow; Leukemia L1210; Melphalan; Mice; Neoplasms; Showdomycin; Structure-Activity Relationship

The systemic availability of melphalan after oral administration is not well known. Most patients are put on a fixed oral dosage regimen. We have studied the disposition of melphalan in 14 patients after single oral doses. Five were also studied after receiving the same dose intravenously. Oral melphalan had a mean plasma terminal phase half-life (t1/2) of 90 +/- 17 min. The mean area under the plasma concentration:time curve (CXT) was 53 +/- 33 micrograms . min/ml. Urinary excretion of oral melphalan averaged 10.9 +/- 4.9% during the first 24 hr. The CXT ratio (oral:intravenous) for the 5 patients studied after both oral and intravenous melphalal (0.6 mg/kg) ranged between 0.25 and 0.89 and averaged 0.56. After oral dosing in 14 fasting patients, the time at which melphalan first appeared in the plasma varied between 15 min and 6 hr. In a myeloma patient who took oral melphalan, no melphalan was found in plasma or urine up to 24 hr. Some instances of failure of tumor response to oral melphalan may be due to inadequate bioavailability rather than inherent tumor resistance.

Topics: Administration, Oral; Adult; Aged; Biological Availability; Female; Half-Life; Humans; Injections, Intravenous; Kinetics; Male; Melphalan; Middle Aged; Neoplasms

Topics: Animals; Antineoplastic Agents; Melphalan; Mice; Neoplasms; Nitrogen Mustard Compounds; Phenylalanine

New concepts and treatments currently available for adjuvant studies are illustrated by a review of ongoing studies sponsored by the National Cancer Institute. More thorough information is needed on immunotherapeutic agents to allow more rationale in the use of these agents. Solid bases to properly select drugs or drug combinations for adjuvant purposes are being established. However, dose-schedule and duration of treatment are still to be defined. Strategies directed at prolonging the benefit of surgical adjuvant chemotherapy remain to be planned. Progress continuously achieved with immunotherapy and chemotherapy should rapidly broaden the spectrum of tumour types to be included in adjuvant studies.

Topics: Antineoplastic Agents; Breast Neoplasms; Cisplatin; Colonic Neoplasms; Cyclophosphamide; Dianhydrogalactitol; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lung Neoplasms; Male; Melphalan; Methotrexate; Neoplasms; Osteosarcoma; Rectal Neoplasms

Topics: Humans; Melphalan; Multiple Myeloma; Neoplasms

The toxicity of Melphalan to murine bone marrow was assessed by automated Coulter counts of femoral marrow nucleated cells. A significant dose-response slope (p less than 0.001) was shown and also a significant variation along the 24 h scale. With food available ad libitum and light from 06.00 to 18.00 hours, the minimum marrow depression occurred around 16.00 hours. Extrapolating these findings to human chemotherapy it would appear that prescription of the drug during the early part of the activity span (usually breakfast) will minimize marrow depression. This differs from a human study in which Melphalan was given at 'bedtime' as an adjuvant to mastectomy in breast carcinoma and in which there was leucopenia at some stage of treatment in all 103 patients. It is recommended that in future cancer therapy protocols test for circadian variability of white cell depression by varying treatment times systematically along the 24 h scale.

Topics: Animals; Bone Marrow; Bone Marrow Cells; Cell Count; Circadian Rhythm; Dose-Response Relationship, Drug; Femur; Male; Melphalan; Mice; Neoplasms; Time Factors

Assays that assess the ability of cells to incorporate labeled precursors into acid-precipitable material in the presence of adriamycin, daunorubicin, puromycin, vinblastine, melphalan, or methotrexate were investigated as an approach to the detection of resistant cells in human tumor samples. Each assay was evaluated with suitable drug-resistant Chinese hamster ovary cell lines and normal human fibroblasts to determine whether the assays reflected the drug sensitivity of these lines. Moreover, the ability to detect the presence of drug-resistance cells in a mixed population was evaluated. Validated assays were then used to measure the drug sensitivity of cell samples from pleural and peritoneal effusions of patients, mainly with carcinoma of the breast or ovary. Though the responsiveness of the majority of the samples in these assays was similar to that of a human fetal lung fibroblast line, 37 of 142 samples displayed responses consistent with the presence of a significant proportion of drug-resistant cells. Of these 37 nonresponsive samples, 12 displayed nonresponsiveness to three drugs.

