melphalan and Lung-Neoplasms

Whole lung irradiation (WLI) represents an important part of multimodal therapy in Ewing sarcoma (EwS) patients diagnosed with pulmonary metastases. This review discusses pulmonary toxicity in EwS patients with pulmonary metastases treated with WLI, who received different modes of high-dose chemotheray (HD-Cth).. Literature was compiled using the Cochrane Library, PubMed database, and the National Institute of Health (NIH) clinical trials register. Relevant patient information, including nature of HD-Cth, acute and late lung toxicities, and pulmonary function disorders, was selected from the above databases.. Nine reports with a total of 227 patients, including 57 patients from a single randomized trial were included in this review. No acute or chronic symptomatic pulmonary toxicities were observed in patients that received WLI after HD busulfan-melphalan (HD-Bu/Mel), but 8% of these patients were diagnosed with asymptomatic restrictive lung disease. Grade 1 or 2 acute or chronic lung adverse effects were observed in up to 30% of patients that received WLI after HD treosulfan/Mel (HD-Treo/Mel) or HD etoposide (E)/Mel. Interstitial pneumonitis was present in 9% of patients treated concurrently with E/Mel and total body irradiation (TBI) with 8 Gy. Radiation doses as well as time between HD-Cth and WLI were both identified as significant risk factors for pulmonary function disorders.. The risk of adverse lung effects after WLI depends on several factors, including cumulative radiation dose and dose per fraction, HD-Cth regimen, and time interval between HD-Cth and WLI. A cumulative radiation dose of up to 15 Gy and a time interval of at least 60 days can potentially lead to a reduced risk of pulmonary toxicities. No evident adverse lung effects were registered in patients that received simultaneous therapy with HD-Cth and TBI. However, pulmonary function testing and lung toxicity reports were lacking for most of these patients.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Combined Modality Therapy; Dose Fractionation, Radiation; Dose-Response Relationship, Radiation; Drug Administration Schedule; Etoposide; Female; Humans; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Male; Melphalan; Procedures and Techniques Utilization; Radiation Pneumonitis; Radiotherapy Dosage; Radiotherapy, Intensity-Modulated; Respiratory Function Tests; Risk; Sarcoma, Ewing; Whole-Body Irradiation; Young Adult

Even after complete surgical resection of pulmonary metastases, many patients develop recurrent disease in the thorax despite the use of systemic chemotherapy, dosage of which is limited because of systemic toxicity. Although subsequent operations are feasible and good long-term results have been reported, sufficient functional lung parenchyma must remain. For this reason, new treatment strategies are explored. Similar to isolated limb and liver perfusion, isolated lung perfusion (ILuP) is a promising surgical technique for the delivery of high-dose chemotherapy with minimal systemic toxicity. The use of biologic response modifiers, such as tumor necrosis factor, is also feasible. ILuP with high-dose chemotherapy has proven to be highly effective in the experimental models of pulmonary metastases with a superior survival advantage compared with systemic treatment. Lung levels are significantly higher after ILuP compared with intravenous therapy without systemic exposure. Phase I human studies have shown that ILuP is technically feasible with low morbidity and without compromising the patient's pulmonary function. Further clinical studies are necessary to determine its definitive effect on local recurrence, long-term toxicity, pulmonary function, and survival.

Topics: Chemoembolization, Therapeutic; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Combined Modality Therapy; Doxorubicin; Humans; Interferon-gamma; Lung Neoplasms; Melphalan; Tumor Necrosis Factor-alpha

This clinical practice guideline, based on a systematic review, evaluates chemotherapy options for patients with relapsed small cell lung cancer (SCLC).. Relevant randomized trials and meta-analyses were identified through a systematic search of the literature. External feedback was obtained from practitioners in Ontario, and the guideline was approved by the provincial lung cancer disease site group.. Six randomized trials met the eligibility criteria and were included for review. One randomized phase III trial of oral topotecan versus no treatment in patients receiving best supportive care found topotecan to have a significant benefit in terms of 6-month survival and quality of life. A randomized phase III trial compared outcomes of carboplatin in patients receiving a combination of etoposide and cisplatin (EP) and found no significant improvement associated with carboplatin, although it was associated with significantly higher grade 3/4 thrombocytopenia. Two randomized trials directly compared chemotherapy regimens (intravenous [i.v.] topotecan versus cyclophosphamide, doxorubicin, and vincristine (CAV); and bis-chloro-ethylnitrosourea, thiotepa, vincristine, and cyclophosphamide (BTOC) versus EP), but these trials found no significant differences in terms of disease response or survival. I.v. topotecan was associated with significantly higher toxicities (grade 4 thrombocytopenia and grade 3/4 anemia) and greater improvement in patient-reported symptoms compared with CAV. Two randomized trials of topotecan-treated patients comparing route of administration (i.v. versus oral) found no significant differences in terms of disease response, survival, or quality of life, although oral administration was associated with increased grade 3 or 4 diarrhea in both trials.. Evidence on the clinical benefit of second-line therapy in SCLC is limited. Topotecan is the most studied agent in this population; it has a response and survival benefit in comparison with placebo, but it also has greater toxicity in comparison with CAV. To date, significant differences in terms of response and survival are not evident in studied chemotherapy options.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Clinical Trials, Phase III as Topic; Etoposide; Female; Humans; Infusions, Intravenous; Lomustine; Lung Neoplasms; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Ontario; Practice Guidelines as Topic; Prognosis; Randomized Controlled Trials as Topic; Salvage Therapy; Survival Analysis; Topotecan

Pulmonary metastasectomy is a widely accepted treatment for many patients with pulmonary metastases from various solid tumors. Nevertheless, 5-year survival is disappointing, with rates of 25-40%, and many patients develop recurrences. Isolated lung perfusion (ILuP) is a promising new technique to deliver high-dose chemotherapy to the lungs, while minimising systemic toxicities. This procedure is technically safe and feasible; however, clinical value and efficacy remain unclear. The aim of this paper is to give a review of literature on ILuP in humans, and to describe the development of the perfusion procedure in our institute.

