melphalan and Rhabdomyosarcoma

In high-grade musculoskeletal sarcomas, adjuvant chemotherapy is often performed to prevent distant metastases. The efficacy of chemotherapy varies according to the histological type of sarcoma. Prognoses are poor in patients with osteosarcoma, Ewing's sarcoma, or rhabdomyosarcoma, when surgery alone is performed. However, because these sarcomas are chemosensitive, their prognoses are improved with adjuvant chemotherapy. On the other hand, the efficacy of chemotherapy is not statistically demonstrated in non-round cell sarcomas, e. g., malignant fibrous histiocytoma. Nowadays, several kinds of antitumor agents are usually used for adjuvant chemotherapy, and many authors have reported various kinds of regimens and their clinical results. Commonly used drugs include adriamycin, ifosfamide, cisplatin, methotrexate, cyclophosphamide, dacarbazine, vincristine, and actinomycin-D. Recently, high-dose chemotherapy combined with autologous peripheral blood or bone marrow stem cell transplantation has been begun in patients who do not respond to standard chemotherapy, and a better prognosis is expected.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Combined Modality Therapy; Cyclophosphamide; Dacarbazine; Dactinomycin; Doxorubicin; Drug Administration Schedule; Humans; Ifosfamide; Melphalan; Mesna; Methotrexate; Osteosarcoma; Rhabdomyosarcoma; Sarcoma; Sarcoma, Ewing; Soft Tissue Neoplasms; Vincristine

To review the importance of prognostic factors in developing new protocols for children with rhabdomyosarcoma (RMS).. Four studies conducted by the Intergroup Rhabdomyosarcoma Study (IRS) Group from 1972 through 1991.. Favorable prognostic factors are: (1) undetectable distant metastases at diagnosis; (2) primary sites in the orbit and nonparameningeal head/neck and genitourinary nonbladder/prostate regions; (3) grossly complete surgical removal of localized tumor at the time of diagnosis; (4) embryonal/botryoid histology; (5) tumor size < or = 5 cm; and (6) age younger than 10 years at diagnosis. The IRS-V protocols are risk-based and refine therapy by reducing exposure to cyclophosphamide and radiation therapy (XRT) in patients at low risk while adding new, active agents such as topotecan or irinotecan to the standard therapy of vincristine, actinomycin D, and cyclophosphamide (VAC) plus XRT for patients with unfavorable histology or advanced disease. Collection of biologic specimens from patients with newly diagnosed disease continues to identify other factors that may distinguish patients with favorable features from those who need more intensive therapy. A new protocol that takes into account their previous treatment is needed for patients with recurrent disease. This program (being planned) does not include bone marrow/stem cell reconstitution because this strategy has thus far failed to improve survival rates of patients with metastases at diagnosis.. Better understanding of biologic differences and new, active agents are needed to improve outcome of patients with unfavorable features at presentation.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Disease-Free Survival; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Infant; Male; Melphalan; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Neoplasm Staging; Pilot Projects; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Rhabdomyosarcoma; Salvage Therapy; Sarcoma; Soft Tissue Neoplasms; Survival Rate; Topotecan; Treatment Outcome; Vincristine

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

The prospect of identifying and developing new agents for treatment of rhabdomyosarcomas is discussed in the light of current prognosis for children with advanced stage disease. Preliminary attempts to identify tumor-specific agents using in vitro cell culture show potential promise, but as yet remain unproven. The more complex system of identifying therapeutically active agents using human tumor xenografts has demonstrated usefulness. The potential problems associated with this system are discussed.

Topics: Animals; Antineoplastic Agents; Child; Drug Screening Assays, Antitumor; Humans; Melphalan; Mice; Neoplasm Transplantation; Rhabdomyosarcoma; Tumor Stem Cell Assay

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

Patients with locally advanced or metastatic/recurrent soft tissue and Ewing's sarcoma (EWS) have few treatment options. The purpose of our phase II study was to assess the feasibility, safety and efficacy of tandem high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) in such patients.. Thirteen patients were enrolled onto this study. The first cycle of HDCT consisted of doxorubicin (150 mg/m(2)) and ifosfamide (14 g/m(2)) mixed with mesna (14 g/m(2)), while the second cycle consisted of melphalan (150 mg/m(2)) and cisplatin (200 mg/m(2)).. Eleven out of 13 patients were able to complete both cycles of HDCT. No treatment-related mortality occurred and grade 3 or 4 toxicity was clinically tolerable. The 5-year progression-free survival (PFS) and overall survival (OS) for all patients was 23% (confidence interval, CI: 0-46%) and 31% (CI: 14-70%), respectively. Out of the four patients still alive, two had EWS and measurable disease at the time of ASCT and achieved a complete remission, remaining progression free 126 and 155 months after ASCT.. Our study demonstrates the feasibility and safety of tandem HDCT in patients with high-risk or metastatic/recurrent sarcoma, with some patients achieving long-term PFS and OS.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Combined Modality Therapy; Disease Progression; Doxorubicin; Feasibility Studies; Female; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Immunoenzyme Techniques; Male; Melphalan; Mesna; Neoplasm Recurrence, Local; Neoplasm Staging; Neuroectodermal Tumors, Primitive, Peripheral; Osteosarcoma; Prognosis; Prospective Studies; Protective Agents; Remission Induction; Rhabdomyosarcoma; Safety; Sarcoma; Sarcoma, Ewing; Survival Rate; Transplantation, Autologous; Treatment Outcome; Young Adult