Topics: Antineoplastic Agents; Ascitic Fluid; Cell Division; Cell Line; Daunorubicin; DNA, Neoplasm; Doxorubicin; Drug Evaluation, Preclinical; Drug Resistance; Humans; In Vitro Techniques; Melphalan; Methotrexate; Neoplasms; Phenotype; Pleural Effusion; Puromycin; RNA, Neoplasm; Vinblastine

Asaley is an L-leucine derivative of sarcolysin which is more active against some rodent tumors. Studies in the USSR demonstrated activity in patients with ovarian and breast carcinoma, Hodgkin's disease, and multiple myeloma. This study in 73 evaluable patients indicated that an appropriate oral dose for patients with adequate bone marrow is 800 mg/M2/day X 4 days at 5-6 week intervals. The most common toxicities were myelosuppression, nausea, and vomiting. Antitumor activity was observed in 2 of 24 evaluable patients with melanoma, and stabilization of previously progressive disease was observed in patients with adenocarcinoma of the colon, multiple myeloma, lymphoma, breast carcinoma, and thyroid carcinoma. Responses were minimal and of short duration but most of the patients had received extensive prior therapy.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Animals; Bone Marrow; Colonic Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Multiple Myeloma; Nausea; Neoplasm Metastasis; Neoplasms; Rats; Remission, Spontaneous; Vomiting

Topics: Antineoplastic Agents; Bleomycin; Busulfan; Humans; Male; Melphalan; Methotrexate; Middle Aged; Neoplasms; Pulmonary Fibrosis

Topics: Asparaginase; Child; Cyclophosphamide; Cytosine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Hodgkin Disease; Humans; Infant; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Melphalan; Mercaptopurine; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Osteosarcoma; Prednisone; Procarbazine; Prognosis; Remission, Spontaneous; Rhabdomyosarcoma; Teniposide; Thioguanine; Vincristine; Wilms Tumor

Histidine-requiring mutants of Salmonella typhimurium that can be reverted to prototrophy by a variety of mutagens were used mutagenic activity in the urine of patients receiving chemotherapeutic agents. Patients given cyclophosphamide and BCNU had detectable urinary mutagenic activity over a 24-hour period, with maximal levels occurring 12 to 21 hours after drug injection. Whereas native cyclophosphamide required the presence of a rat liver extract to be mutagenic in the test system, the cyclophosphamide metabolites in the urine were fully active in the absence of added liver extract. Mutagenic activity was detected in only the first voided urine specimen of patients receiving fluorouracil. Patients receiving Adriamycin, methotrexate, Mitomycin C, and low doses or oral melphalan did not have detectable mutagenic activity in their urines. One thousand and ten random urine speciments were screened for mutagenic activity. Only eight had greater than 26 revertant colonies per plate. Four of the eight had received metronidazole (Flagyl) for vaginitis while two others had received chemotherapeutic drugs. We were unable to detect increased mutagenic metabolites in the urine of 43 patients with known malignancies, using the standard assay conditions.

Topics: Antineoplastic Agents; Biological Assay; Cyclophosphamide; Ethylnitrosourea; Fluorouracil; Humans; Mechlorethamine; Melphalan; Metronidazole; Mitomycins; Mutagens; Neoplasms; Salmonella typhimurium

Acute myelocytic leukemia occurring many years after intensive radiotherapy and/or chemotherapy has been reported in 82 patients with Hodgkin's disease, 58 patients with multiple myeloma, and 40 patients with chronic lymphocytic leukemia. The precise incidence of this occurrence is uncertain, since the total number of patients at risk is unknown. Most patients with Hodgkin's disease had received intensive radiation therapy. Many also received chemotherapy. One-third of the patients with myeloma were treated only with melphalan. Acute leukemia may occur as part of the natural history of Hodgkin's disease and multiple myeloma; it has been seen with increasing frequency in recent years due to improved survival secondary to better treatment. It is also possible that radiotherapy and/or chemotherapy may be causally related to the development of acute leukemia.

Topics: Antineoplastic Agents; Hodgkin Disease; Humans; Leukemia, Lymphoid; Melphalan; Multiple Myeloma; Neoplasms; Radiotherapy

Immunological function was studied in 48 patients before, during and after cancer treatment, using cutaneous tests, spontaneous rosettes test and the PHA and PWM lymphocyte stimulation tests. Chemotherapeutic drugs were used individually or in combination for 5 days a month and were preceeded by a cellular synchronization using Vincristine (1 mg/m2/day). When treatment was discontinued, we observed in 30 patients increased rates of spontaneous rosettes and of thymidine uptake. We noticed in several cases that the cutaneous tests became positive even if they were negative before and during treatment. The I.O.P. appeared 5 days after chemotherapy was discontinued and lasted 8 to 12 days. The topography of the neoplasm had no influence on the I.O.P. Failure to manifest I.O.P. is not indicative of a negative response of the tumor to chemotherapy (9 positive responses to chemotherapy out of 18 patients without I.O.P.) But the I.O.P. was a fairly constant feature in patients with positive response to chemotherapy and with favorable prognosis (28/30).