The prognosis of metastatic/high-risk localized small round-cell tumors (SRCTs) treated conventionally is dismal. In this phase II study, we explored a high-dose chemotherapy (HD-CT) approach and analyzed the clinical significance of fusion transcripts detection.. From June 1997 to November 1999, 28 SRCT patients (median age, 26 years; 14 peripheral primitive neuroectodermal tumors [pPNETs], seven rhabdomyosarcomas [RMSs], and seven desmoplastic small round-cell tumors [DSRCTs]) received induction chemotherapy with ifosfamide, epirubicin, and vincristine followed by HD-CT. Local treatment (radiotherapy and/or surgery) was performed when possible. Molecular analysis was performed on peripheral-blood and leukapheresis products by reverse-transcriptase polymerase chain reaction.. Overall response (OR) was 65% (18 of 28), with 40% complete response and 25% partial response. According to histology, the OR rate was 86% in pPNET and 43% in both RMS DSRCT. With a median follow-up of 35 months, median overall survival was 16 months and median progression-free survival (PFS) was 10 months. PFS was statistically better in pPNET than other histologic types (P =.0045). No correlation was found between the fusion transcript and clinical outcome during follow-up. Furthermore, transcript detection in leukapheretic products was not of prognostic significance.. Intensive HD-CT seems to enhance the response rate and survival when compared with conventional treatment in poor-prognosis pPNET. The poor results of this treatment in RMS and DSRCT do not support the inclusion of such an approach in these patient subsets. No definitive conclusions can currently be drawn concerning the clinical implications of the detection of fusion transcripts during treatment or follow-up.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Cyclophosphamide; Epirubicin; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Male; Melphalan; Middle Aged; Mitoxantrone; Neuroectodermal Tumors, Primitive, Peripheral; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Rhabdomyosarcoma; Survival Analysis; Thiotepa; Vincristine

This study was designed to estimate the partial and complete response rates (CR and PR) of two novel drug pairs (vincristine and melphalan vs. ifosfamide and etoposide) and to improve overall survival of previously untreated patients with metastatic rhabdomyosarcoma.. One hundred twenty-eight patients were randomly assigned to phase II window therapy consisting of vincristine and melphalan (VM-containing regimen) or ifosfamide and etoposide (IE-containing regimen). Brief window therapy (12 wks) was immediately followed-up by vincristine, dactinomycin, and cyclophosphamide (VAC), chemotherapy, surgery, and irradiation, with continuation of either VM or IE in patients with initial response. Major endpoints were initial CR and PR rates after the phase II window phase of therapy, failure-free survival (FFS), and survival.. Patients who received the VM-containing regimen experienced significantly more anemia, neutropenia, thrombocytopenia, and had more cyclophosphamide dose reductions. The initial PR and CR rates were not significantly different for patients treated with either regimen (VM, 74%; IE, 79%; P = 0.428). However, FFS and overall survival (OS) at 3 years were significantly better with the IE-containing regimen (FFS: 33% vs. 19%; P = 0.043; OS: 55% vs. 27%; P = 0.012).. Although the VM-containing regimen produced a high response rate, inclusion of melphalan appeared to limit the cyclophosphamide dose that could be administered, and ultimately, this regimen was associated with a significantly worse outcome than was the IE-containing regimen. Also, the IE-containing regimen was associated with a gratifyingly high survival rate at 3 years (55%), which is significantly higher than has been observed on any previous Intergroup Rhabdomyosarcoma Study Group regimen for similar patients. We believe that this promising outcome indicates that this drug pair merits further randomized testing in metastatic rhabdomyosarcoma.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bronchiolitis Obliterans; Chemotherapy, Adjuvant; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Humans; Ifosfamide; Infant; Kidney Diseases; Life Tables; Male; Melphalan; Neoplasm Metastasis; Radiotherapy, Adjuvant; Remission Induction; Rhabdomyosarcoma; Sepsis; Soft Tissue Neoplasms; Survival Analysis; Treatment Outcome; Vincristine

The European Collaborative MMT4-91 trial was conducted as a prospective nonrandomized study to evaluate the potential benefit of high-dose melphalan as consolidation of first complete remission in children with stage IV rhabdomyosarcoma.. Fifty-two patients in complete remission after six courses of chemotherapy received "megatherapy": 42 received melphalan alone, whereas 10 received melphalan in combination with etoposide, carboplatin/etoposide, or thiotepa/busulfan and etoposide. The outcome of this group of patients was compared with that observed in 44 patients who were also in complete remission after six courses of identical chemotherapy (plus surgery or radiotherapy) but went on to receive a total of up to 12 courses of conventional chemotherapy (four cycles). No differences were found between the two groups regarding clinical characteristics, chemotherapy received before complete remission, or response to chemotherapy. In particular, there was no significant difference between the groups for site of primary tumor, histologic subtype, age at presentation, presence of bone or bone marrow metastases, or number of metastases.. The 3-year event-free survival (EFS) and overall survival (OS) rates were 29.7% and 40%, respectively, for those receiving high-dose melphalan or other multiagent high-dose regimens and 19.2% and 27.7%, respectively, for those receiving standard chemotherapy. The difference was not statistically significant (P =.3 and P =.2 for EFS and OS, respectively). There was a significant prolongation in the time from the last day of high-dose chemotherapy or the end of chemotherapy cycle 4 to the time of relapse in those receiving megatherapy (168 days for patients receiving megatherapy v 104 days for those receiving standard therapy; P =.05).. The addition of a high-dose alkylating agent to consolidation therapy may have prolonged progression-free survival in this poor-risk patient group, but it did not significantly improve the ultimate outcome.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Cell Transplantation; Child; Child, Preschool; Combined Modality Therapy; Dactinomycin; Epirubicin; Humans; Ifosfamide; Infant; Melphalan; Prospective Studies; Rhabdomyosarcoma; Treatment Outcome; Vincristine

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 describe events that led to successful testing of melphalan, one of the nitrogen mustard compounds, in children with newly diagnosed, poor-risk rhabdomyosarcoma (RMS). Preclinical studies with xenografts of human RMS, growing in the flanks of immune-deprived mice, had indicated superior oncolytic activity by melphalan compared with other agents commonly used to treat this tumor. However, in a conventional phase II trial, melphalan failed to produce partial responses in 12 of 13 heavily pretreated patients with recurrent tumors. Subsequent comparison of the drug's pharmacokinetics in mice and patients indicated that its poor clinical performance was not the result of interspecies differences in drug disposition. Therefore, we elected to retest melphalan in untreated patients, before they were enrolled in a phase III study. Of 13 children who received the drug for 6 weeks, ten had partial responses, confirming the significant antitumor activity seen in the xenograft system. These findings illustrate the inherent limitations of phase II drug trials in previously treated patients and suggest a useful paradigm for the development of antineoplastic drugs.

Topics: Adolescent; Child; Child, Preschool; Clinical Trials as Topic; Drug Evaluation; Drug Resistance; Female; Humans; Male; Melphalan; Metabolic Clearance Rate; Models, Biological; Rhabdomyosarcoma

Isolated lung perfusion (ILuP) and selective pulmonary artery perfusion (SPAP) are experimental surgical techniques to deliver high-dose chemotherapy selectively to the lung for the treatment of lung metastases. ILuP with melphalan (MN) has shown to be feasible in clinical studies but can only be used once because it is invasive. SPAP as an endovascular technique can be repeated several times, but no results have been reported so far. Pharmacokinetics and efficacy of SPAP with MN were studied in a rodent lung metastasis model and compared it with ILuP and intravenous (IV) therapy.. Pharmacokinetics: forty-five Wag-Rij rats were randomized into three groups: IV 0.5 mg MN, ILuP 0.5 mg MN and SPAP 0.5 mg MN. Every treatment group was again randomized in three groups: 15 min treatment, 30 min treatment and 30 min treatment with 30 min reperfusion. Blood and tissue samples were taken for MN concentrations.. twenty-five Wag-Rij rats were randomized into five groups: control, sham thoracotomy, IV 0.5 mg MN, ILuP 0.5 mg MN and SPAP 0.5 mg MN. At day 0, bilateral lung metastases were induced, and treatment followed at day 7. At day 28, rats were sacrificed and pulmonary metastases counted. Survival: thirty Wag-Rij rats were randomized into five groups: control, sham ILuP, IV 0.5 mg MN, ILuP 0.5 mg MN, SPAP 0.5 mg MN. At day 0, left-sided lungmetastases were induced with treatment at day 7. Endpoints were death due to disease or survival up to 90 days.. Pharmacokinetics: SPAP and ILuP resulted in significantly higher left lung MN concentrations compared with IV (P = 0.05).. SPAP (30 ± 22 nodules) and ILuP (20 ± 9 nodules) resulted in significantly less nodules compared with IV (113 ± 17 nodules; P < 0.01). Survival: median survival of SPAP (74 ± 8 days) was equal to ILuP MN (71 ± 10 days) but significantly longer compared with IV (54 ± 7 days; P < 0.01 both).. SPAP with MN for the treatment of sarcoma lung metastases in rats is equally effective to ILuP but resulted in a significantly better survival compared with IV MN. As SPAP can be applied as a minimally invasive endovascular procedure, continued research with this technique is warranted.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Chemotherapy, Cancer, Regional Perfusion; Injections, Intra-Arterial; Injections, Intravenous; Lung Neoplasms; Melphalan; Neoplasm Transplantation; Pulmonary Artery; Random Allocation; Rats; Rats, Inbred Strains; Rhabdomyosarcoma; Survival Analysis

Three pediatric patients with infratentorial metastatic non-epithelial malignant brain tumors were successfully treated by radical surgical resection followed by aggressive radiochemotherapy. One patient with neuroblastoma and two with rhabdomyosarcoma were successfully treated by first line multimodal treatments, but developed infratentorial metastasis after several months of remission. All patients revealed intracranial metastases manifesting as rapidly progressing neurological symptoms caused by mass effect in the posterior fossa. Radical surgical resection was performed without morbidity. The patients were then treated by adjuvant radiochemotherapy with or without autologous peripheral blood stem cell transplantation, resulting in complete remission. Two patients developed extracranial recurrences 4 months after the treatments for intracranial metastases. One patient was treated by second high-dose chemotherapy with allogeneic cord blood transplantation, again resulting in complete remission. Another patient was treated by second chemotherapy and maintaining stable disease. The other patient maintained complete remission. All three patients were alive without neurological deficit for 8, 11, and 12 months after diagnosis of brain metastasis. Patients with infratentorial brain metastases of highly malignant pediatric non-epithelial tumors are in a severe clinical state, but still can have longer and useful lives with aggressive multimodal treatments combined with radical surgical resection.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Camptothecin; Carboplatin; Chemotherapy, Adjuvant; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Dactinomycin; Doxorubicin; Etoposide; Humans; Ifosfamide; Infant; Infratentorial Neoplasms; Irinotecan; Melphalan; Neoplasm Metastasis; Neuroblastoma; Rhabdomyosarcoma; Thiotepa; Topotecan; Vincristine

The role of high-dose chemotherapy; with subsequent autologous bone marrow rescue (AutoBMR) for high risk or recurrence of advanced solid tumor was evaluated in 16 children (August 1998-March 2001). At present, 11 (69%) patients are still alive, showing no evidence of the disease, 11-31 mo after therapy (median follow-up of 17 mo). Tumor progression was reported in 5 (31%) at months 5, 6, 8, 9 and 11 (after AutoBMR rhabdosarcoma--3; Ewing's sarcoma--2). Overall and recurrence-free survival among all patients was 74 and 66%, respectively.