Topics: Breast Neoplasms; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Immune Adherence Reaction; Liver Neoplasms; Lung Neoplasms; Lymphocyte Activation; Melphalan; Methotrexate; Neoplasms; Ovarian Neoplasms; Thiotepa; Vincristine

Topics: Antineoplastic Agents; Breast Neoplasms; Busulfan; Carcinogens; Cyclophosphamide; Humans; Leukemia, Myeloid; Lung Neoplasms; Melphalan; Methotrexate; Neoplasms; Pancreatic Neoplasms; Rectal Neoplasms; Triaziquone; Urinary Bladder Neoplasms

Topics: Adenine Nucleotides; Adenosine Diphosphate; Amidines; Antibiotics, Antineoplastic; Bleomycin; Blood Platelets; Breast Neoplasms; Bronchial Neoplasms; Cyclophosphamide; Doxorubicin; Firefly Luciferin; Fluorouracil; Glyoxal; Hodgkin Disease; Humans; Hydrazones; Leukemia; Luciferases; Lymphocytes; Melphalan; Methotrexate; Neoplasms; Nephelometry and Turbidimetry; Plasmacytoma; Platelet Aggregation; Vinca Alkaloids

Topics: Adult; Antibody Formation; Bone Marrow; Cell Division; Chromosome Aberrations; Female; Fluorouracil; Humans; Immunity, Cellular; Male; Melphalan; Methotrexate; Middle Aged; Mitosis; Neoplasms; Thiotepa

Topics: Blood; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Hyperthermia, Induced; Melphalan; Neoplasms; Thiotepa

Topics: Antineoplastic Agents; Busulfan; Chlorambucil; Cyclophosphamide; Cytarabine; Daunorubicin; Education, Medical, Continuing; Fluorouracil; Humans; Melphalan; Mercaptopurine; Methotrexate; Neoplasms; Procarbazine; Triaziquone; Vinblastine; Vincristine

Topics: Adolescent; Adult; Chemotherapy, Cancer, Regional Perfusion; Diathermy; Electric Stimulation Therapy; Female; Histocytochemistry; Hot Temperature; Humans; Male; Melphalan; Neoplasms; Thiotepa

Topics: Antineoplastic Agents; Cyclophosphamide; Female; Humans; Male; Melphalan; Neoplasms; Radiotherapy Dosage; Thiotepa; Tungsten

Topics: Animals; Benzyl Compounds; Brain; DDT; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; Kinetics; Leukemia; Liver; Lung Neoplasms; Lymphocytes; Mathematics; Melphalan; Mercaptopurine; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Nitrosourea Compounds; Rats; Thiotepa; Time Factors

Topics: Adult; Antineoplastic Agents; Cell Survival; Cyclophosphamide; Depression, Chemical; Etiocholanolone; Female; Fluorouracil; Humans; Injections, Intramuscular; Leukocyte Count; Leukocytes; Leukopenia; Male; Melphalan; Neoplasms; Stimulation, Chemical

Topics: Antineoplastic Agents; Biological Assay; Biopsy; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Male; Melphalan; Methotrexate; Neoplasms; Organ Culture Techniques; Triaziquone; Vinblastine; Vincristine

Topics: Burns; Chemotherapy, Cancer, Regional Perfusion; Edema; Extremities; Fasciotomy; Humans; Melphalan; Muscular Diseases; Neoplasms; Paralysis; Peripheral Nervous System Diseases; Temperature

Topics: Antineoplastic Agents; Cell Survival; Cyclophosphamide; Fluorouracil; Humans; Melphalan; Multiple Myeloma; Myeloma Proteins; Neoplasms; Time Factors

Topics: Adult; Alkaline Phosphatase; Bone Diseases; Chemistry, Clinical; Chloramphenicol; Fenclonine; Humans; Liver Diseases; Melphalan; Neoplasms; Phenylalanine; Phenylketonurias; Stereoisomerism

Topics: Adolescent; Aged; Bone Neoplasms; Female; Hemangiosarcoma; Hodgkin Disease; Humans; Leukopenia; Lymphoma, Large B-Cell, Diffuse; Male; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Sarcoma, Ewing; Testicular Neoplasms; Thrombocytopenia; Tonsillar Neoplasms; Uterine Neoplasms

Topics: Antineoplastic Agents; Azathioprine; Chlorambucil; Cyclophosphamide; Hair; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Melphalan; Mercaptopurine; Methotrexate; Neoplasms; Scleroderma, Systemic; Skin Diseases; Vinblastine

Topics: Animals; Antineoplastic Agents; Cell Line; Culture Media; Culture Techniques; Dactinomycin; Female; Floxuridine; Glyceraldehyde; Hexoses; Hot Temperature; Leukemia L1210; Melphalan; Mice; Neoplasms; Oxalates; Sodium; Vinblastine

Topics: Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melanoma; Melphalan; Neoplasms; Osteosarcoma; Skin Neoplasms; Thiotepa

Topics: Adolescent; Adult; Aged; Anemia; Cardiomyopathies; Chemotherapy, Cancer, Regional Perfusion; Child; Cyclophosphamide; Electrocardiography; Humans; Leg; Leukopenia; Melphalan; Middle Aged; Neoplasms; Tachycardia; Thiotepa; Vascular Diseases

Topics: Alkylating Agents; Animals; Benzopyrenes; Carcinoma 256, Walker; Carcinoma, Hepatocellular; Female; Fibrosarcoma; Hematopoietic System; Kidney; Leukemia L1210; Liver; Liver Neoplasms; Male; Melphalan; Mice; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds; Plasmacytoma; Rats; Sarcoma, Experimental; Sarcoma, Yoshida