Topics: Adolescent; Age Factors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Transplantation; Carboplatin; Carmustine; Child; Child, Preschool; Cytarabine; Dacarbazine; Data Interpretation, Statistical; Disease-Free Survival; Doxorubicin; Female; Follow-Up Studies; Hodgkin Disease; Humans; Infant; Lymphoma, Non-Hodgkin; Male; Melphalan; Podophyllotoxin; Rhabdomyosarcoma; Sarcoma, Ewing; Sex Factors; Statistics, Nonparametric; Time Factors; Transplantation, Autologous; Vinblastine

Our previous studies exploring melphalan resistance in the human rhabdomyosarcoma xenograft TE-671 MR revealed elevation of DNA polymerase-alpha and DNA polymerase-beta. The present study evaluated the alteration of melphalan activity in TE-671 (melphalan-sensitive) and TE-671 MR (melphalan-resistant) subcutaneous xenografts in nude mice after DNA polymerase-alpha was inhibited using aphidicolin glycinate (AG) and DNA polymerase-beta was inhibited using dideoxycytidine (DDC). Administration of AG or DDC did not produce toxicity or demonstrate antineoplastic activity when given alone. AG (90 mg/m2) enhanced the activity of melphalan against TE-671, with growth delays increasing by 8.4, 15.8, and 21.2 days over the regimen with melphalan only. AG (180 mg/m2) only modestly increased melphalan activity against TE-671 MR, with the growth delays increasing from 9.6 and 12.1 days using melphalan alone to 12.1 and 14.5 days using melphalan plus AG. AG (180 mg/m2) plus melphalan (the dose lethal to 10% of animals) produced greater weight loss compared with melphalan alone, whereas DDC plus melphalan produced no additional toxicity. DDC modestly enhanced the activity of melphalan plus AG against TE-671 MR. AG plus O6-benzylguanine did not increase the activity of 1,3-bis(2-chloroethyl)-1-nitrosourea against TE-671 or TE-671 MR. AG (90 mg/m2 and 180 mg/m2) inhibited DNA polymerase-alpha to 80% and 72% of control in TE-671 and 64% and 37% in TE-671 MR, and DDC inhibited DNA polymerase-beta to 59% in TE-671 and 48% in TE-671 MR. These results suggest a role for AG-mediated enhancement of melphalan activity, particularly in the treatment of newly diagnosed, melphalan-sensitive tumors.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Aphidicolin; Carmustine; DNA Polymerase I; DNA Polymerase II; Drug Synergism; Enzyme Inhibitors; Female; Guanine; Humans; Male; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Rhabdomyosarcoma; Zalcitabine

Alkylation of DNA was studied after treatment with [3H]melphalan (phenylalanine mustard; 1-2 microM) using a human tumour cell line, RD, in culture, or Escherichia coli (WP2 or WP2-uvrA strains) in growth medium. After 6 h at 37 degrees C, treated cells were isolated and re-suspended in fresh growth media. Samples were taken at times up to 48 h for isolation of DNA, and in some cases also RNA and protein (which were found to be alkylated to about the same extent as DNA). Alkylated DNA was analysed as previously described (M.R. Osborne and P.D. Lawley, Chem.-Biol. Interact 89 (1993) 49-60). The four principal products, mono-7-alkylguanine (G-M-OH); mono-3-alkyladenine (A-M-OH); and the cross-linked products G-M-G and A-M-G, were identified in DNA from melphalan treated cells, and quantitatively determined. In each case, alkylation of cellular macromolecules was maximal after about 6 h. In DNA of the human tumour cell line, the relative amounts of adenine products decreased with time, most markedly with A-M-OH to 42% of the 2-h value after 48 h. In DNA of both bacterial strains, A-M-OH was virtually undetectable even at early times. Comparisons between the time course of relative decreases in amounts of these alkylpurine products and the corresponding values for alkylated DNA in vitro suggest that the adenine products are subject to removal by repair enzyme action in E. coli of either strain.

Topics: Alkylation; Bacterial Proteins; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; DNA Adducts; DNA, Bacterial; DNA, Neoplasm; Escherichia coli; Humans; Melphalan; Neoplasm Proteins; Purines; Rhabdomyosarcoma; RNA, Bacterial; RNA, Neoplasm; Tumor Cells, Cultured

Flunarizine, a diphenylpiperazine calcium channel blocker, is known to increase tumor blood flow. It also interferes with calmodulin function, repair of DNA damage and drug resistance associated with P-glycoprotein. Flunarizine was tested for its ability to modulate either cyclophosphamide- or melphalan-induced growth delay for a drug-resistant rhabdomyosarcoma xenograft (TE-671 MR) and the drug-sensitive parent line (TE-671), in which P-glycoprotein is not involved in the mechanism of drug resistance. Tumour blood flow was increased by 30% after a flunarizine dose of 4 mg kg-1, but no modification in growth delay was induced by melphalan (12 mg kg-1). In contrast, a 60 mg kg-1 dose of flunarizine had no effect on tumour blood flow, but the same dose created significant enhancement in melphalan-induced tumour regrowth delay in both tumour lines. The dose-modifying factor for flunarizine as an adjuvant to melphalan was approximately 2 for both tumour lines. Although blood flow measurements were not performed with the combination of flunarizine and melphalan, the results from flunarizine alone suggested that augmentation of melphalan cytotoxicity is not mediated by changes in blood flow. In contrast, flunarizine did not affect drug sensitivity to cyclophosphamide in groups of animals bearing the drug-sensitive parent tumour line. These results suggest that the mechanism of drug sensitivity modification by flunarizine is not related to modification of tumour blood flow, but may be mediated by modification of transport mechanisms that are differentially responsible for cellular uptake and retention of melphalan as compared with cyclophosphamide.