Topics: Antineoplastic Agents; Bone Marrow Transplantation; Chemotherapy, Cancer, Regional Perfusion; Cyclophosphamide; Hematopoiesis; Humans; Melphalan; Neoplasms; Tissue Preservation; Transplantation, Autologous

Topics: Anemia, Hemolytic; Blood Protein Disorders; Chlorambucil; Cryoglobulins; Cyclophosphamide; Diagnosis, Differential; Heavy Chain Disease; Humans; Melphalan; Neoplasms; Plasmacytoma; Waldenstrom Macroglobulinemia

Topics: Adult; Animals; Cell- and Tissue-Based Therapy; Female; Humans; Immunosuppressive Agents; Lymph Nodes; Lymphocyte Transfusion; Lymphocytes; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasms; Skin Neoplasms; Spleen; Swine; Transplantation, Heterologous; Transplantation, Homologous

Topics: Adenocarcinoma; Antineoplastic Agents; Chlorambucil; Colchicine; Culture Techniques; Cyclophosphamide; Dactinomycin; Female; Floxuridine; Fluorouracil; Hodgkin Disease; Humans; Melphalan; Mercaptopurine; Methotrexate; Nandrolone; Neoplasms; Nitrogen Mustard Compounds; Norethindrone; Prednisolone; Progesterone; Testosterone; Thiotepa; Uterine Neoplasms; Vinblastine

Topics: Antineoplastic Agents; Bone Marrow Transplantation; Female; Humans; Infusions, Parenteral; Male; Melphalan; Neoplasms; Perfusion; Transplantation, Autologous

Topics: Extracorporeal Circulation; Extremities; Hematologic Diseases; Humans; Melphalan; Neoplasms; Perfusion; Regional Blood Flow; Thiotepa

Topics: Antineoplastic Agents; Humans; Melphalan; Neoplasms

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Scirrhous; Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Squamous Cell; Culture Techniques; Flavonoids; Fluorouracil; HeLa Cells; Humans; Lung Neoplasms; Melphalan; Mercaptopurine; Methods; Mitomycins; Neoplasms; Rectal Neoplasms; Stomach Neoplasms

Topics: Adenocarcinoma; Aged; Breast Neoplasms; Colonic Neoplasms; Cyclophosphamide; Female; Hodgkin Disease; Humans; Intestinal Neoplasms; Liver Neoplasms; Male; Melphalan; Middle Aged; Neoplasms; Palliative Care; Stomach Neoplasms; Thiotepa

Topics: Adolescent; Adult; Aged; Bone Marrow; Child; Cyclophosphamide; Extremities; Female; Hematopoiesis; Humans; Male; Melphalan; Middle Aged; Neoplasms; Thiotepa; Thromboangiitis Obliterans

Topics: Adult; Alkylating Agents; Antimetabolites; Antineoplastic Agents; Dactinomycin; Female; Fluorouracil; Hodgkin Disease; Humans; Lung Neoplasms; Male; Melphalan; Methotrexate; Middle Aged; Neoplasms; Phytotherapy; Plants, Medicinal; Plants, Toxic; Podophyllum; Radiography; Sarcoma, Ewing; Thiotepa; Vincristine

Topics: Animals; Antineoplastic Agents; HeLa Cells; Histocytochemistry; Humans; Melphalan; Microscopy, Electron; Neoplasms; Rats; Sarcoma, Yoshida

Topics: Aged; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Female; Hand; Humans; Leg; Male; Melphalan; Neoplasms

Objective improvement after therapy with melphalan occurred in all patients producing only Bence Jones kappa proteins, in half of the patients with myeloma serum proteins, and in none of those producing only Bence Jones lambda proteins.

Topics: Bence Jones Protein; Blood Proteins; Drug Therapy; Humans; Leukopenia; Melphalan; Multiple Myeloma; Myeloma Proteins; Neoplasms; Prognosis; Toxicology

Topics: Alkylating Agents; Antineoplastic Agents; Carcinogens; Carcinoma; Chlorambucil; Cyclophosphamide; Dogs; Melphalan; Methotrexate; Naphthalenes; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds; Pharmacology; Research; Toxicology; Urinary Bladder Neoplasms

Topics: Animals; Bone Marrow; Carcinoma 256, Walker; Chromatography; DNA; Intestines; Kidney; Liver; Melphalan; Metabolism; Muscles; Mustard Plant; Neoplasms; Pharmacology; Phenylalanine; Plasma; Rats; Research; Spleen; Thymus Gland; Tritium; Tyrosine

Topics: Blood; Blood Cells; Carbon Isotopes; Carcinoma, Krebs 2; Chromatography; Intestinal Absorption; Melphalan; Metabolism; Mice; Neoplasms; Physiology; Radiometry; Rats; Research; Sarcoma; Sarcoma, Yoshida; Toxicology; Urine

Topics: Animals; Antineoplastic Agents; Melphalan; Neoplasms; Neoplasms, Experimental; Peptides; Pharmacology; Research

Topics: Blood; Cell Nucleus; Chemotherapy, Cancer, Regional Perfusion; Cytoplasm; Drug Therapy; Humans; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Thiotepa

Topics: Beta-Globulins; Blood Protein Disorders; Blood Protein Electrophoresis; Clavicle; Drug Therapy; gamma-Globulins; Geriatrics; Immunoglobulin G; Melphalan; Multiple Myeloma; Myelography; Neoplasms; Radiography; Spinal Neoplasms

Topics: Animals; Antineoplastic Agents; Melphalan; Neoplasms; Neoplasms, Experimental; Pharmacology; Rats; Research; Sarcoma; Sarcoma, Yoshida

Topics: Child; Humans; Melphalan; Mustard Plant; Neoplasms; Phenylalanine; Toxicology

Topics: Adolescent; Antineoplastic Agents; Busulfan; Child; Cyclophosphamide; Drug Therapy; Humans; Infant; Leukemia; Leukemia, Myeloid; Melphalan; Mercaptopurine; Multiple Myeloma; Neoplasms; Phosphorus Isotopes; Prednisone

Topics: Humans; Melphalan; Neoplasms; Tetracycline

Topics: Antineoplastic Agents; Cyclophosphamide; Humans; Melphalan; Neoplasms

Topics: Alkylating Agents; Anti-Bacterial Agents; Antineoplastic Agents; Black People; Chemotherapy, Cancer, Regional Perfusion; Child; Chlorambucil; Cyclophosphamide; Dactinomycin; Dermatologic Agents; DNA; DNA, Neoplasm; Fluorouracil; Geriatrics; Humans; Mechlorethamine; Melphalan; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Pharmacology; Thiotepa; Toxicology; Triethylenemelamine; Vinblastine; Vincristine

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Mechlorethamine; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasms; Postoperative Complications; Surgical Procedures, Operative; Thiotepa; Toxicology; Wound Healing

Topics: Abdominal Neoplasms; Angiography; Breast Neoplasms; Geriatrics; Gold; Humans; Injections; Iodine Isotopes; Leukemia; Lymphatic Metastasis; Lymphatic System; Lymphography; Lymphoma; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Methotrexate; Neoplasms; Radioisotopes; Radionuclide Imaging; Retroperitoneal Neoplasms; Scandium; Thiotepa; Yttrium

Topics: Blood Flow Velocity; Body Temperature; Cardiac Surgical Procedures; Chemotherapy, Cancer, Regional Perfusion; Cold Temperature; Dogs; Electric Countershock; Electrocardiography; Femoral Artery; Heart, Artificial; Hypothermia; Hypothermia, Induced; Jugular Veins; Mechlorethamine; Melphalan; Neoplasms; Neurosurgery; Perfusion; Research; Thiotepa; Thoracic Surgery; Thoracotomy; Ventricular Fibrillation

Topics: Female; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Melphalan; Multiple Myeloma; Neoplasms; Osteosarcoma; Ovarian Neoplasms; Research; Sarcoma; Sarcoma, Ewing; Testicular Neoplasms; Thymoma

Topics: Blood Chemical Analysis; Blood Platelets; Blood Proteins; Blood Sedimentation; Calcium; Hemoglobinometry; Humans; Leukocyte Count; Melphalan; Multiple Myeloma; Neoplasms; Prognosis; Proteinuria; Toxicology

Topics: Animals; Carcinoma 256, Walker; DNA; DNA, Neoplasm; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Phosphorus Isotopes; Rats; Research; RNA; RNA, Neoplasm; Sarcoma; Sarcoma, Yoshida; Tissue Culture Techniques

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; Fluorouracil; Leukemia; Leukemia, Experimental; Melphalan; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Oncogenic Viruses; Pharmacology; Research; Triethylenemelamine

Topics: Antineoplastic Agents; Cricetinae; Cyclophosphamide; Dactinomycin; Melphalan; Mice; Mitomycin; Mitomycins; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Pharmacology; Research; Sarcoma; Sarcoma, Experimental; Thiotepa

Topics: Alkaloids; Antineoplastic Agents; Ascites; Cyclophosphamide; Electrons; Lymphoma; Mannomustine; Melphalan; Mice; Microscopy; Microscopy, Electron; Neoplasms; Neoplasms, Experimental; Pharmacology; Research

Topics: Breast Neoplasms; Carcinoma, Bronchogenic; Dysgerminoma; Female; Gastrointestinal Neoplasms; Hodgkin Disease; Humans; Liver Neoplasms; Lymphoma; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Multiple Myeloma; Neoplasms; Ovarian Neoplasms; Sarcoma

Topics: Choriocarcinoma; Dysgerminoma; Female; Humans; Male; Melphalan; Neoplasms; Ovarian Neoplasms; Pregnancy; Teratoma; Testicular Neoplasms

Topics: Albuminuria; Blood Protein Electrophoresis; Humans; Leukocyte Disorders; Leukopenia; Mechlorethamine; Melphalan; Multiple Myeloma; Neoplasms; Thrombocytopenia