Topics: Animals; Cell Line; Drug Interactions; Drug Resistance; Female; Flunarizine; Humans; Male; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Muscles; Regional Blood Flow; Rhabdomyosarcoma; Transplantation, Heterologous

Peripheral blood stem cells (PBSC) were used to augment autologous bone marrow transplantation (ABMT), aiming to hasten engraftment after high dose treatment in a group of heavily pretreated patients. PBSC were obtained by leukapheresis during the rebound after standard chemotherapy. In 11 patients aged 7-17 years, high dose chemotherapy consisted of busulphan 16 mg/kg orally with melphalan 160 mg/m2 intravenously for seven patients, and melphalan 200 mg/m2 intravenously alone for four. The median number of granulocyte-macrophage colony forming units in the reinfused PBSC was 3.42 x 10(4)/kg (3.03-18.01) and bone marrow 12.4 x 10(4)/kg (4.16-28.6). Neutrophil recovery to > or = 0.5 x 10(9)/l and platelet transfusion independence occurred at a median of 14 days (11-18) and 22 days (9-84) respectively. In five patients the early engraftment was transient with neutrophils again dropping below 0.5 x 10(9)/l then slowly recovering. There was one toxic death due to sepsis. PBSC harvesting in these children was undertaken without interrupting routine chemotherapy and without the use of bone marrow growth factors. In some patients PBSC failed to influence engraftment and the use of combined chemotherapy and growth factor priming for PBSC collection may give improved results.

Topics: Acute Disease; Adolescent; Bone Marrow Transplantation; Busulfan; Child; Combined Modality Therapy; Cryopreservation; Female; Hemangiosarcoma; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Leukapheresis; Leukemia, Myeloid; Male; Melphalan; Rhabdomyosarcoma; Sarcoma, Ewing

Previous investigations have revealed that the human TE-671 MR human rhabdomyosarcoma xenograft selected in vivo for melphalan resistance (M. C. Rosenberg, et al., Cancer Res., 49: 6917-6922, 1989) is cross-resistant to a wide variety of alkylating agents and to bleomycin, but is collaterally sensitive to etoposide. Although glutathione levels were noted to be elevated in TE-671 MR compared to the melphalan-sensitive parental TE-671 xenograft, treatment with buthionine sulfoximine to deplete glutathione levels did not fully restore melphalan sensitivity in the TE-671 MR xenograft. The present studies were undertaken to search for additional mechanisms of resistance in the TE-671 MR xenograft. Drug sensitivity testing performed at the dose of agents that was lethal to 10% of the animals revealed that the TE-671 MR xenograft maintained resistance to the bifunctional cross-linking agent 1,3-bis(2-chloroethyl)-1-nitrosourea and was cross-resistant to the topoisomerase I poison topotecan. Treatment with buthionine sulfoximine did not sensitize the TE-671 MR xenograft to 1,3-bis(2-chloroethyl)-1-nitrosourea. Further, even though O6-alkylguanine-DNA alkyltransferase levels were high in both the TE-671 and TE-671 MR xenografts, depletion of O6-alkylguanine-DNA alkyltransferase activity by treatment with O6-benzylguanine substantially sensitized the TE-671 xenografts but not the TE-671 MR xenografts, suggesting an additional mechanism of resistance. Measurement of additional enzyme activities that might be involved in DNA repair revealed significant elevations in DNA polymerase alpha (46 +/- 8 (SD) units/mg protein in TE-671, 69 +/- 6 units/mg protein in TE-671 MR, P < 0.05) and DNA polymerase beta (0.43 +/- 0.01 units/mg protein in TE-671, 0.78 +/- 0.12 units/mg protein in TE-671 MR, P < 0.05) but not DNA polymerase delta or total DNA ligase. Examination of topoisomerases by activity assays and Western blotting revealed a 2-fold increase in topoisomerase II and a 2-fold decrease in topoisomerase I in the TE-671 MR xenograft compared to the parental xenograft, apparently explaining the collateral sensitivity to etoposide and cross-resistance to topotecan. These results suggest that TE-671 MR xenografts contain multiple changes in activities of DNA repair-related proteins and other nuclear proteins that could contribute to alkylating agent resistance.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Camptothecin; Carmustine; DNA Polymerase I; DNA Polymerase II; DNA Topoisomerases, Type II; Drug Resistance; Drug Screening Assays, Antitumor; Female; Humans; Male; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Rhabdomyosarcoma; Topotecan; Transferases; Transplantation, Heterologous

We report the activity and toxicity of intrathecal melphalan in the treatment of human neoplastic meningitis in the subarachnoid space of athymic nude rats. Animals received injections via chronic indwelling subarachnoid catheters with 5 x 10(5) or 5 x 10(6) TE-671 human rhabdomyosarcoma cells or 5 x 10(6) D-54 MG human glioma cells and were treated with melphalan on days 8, 5, or 5, respectively. Melphalan toxicity in nontumor-bearing rats was assessed at single doses of a 2.0, 3.0, 4.0, or 5.0 mM solution, with clinical and histological evidence of neurotoxicity observed at the 4.0 and 5.0 mM levels. Multiple-dose toxicity studies using a dosing schedule of twice a week for two weeks with a 0.25, 0.5, 0.75, 1.0, 1.5, or 2 mM solution revealed dose-dependent clinical and histological evidence for toxicity at all dosages. Treatment of TE-671 with a single dose of 2.0 mM intrathecal melphalan produced an increase in median survival of 442% compared with saline controls (P < 0.003). Comparison of a single dose of 1.0 or 2.0 mM melphalan with a multiple dose regimen at 0.25 or 0.5 mM melphalan in the treatment of TE-671 revealed increases in median survival of 50% for 1.0 mM, 57% for 2.0 mM, 79% for 0.5 mM, and 111% for 0.25 mM concentrations. Comparison of a single dose of 1 mM melphalan with multiple doses of 0.25 mM melphalan in the treatment of D-54 MG revealed an increase in median survival of 475+% for each of the regimens. Intrathecal melphalan may be an important new addition in the treatment of neoplastic meningitis and is currently being evaluated clinically in a Phase 1 trial.