Topics: Humans; Melphalan; Multiple Myeloma; Neoplasms

Topics: Antineoplastic Agents; Humans; Male; Melphalan; Neoplasm Regression, Spontaneous; Neoplasms; Research; USSR

Topics: Breast Neoplasms; Dysgerminoma; Female; Follicle Stimulating Hormone; Hexestrol; Humans; Melphalan; Neoplasms; Ovarian Follicle; Ovarian Neoplasms; Pharmacology; Pituitary Diseases; Pituitary Gland; Progesterone; Rats; Research; Thiotepa

Topics: Antineoplastic Agents; Colchicine; Cyclophosphamide; Mannomustine; Melphalan; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Podophyllum; Research; Skin Neoplasms

Topics: Chemotherapy, Cancer, Regional Perfusion; Extracorporeal Circulation; Lymphatic Metastasis; Melanoma; Melphalan; Mice; Mustard Plant; Neoplasms; Neoplasms, Experimental; Pharmacology; Phenylalanine; Research

Topics: Chemotherapy, Cancer, Regional Perfusion; Heart, Artificial; Mechlorethamine; Melphalan; Neoplasms; Perfusion; Thiotepa

Topics: Adolescent; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Child; Chondrosarcoma; Dogs; Femur; Fibula; Hemangiosarcoma; Humans; Melanoma; Melphalan; Mesenchymoma; Neoplasms; Nitrogen Mustard Compounds; Osteosarcoma; Sarcoma; Sarcoma, Ewing; Ulna; Uracil

Topics: Abdomen; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Cyclophosphamide; Female; Geriatrics; Hodgkin Disease; Humans; Hypothermia; Hypothermia, Induced; Leiomyosarcoma; Mechlorethamine; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Pelvis; Rectal Neoplasms; Retroperitoneal Neoplasms; Uterine Cervical Neoplasms; Vaginal Neoplasms

Topics: Aorta; Aorta, Abdominal; Bone Neoplasms; Carotid Arteries; Chemotherapy, Cancer, Regional Perfusion; Chondrosarcoma; Dactinomycin; Dogs; Fibrosarcoma; Iliac Artery; Iliac Vein; Leiomyosarcoma; Liposarcoma; Lymphoma, Non-Hodgkin; Melphalan; Mesothelioma; Neoplasms; Neuroblastoma; Osteosarcoma; Rhabdomyosarcoma; Sarcoma; Sarcoma, Kaposi; Subclavian Artery; Vena Cava, Inferior

Topics: Aziridines; Breast Neoplasms; Cyclophosphamide; Female; Humans; Melphalan; Neoplasms; Ovarian Neoplasms; Surgical Procedures, Operative; Thiotepa; Triethylenemelamine

Topics: Adenine; Bone Marrow Transplantation; Breast Neoplasms; DNA; Female; Folic Acid; Humans; Lung Neoplasms; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Neoplasms; Ovarian Neoplasms; Perfusion; Sarcoma; Thiotepa; Triethylenemelamine

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Brain Neoplasms; Cyclophosphamide; Dactinomycin; Ependymoma; Mannitol; Melphalan; Mice; Neoplasms; Neoplasms, Experimental; Neuroectodermal Tumors, Primitive; Pharmacology; Research; Toxicology

Topics: Geriatrics; Hodgkin Disease; Iatrogenic Disease; Leukopenia; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Neoplasms; Radiography, Thoracic; Sarcoma; Thrombocytopenia; Toxicology

Topics: Adolescent; Alkylating Agents; Antineoplastic Agents; Aziridines; Black People; Burkitt Lymphoma; Child; Cyclophosphamide; Dactinomycin; Epidemiology; Humans; Kenya; Lymphoma; Mandibular Neoplasms; Maxillary Neoplasms; Melphalan; Neoplasms; Oncogenic Viruses

Topics: Antineoplastic Agents; Biological Assay; Biopsy; Humans; Melphalan; Methotrexate; Myxosarcoma; Neoplasms; Nucleic Acids; Organ Culture Techniques; Phosphates; Phosphorus Isotopes; Silicones; Tissue Culture Techniques

Topics: Humans; Melphalan; Multiple Myeloma; Neoplasms; Plasmacytoma

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Carcinoma; Drug Therapy; Humans; Kidney Neoplasms; Kidney Pelvis; Melphalan; Neoplasms; Nephrectomy

Topics: Animals; Antineoplastic Agents; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Carcinoma, Krebs 2; Feeding and Eating Disorders; Leukopenia; Melanoma; Melphalan; Neoplasms; Neoplasms, Experimental; Pharmacology; Research; Sarcoma; Sarcoma, Experimental

Topics: Carbon Dioxide; Carbon Isotopes; Feces; Melphalan; Metabolism; Neoplasms; Neoplasms, Experimental; Pharmacology; Radiometry; Research; Urine

Topics: Animals; Blood Protein Electrophoresis; Busulfan; Cyclophosphamide; Freund's Adjuvant; gamma-Globulins; Melphalan; Mice; Multiple Myeloma; Neoplasm Proteins; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds; Pharmacology; Plasmacytoma; Proteinuria; Research; Staphylococcal Infections

Topics: Bone Neoplasms; Elbow; Giant Cell Tumor of Bone; Giant Cell Tumors; Melphalan; Neoplasms; Neoplasms, Radiation-Induced; Pathology; Radiography; Sarcoma

Topics: Carotid Arteries; Chemotherapy, Cancer, Regional Perfusion; Facial Neoplasms; Humans; Lip Neoplasms; Mandibular Neoplasms; Maxillary Neoplasms; Melphalan; Mouth Neoplasms; Neoplasms; Parotid Neoplasms; Thiotepa; Tongue Neoplasms

Topics: Chemotherapy, Cancer, Regional Perfusion; Coccidioidomycosis; Dactinomycin; Drug Hypersensitivity; Drug Therapy; Hematologic Diseases; Humans; Melanoma; Melphalan; Mycetoma; Neoplasms; Sarcoma; Sepsis; Toxicology

Topics: Bone Neoplasms; Cobalt Isotopes; Dactinomycin; Drug Therapy; Humans; Mandible; Mandibular Neoplasms; Melphalan; Methotrexate; Neoplasms; Osteomyelitis; Osteosarcoma; Pathology; Radiography; Radium; Sarcoma

Topics: Blood Cell Count; Blood Protein Electrophoresis; Blood Sedimentation; Bone Marrow Examination; Calcium; Drug Therapy; Electrophoresis; Geriatrics; Hemoglobinometry; Hemorrhagic Disorders; Humans; Hypercalcemia; Immunoelectrophoresis; Kidney Function Tests; Melphalan; Multiple Myeloma; Neoplasms; Radiography; Urethane; Urine

Topics: Blood Protein Disorders; Blood Protein Electrophoresis; Cyclophosphamide; Drug Therapy; gamma-Globulins; Geriatrics; Hospitals, General; Humans; Leukemia; Leukemia, Lymphoid; Lymphocytes; Melphalan; Multiple Myeloma; Myeloma Proteins; Neoplasms; Vascular Diseases; Waldenstrom Macroglobulinemia

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Drug Therapy; Hodgkin Disease; Lymphatic System; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mannomustine; Melphalan; Neoplasms; Piperazines; Sarcoma

Topics: DNA; DNA, Neoplasm; Genetics; Melphalan; Neoplasms; Nucleoproteins; Rats; Research; RNA; RNA, Neoplasm; Sarcoma; Sarcoma, Experimental

Topics: Combined Modality Therapy; Drug Therapy; Melphalan; Multiple Myeloma; Neoplasms; Phosphorus; Phosphorus Isotopes; Phosphorus, Dietary; Radioactivity

Topics: Brain; Leukopenia; Melphalan; Mice; Neoplasms; Pharmacology; Rabbits; Rats; Research; Sarcoma; Sarcoma, Experimental; Tissue Extracts

Topics: Administration, Oral; Antineoplastic Agents; Demecolcine; Drug Synergism; Esophagus; Gastrointestinal Neoplasms; Geriatrics; Humans; Melphalan; Neoplasms; Palliative Care; Rectum; Stomach Neoplasms

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melphalan; Neoplasms

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Hematopoiesis; Melphalan; Neoplasms; Neoplasms, Experimental; Olivomycins; Research

Topics: Antineoplastic Agents; Melphalan; Neoplasms; Neoplasms, Experimental; Pharmacology; Phenylalanine; Rats; Research; Toxicology

Topics: Antineoplastic Agents; Dactinomycin; Humans; Melphalan; Neoplasms; Perfusion; Sarcoma

Topics: Cobalt; Cobalt Isotopes; Etoposide; Melphalan; Neoplasms

Topics: Benz(a)Anthracenes; Cellophane; Connective Tissue; Melphalan; Neoplasms; Neoplasms, Connective Tissue; Pharmacology; Rats; Research; Sarcoma; Sarcoma, Experimental; Toxicology; Urethane

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Antineoplastic Agents; Aziridines; Bone Marrow Transplantation; Colchicine; Cyclophosphamide; Dactinomycin; Hodgkin Disease; Mechlorethamine; Melphalan; Neoplasms; Radioisotopes; Radiotherapy, High-Energy; Triethylenemelamine; Vinblastine

Topics: Carcinogens; Carcinoma, Hepatocellular; Hepatectomy; Liver Neoplasms; Melphalan; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Research; Skin Neoplasms; Tissue Culture Techniques

Topics: Adolescent; Child; Geriatrics; Head and Neck Neoplasms; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mandibular Neoplasms; Maxillary Neoplasms; Melanoma; Melphalan; Multiple Myeloma; Neoplasms; Orbital Neoplasms; Plasmacytoma; Sarcoma; Sarcoma, Kaposi

Topics: Animals; Carcinoma, Ehrlich Tumor; DNA; DNA, Neoplasm; Melphalan; Metabolism; Mice; Neoplasm Transplantation; Neoplasms; Pharmacology; Phosphorus Isotopes; Rats; Research; RNA; RNA, Neoplasm; Sarcoma; Sarcoma, Yoshida