Topics: Animals; Brain Neoplasms; Demyelinating Diseases; Disease Models, Animal; Drug Screening Assays, Antitumor; Female; Glioma; Humans; Injections, Spinal; Melphalan; Meningitis; Rats; Rats, Nude; Rhabdomyosarcoma; Subarachnoid Space; Transplantation, Heterologous; Tumor Cells, Cultured

The efficacy of the topoisomerase I inhibitor CPT-11 [7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxycamptothec in] has been evaluated against a panel of human tumor xenografts derived from adult and pediatric malignancies. Tumors included eight colon adenocarcinomas representing intrinsically chemorefractory malignancies, six lines derived from childhood rhabdomyosarcoma (three embryonal and three alveolar) representing a chemoresponsive histiotype, and sublines of rhabdomyosarcomas selected in vivo for resistance to vincristine, melphalan, and the topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan). CPT-11 was given by i.v. administration daily for 5 days each week for 2 weeks (one cycle of therapy) or on the same schedule with cycles repeated every 21 days. The maximum tolerated dose for a single cycle of treatment was 40 mg/kg/dose, and for 3 cycles the maximum tolerated dose was 10 mg/kg/dose. Treatment was started against advanced tumors. Against colon adenocarcinomas CPT-11 administered for one cycle at the maximum tolerated dose caused complete or partial regression (> or = 50% reduction in tumor volume) in 5 of 8 lines. One cycle of CPT-11 therapy caused significant inhibition of tumor growth, without 50% regression, in 2 of 3 other colon adenocarcinomas. Rhabdomyosarcoma xenografts derived from untreated patients were highly responsive to CPT-11, which caused complete regression in 5 of 6 lines even at 20 or 10 mg/kg/dose. CPT-11 retained complete activity against rhabdomyosarcomas selected for resistance to vincristine and caused complete regressions in a line selected for resistance to melphalan that was also completely cross-resistant to topotecan. Of note was the observation that CPT-11 was as active against two xenografts selected for primary resistance to topotecan as it was against the respective parental tumors. Preliminary data indicate that CPT-11, like the topoisomerase I inhibitor topotecan, may have increased therapeutic efficacy when administered at a low dose for protracted periods (3 cycles). A comparison of the efficacy of CPT-11 with topotecan is presented.

Topics: Adolescent; Adult; Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Child; Colonic Neoplasms; Drug Administration Schedule; Drug Resistance; Drug Screening Assays, Antitumor; Female; Humans; Irinotecan; Male; Melphalan; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Rhabdomyosarcoma; Topotecan; Transplantation, Heterologous; Tumor Cells, Cultured; Vincristine

An automated column-switching high-performance liquid chromatographic (HPLC) method with ultraviolet detection is described for a simple and rapid determination of melphalan, an alkylating agent, in human plasma following direct sample injection. The system consists of a pretreatment column and an analytical column connected in series via a switching valve. Plasma samples are loaded onto a pretreatment column with an aqueous mobile phase, with which the sample to be analyzed is retained and the solubilized plasma proteins are flushed to be discarded. The retained compound is eluted from the pretreatment column onto the analytical column by using the chromatographic mobile phase with a higher elution capacity. The column-switching technique can be used to achieve an automated assay. Analytical recovery of the compound was 99.1%, and the coefficients of both intra- and interday variations did not exceed 3.5%. The detection limit was 10 ng/ml for the compound. Recovery of melphalan in plasma was only 2.1% after 4 weeks at 25 degrees C, as compared to 24.5% at 5 degrees C and 100.1% at -20 degrees C.

Topics: Adolescent; Blood Proteins; Bone Marrow Transplantation; Bone Neoplasms; Chromatography, High Pressure Liquid; Female; Humans; Melphalan; Protein Binding; Rhabdomyosarcoma

The effects of regional hyperthermia (42 degrees C for 70 min) on the antitumor activity of melphalan were examined in athymic mice bearing melphalan-resistant human rhabdomyosarcoma (TE-671 MR) xenografts growing in the right hind limb, and results were compared with similar studies of melphalan-sensitive (TE-671) parent xenografts. Melphalan alone at a dose of 36 mg/m2 (0.5 of the 10% lethal dose) produced growth delays of 4.1 to 10.2 days in TE-671 MR xenografts and 21.8 to 28.7 days in TE-671, respectively. Hyperthermia alone produced growth delays of 0.9 days in TE-671 MR xenografts and 0.8 days in TE-671. Combination therapy with melphalan and hyperthermia produced growth delays of 7.2 to 13.3 days in TE-671 MR xenografts and 34.3 to 42.8 days in TE-671, respectively, representing a mean thermal enhancement ratio of 1.7 in TE-671 MR and 1.5 in TE-671. Measurement of glutathione levels in TE-671 MR xenografts following treatment with melphalan, hyperthermia, or melphalan plus hyperthermia revealed significant reductions in glutathione content with the nadir (60% of control values) seen 6 h following treatment. Glutathione levels in TE-671 xenografts following identical therapy revealed no differences from control values. Hyperthermia plus melphalan did not result in a higher tumor-to-plasma melphalan ratio compared with treatment with melphalan alone in either TE-671 MR or TE-671 xenografts. These studies suggest that heat-induced alterations in tumor glutathione or melphalan levels are not responsible for the increase in melphalan activity produced by hyperthermia. Combination therapy with melphalan plus regional hyperthermia offers promise for treatment of melphalan-resistant neoplasms.