Topics: Antimetabolites; Antineoplastic Agents; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Geriatrics; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Melanoma; Melphalan; Methotrexate; Mouth Neoplasms; Neoplasms; Neoplasms, Muscle Tissue; Nitrogen Mustard Compounds; Sarcoma; Toxicology; Triethylenemelamine

Topics: Antineoplastic Agents; Cytosine; Erythrocyte Count; Leukocyte Count; Melphalan; Neoplasm Metastasis; Neoplasms; Pyrimidines; Rats; Research; Sarcoma; Sarcoma, Experimental; Toxicology

Topics: Animals; Carcinoma; Carcinoma, Ehrlich Tumor; Cyclophosphamide; Cytostatic Agents; Mannomustine; Mechlorethamine; Melphalan; Metabolism; Mice; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds; Phosphorus Isotopes; Radiation Injuries; Radiation Injuries, Experimental; Research; Triethylenemelamine

Topics: Aminopterin; Antineoplastic Agents; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Chlorambucil; Dactinomycin; Fibrosarcoma; Fluoresceins; Humans; Infusions, Parenteral; Injections, Intra-Arterial; Lymphoma; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Neoplasms; Pharmacology; Thiotepa; Toxicology

Topics: Antineoplastic Agents; Barium Sulfate; Colchicine; Esophageal Neoplasms; Humans; Melphalan; Neoplasms; Radiography, Thoracic

Topics: Humans; Male; Melphalan; Neoplasm Metastasis; Neoplasms; Neoplasms, Germ Cell and Embryonal; Neoplasms, Second Primary; Testicular Neoplasms

Topics: Female; Humans; Mechlorethamine; Melphalan; Neoplasms; Nitrogen; Nitrogen Mustard Compounds; Phenylalanine; Uterine Neoplasms

Topics: Humans; Melphalan; Neoplasms

Topics: Animals; Melphalan; Neoplasms; Neoplasms, Experimental

Topics: Antineoplastic Agents; HeLa Cells; Humans; Melphalan; Neoplasms; Tissue Culture Techniques

Topics: Antineoplastic Agents; Humans; Melphalan; Neoplasms; Oxidoreductases; Sarcoma

Topics: Mechlorethamine; Melphalan; Neoplasms; Nitrogen Mustard Compounds

Regional isolation perfusion with an alkylating agent was carried out in a small community hospital, using readily available equipment, ten times in nine cases of advanced malignant disease. Visible regression of tumor, either grossly or histologically, occurred in seven patients and decided subjective improvement occurred in five patients. The long range effect of the procedure could not be determined in the present series, not enough time having elapsed. Side effects included jaundice in four patients, massive necrosis of the tumor in one patient, nausea and vomiting in three patients, postoperative edema in five patients, wound infection in two patients, Horner's syndrome in one patient, temporary alopecia in three patients, and depression of hemoglobin level in seven patients, of the leukocyte count in four patients and of the platelet count in four patients.A feature of the procedure used in the present series was a system of monitoring the escape of alkylating agent into the systemic circulation.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Edema; Extracorporeal Circulation; Female; Humans; Male; Melphalan; Middle Aged; Neoplasms; Perfusion; Tumor Necrosis Factor-alpha

Topics: Mechlorethamine; Melphalan; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds; Nucleic Acids; Phenylalanine; Pyrimidines; Uracil Mustard

Topics: Melphalan; Neoplasms; Peptides; Phenylalanine

Topics: Humans; Mechlorethamine; Melphalan; Neoplasms; Nitrogen Mustard Compounds; Triazines; Triethylenemelamine

Topics: Animals; Mechlorethamine; Melphalan; Methionine; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds

Topics: Isomerism; Mechlorethamine; Melphalan; Neoplasms; Nitrogen Mustard Compounds; Phenylalanine

Topics: Carmustine; Cobalt; Cobalt Radioisotopes; Etoposide; Humans; Melphalan; Neoplasms; Radioactivity

Topics: Carmustine; Esophageal Neoplasms; Humans; Melphalan; Neoplasms; Radiotherapy

Topics: Dysgerminoma; Female; Humans; Male; Melphalan; Neoplasms; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Phenylalanine; Seminoma; Testicular Neoplasms; Testis

Topics: Antineoplastic Agents; Humans; Melphalan; Neoplasms; Phenylalanine

Topics: Carmustine; Etoposide; Humans; Melphalan; Neoplasms; Radiotherapy

Topics: Melphalan; Neoplasms; Phenylalanine; Sarcoma; Sarcoma, Experimental

Topics: Animals; Melphalan; Neoplasms; Neoplasms, Experimental; Phenylalanine

Topics: Carmustine; Etoposide; Humans; Melphalan; Neoplasms

Topics: Carmustine; Etoposide; Humans; Melphalan; Neoplasms; Radium

Topics: Carmustine; Etoposide; Humans; Melphalan; Neoplasms; Radium

Topics: Etoposide; Humans; Melphalan; Neoplasms; Radium; Tongue; Tongue Neoplasms