Topics: Animals; Combined Modality Therapy; Drug Resistance; Female; Humans; Hyperthermia, Induced; Male; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Rhabdomyosarcoma; Transplantation, Heterologous

Investigations with the melphalan-resistant human rhabdomyosarcoma xenograft TE-671 MR were carried out to identify patterns of cross-resistance and collateral sensitivity and to define the mechanism(s) mediating melphalan resistance. TE-671 MR was cross-resistant to thio-TEPA, mitomycin, vincristine, and cisplatin, and partially resistant to chlorambucil and cyclophosphamide. TE-671 MR and the parent line TE-671 were both resistant to 1,3-bis(2-chloroethyl)-nitrosourea and expressed similar levels of O6-alkylguanine-DNA alkyltransferase. TE-671 MR retained full sensitivity to actinomycin D and demonstrated enhanced sensitivity to VP-16 compared to TE-671. Treatment of TE-671 MR with melphalan plus VP-16 resulted in greater than additive growth delays. The frequency of hypoxic regions was similar in TE-671 MR and TE-671, respectively. Measurement of tumor-to-plasma levels at 180 min following i.p. administration of melphalan at 0.5 of the 10% lethal dosage showed mean tumor-to-plasma ratios of 3.81 in TE-671 MR and 7.38 in TE-671, respectively. The lower drug levels in TE-671 MR may be contributing to the resistance to melphalan and thus indicate the need for further studies to define the reasons for these differences in tumor drug level.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance; Drug Screening Assays, Antitumor; Etoposide; Female; Male; Melphalan; Methyltransferases; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; O(6)-Methylguanine-DNA Methyltransferase; Oxygen; Rhabdomyosarcoma

Based on previous work demonstrating the activity of cyclophosphamide and melphalan in a series of human medulloblastoma and rhabdomyosarcoma cell lines and transplantable xenografts, investigations were conducted to define the effects of combining cyclophosphamide or melphalan with VP-16. These studies demonstrated a synergistic interaction between cyclophosphamide and VP-16 and melphalan and VP-16 in the treatment of the human rhabdomyosarcoma cell line TE-671 growing in athymic mice. The combination of cyclophosphamide or melphalan with VP-16 may warrant consideration as a therapeutic strategy for solid tumors sensitive to bifunctional alkylating agents.

Topics: Alkylating Agents; Animals; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; DNA, Neoplasm; Drug Synergism; Etoposide; Female; Male; Melphalan; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Rhabdomyosarcoma; Transplantation, Heterologous

A melphalan-resistant human rhabdomyosarcoma xenograft, TE-671 MR, was established in athymic mice by serial melphalan treatment of the parent xenograft, TE-671, at the 10% lethal dosage (LD10); significant resistance was evident after ten passages of the tumor. TE-671 MR demonstrated a doubling time of 3.5 days and a latency period to 1000-mm3 tumors of 27.5 days. The glutathione level of TE-671 MR was 2.36 mumol/g tumor, wet weight, 2-fold higher than the parent line. The glutathione S-transferase activity of TE-671 MR was 117.8 mumol/min/mg protein, essentially unchanged from the parent line. Although TE-671 MR demonstrated cross-resistance to vincristine, dot blot analysis did not reveal an elevated expression of mdr1 mRNA in the resistant line. TE-671 MR demonstrated a 9.7-day growth delay following treatment with melphalan at the LD10 (compared to 20.9 days for the parent line). Treatment with L-buthionine-SR-sulfoximine (BSO) resulted in increased sensitivity to melphalan subsequently administered at 50% of the LD10 (melphalan alone, growth delays of 3.7 and 4.6 days in duplicate trials; melphalan plus BSO, growth delays of 7.2 and 9.8 days). Sensitivity to melphalan equal to that of the parent line TE-671 was not achieved, however. Treatment with BSO did not result in significantly enhanced sensitivity to subsequently administered vincristine (50% of the LD10) (vincristine alone, growth delays of 6.8 and 6.9 days in duplicate trials; vincristine plus BSO, growth delays of 10.9 and 7.5 days). These results suggest that generation of melphalan resistance may be associated with development of cross-resistance to vincristine; this resistance may be associated with (although not necessarily mediated by) glutathione elevation; this resistance may be partially overcome by BSO-mediated depletion of glutathione.

Topics: Animals; Buthionine Sulfoximine; Drug Interactions; Drug Resistance; Female; Glutathione; Glutathione Transferase; Humans; Male; Melphalan; Methionine Sulfoximine; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Rhabdomyosarcoma; Transplantation, Heterologous; Vincristine

PTT.119 [p-F-phe-m-bis(2-chloroethyl)amino-L-phe-met ethoxy HCl], a synthetic tripeptide mustard, was evaluated for therapeutic efficacy against a spectrum of childhood rhabdomyosarcomas (RMS) maintained as xenografts in immune-deprived mice. These xenografts were established from previously untreated tumors, and sublines were selected in mice for resistance to L-phenylalanine mustard (L-PAM). PTT.119 caused regression of four of six RMS lines established from untreated tumors, and demonstrated activity similar to that of L-PAM in this model. Against tumors Rh18/L-PAM and Rh28/L-PAM, selected in situ for L-PAM resistance, PTT.119 had no significant activity. Rh28/L-PAM was cross-resistant also to oxazophosphorine mustards (ifosfamide, cyclophosphamide), and both tumors were cross-resistant to adriamycin and vincristine. PTT.119 caused hematologic toxicity similar to that of L-PAM, characterized by a marked decrease in white blood cells and thrombocytopenia.

Topics: Animals; Antineoplastic Agents; Cell Line; Drug Resistance; Drug Screening Assays, Antitumor; Female; Humans; Immunosuppression Therapy; Leukocyte Count; Melphalan; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Nitrogen Mustard Compounds; Platelet Count; Rhabdomyosarcoma

Topics: Child; Combined Modality Therapy; Humans; Male; Melphalan; Radiation Tolerance; Rhabdomyosarcoma

Primary resistance to vincristine (VCR) has been selected in rhabdomyosarcoma xenograft HxRh12 by sequential administration of VCR at 1.5 and subsequently 3 mg/kg/passage. The resistant tumor (HxRh12/VCR-3) was approximately 4-fold resistant to VCR and resistance was stable in the absence of selecting pressure (greater than 2 yr). HxRh12/VCR-3 was 2- to 3-fold cross-resistant to L-phenylalanine mustard (L-PAM) but only slightly cross-resistant to ifosfamide. To determine whether selection for primary resistance to L-PAM conferred cross-resistance to VCR we selected an L-PAM-resistant subline of rhabdomyosarcoma xenograft HxRh28 (HxRh28/L-PAM-13). This tumor was 2- to 3-fold resistant to L-PAM and 3-(p-fluorophenyl)-L-alanyl-3-[m-bis-(2-chloroethyl)-aminophenyl]-L- alanyl-L-methionine ethoxyhydrochloride, cross-resistant to cyclophosphamide and ifosfamide, and completely resistant to VCR under in vivo conditions. Pharmacokinetic studies in HxRh12/VCR-3 showed decreased retention of [G-3H]VCR but not alteration in metabolism. Expression of mdr1, a gene that encodes P-glycoprotein, associated with the multiple drug resistance phenotype, was examined. Expression of mdr1 was detected in both HxRh12 and HxRh28 tumors, sensitive to VCR, but there was no increase in expression in tumors selected for primary resistance to VCR or L-PAM. Data suggest that mechanisms other than those associated with "classical" multiple drug resistance confer resistance in these tumors. In clinical evaluation against childhood rhabdomyosarcoma, L-PAM has demonstrated only slight activity in patients relapsing on conventional therapy (including VCR) but demonstrated marked activity in patients with advanced previously untreated disease. It appears likely, therefore, that cross-resistance between VCR and L-PAM as demonstrated in this model may have clinical significance.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line; Drug Resistance; Female; Gene Expression Regulation; Humans; Melphalan; Membrane Glycoproteins; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Rhabdomyosarcoma; Transplantation, Heterologous; Vincristine

Melphalan has been evaluated against a series of seven childhood rhabdomyosarcomas, each derived from a different patient and maintained in vivo as xenografts in immune-deprived mice. Six lines were derived from untreated tumors and one from a patient refractory to conventional therapy. At the maximum tolerated dose (LD10) a single administration of melphalan caused complete regressions of advanced tumor in six of seven lines, including xenografts derived from the refractory patient. This agent demonstrated activity over a broad range of doses, and was considerably more active than vincristine, cyclophosphamide, doxorubicin, and dactinomycin in the model.

Topics: Animals; Cell Division; Cell Line; Child; Female; Humans; Melphalan; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Rhabdomyosarcoma; Transplantation, Heterologous

Cells of rat rhabdomyosarcoma Ra-2 inoculated intravenously were trapped only in lungs and formed progressively growing monoclonal metastases. The population of clones was sensitive to the sarcolysin treatment (10-30 mg/kg) at all stages of clone formations (from 1 to 14 days). The drug acted by two ways: by the reduction of the number of clones and by the clone growth rate inhibition. Independent variability of both types of the clone sensitivity resulted in the highly heterogeneous response of clone populations to the sarcolysin treatment.

Topics: Animals; Clone Cells; Colony-Forming Units Assay; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Lung Neoplasms; Male; Melphalan; Neoplasm Transplantation; Rats; Rhabdomyosarcoma; Time Factors

A laboratory model of childhood rhabdomyosarcoma (RMS) has been used to evaluate cytotoxic agents used in current clinical protocols, and DNA-reacting agents that have had either limited or no evaluation in this histiotype. Seven lines of RMS each derived from a different patient were grown as xenografts in immune-deprived mice, six of these being from specimens derived from previously untreated patients. Of the 'conventional' agents, vincristine was the most effective. Of the other agents evaluated [L-phenylalanine mustard (L-PAM), cis-dichlorodiammineplatinum (cis-DDP), mitomycin C and 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC)], L-PAM caused complete regressions in six of seven lines, including those resistant to cyclophosphamide. DTIC had marked activity in five tumors, and mitomycin C in three lines. Cyclophosphamide was active in five tumors, although efficacy was less marked in two lines in comparison to DTIC and mitomycin C.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Cell Line; Child; Cisplatin; Cyclophosphamide; Dacarbazine; Dactinomycin; Doxorubicin; Female; Humans; Melphalan; Mice; Mice, Inbred CBA; Mitomycin; Mitomycins; Neoplasm Transplantation; Rhabdomyosarcoma; Transplantation, Heterologous; Vincristine

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

Topics: Adjuvants, Pharmaceutic; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Female; Humans; Infant; Leg; Mechlorethamine; Melphalan; Rhabdomyosarcoma

Topics: Adenocarcinoma; Ameloblastoma; Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Carcinoma; Carcinoma, Squamous Cell; Cyclophosphamide; Ethylenediamines; Facial Neoplasms; Fibrosarcoma; Glioma; Humans; Infusions, Parenteral; Mechlorethamine; Melanoma; Melphalan; Meningioma; Methotrexate; Osteosarcoma; Perfusion; Quinones; Retinoblastoma; Rhabdomyosarcoma; Sarcoma; Thiotepa

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