Topics: Animals; Antineoplastic Agents; Blood Transfusion, Autologous; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials, Phase I as Topic; Combined Modality Therapy; Drug Screening Assays, Antitumor; Embolism, Air; Equipment Design; Extracorporeal Membrane Oxygenation; Feasibility Studies; Humans; Hydroxyethyl Starch Derivatives; Hyperthermia, Induced; Intraoperative Complications; Isotonic Solutions; Lung Neoplasms; Melphalan; Pilot Projects; Rheology; Ringer's Lactate; Sarcoma; Solutions; Temperature; Treatment Outcome

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Clostridium Infections; Clostridium perfringens; Embolization, Therapeutic; Fatal Outcome; Hemolysis; Humans; Liver Neoplasms; Lung Neoplasms; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasms, Multiple Primary; Prednisone; Sepsis

Mitomycin has proven to be among the most active drugs available for the single-agent treatment of non-small cell lung cancer (NSCLC). In combination with vinca alkaloids and cisplatin, mitomycin can produce response rates greater than or equal to 50% in properly selected patients. In our experience, such responses were achieved using moderate doses (7 or 8 mg/m2) of mitomycin, which also resulted in fewer hematologic and other toxicities. Delivery of MVP (mitomycin/vinca alkaloid/cisplatin) to 150 patients with stages III and IV NSCLC during the last decade showed maximal response was achieved after two or three cycles of therapy. A comparative analysis of results reported using MVP regimens suggests that high response rates are associated with greater dose-intensive use of cisplatin and lesser dose-intensive use of mitomycin. Although the role of MVP in the treatment of advanced NSCLC is unclear, use of mitomycin-containing regimens as part of a multidisciplinary approach to stage IIIA NSCLC has yielded high response rates and has successfully downstaged patients prior to surgery. Randomized clinical trials will be required to validate these findings, but the focus of future research should be on discovering new agents with greater activity and on developing new approaches wherein these agents can be delivered with maximum efficacy and minimum toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Combined Modality Therapy; Humans; Lung Neoplasms; Melphalan; Methotrexate; Mitomycin; Mitomycins; Progesterone; 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: Alkylating Agents; Busulfan; Carcinoma, Bronchogenic; Carmustine; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Mechlorethamine; Melphalan; Neoplasms; Ovarian Neoplasms; Testicular Neoplasms

A 20-year-old student presented with diarrhoea and miliary mottling in the chest radiograph. Biopsy specimens of lung and cervical lymph node showed diffuse multifocal carcinoid tumour. No deterioration in clinical state, radiographic appearances or lung function has occurred after two years' treatment with melphalan.

Topics: Adult; Amyloid; Biopsy; Carcinoid Tumor; Humans; Lung Neoplasms; Lymph Nodes; Male; Melphalan

Up to 66% of patients show local pulmonary disease progression after pulmonary metastasectomy. Regional treatment with isolated lung perfusion (ILuP) may improve local control with minimal systemic adverse effects. The aims of this study were to evaluate local and distant control after ILuP, determine the effect on overall survival compared with historical controls, and confirm the safety and feasibility of ILuP.. A total of 107 patients with resectable pulmonary metastases of colorectal carcinoma, osteosarcoma, and soft-tissue sarcoma were included in a prospective phase II study of pulmonary metastasectomy combined with ILuP with 45 mg melphalan at 37°C. Local and distant control, overall survival, lung function, and 90-day mortality and morbidity were monitored.. We report 0% mortality, low morbidity, and no long-term pulmonary toxicity. For colorectal carcinoma, median time to local pulmonary progression, median time to progression, and median survival time were 31, 14, and 78 months, respectively. Median time to local progression was not reached for sarcoma, whereas median time to progression and median survival time were 13 and 39 months, respectively. The 5-year disease-free rate and pulmonary progression-free rate were 26% and 44% for colorectal carcinoma and 29% and 63% for sarcoma, respectively.. ILuP with melphalan combined with metastasectomy is feasible and safe. Compared with historical controls, favorable results were obtained in this phase II study for local control. Further evaluation of locoregional lung perfusion techniques with other chemotherapeutic drugs is warranted.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Bone Neoplasms; Colorectal Neoplasms; Combined Modality Therapy; Disease Progression; Female; Historically Controlled Study; Humans; Lung Neoplasms; Male; Melphalan; Metastasectomy; Middle Aged; Perfusion; Prospective Studies; Sarcoma; Survival Analysis

The 5-year overall survival rate of patients undergoing complete surgical resection of pulmonary metastases (PM) from colorectal cancer (CRC) and sarcoma remains low (20-50%). Local recurrence rate is high (48-66%). Isolated lung perfusion (ILuP) allows the delivery of high-dose locoregional chemotherapy with minimal systemic leakage to improve local control.. From 2006 to 2011, 50 patients, 28 male, median age 57 years (15-76), with PM from CRC (n = 30) or sarcoma (n = 20) were included in a phase II clinical trial conducted in four cardiothoracic surgical centers. In total, 62 ILuP procedures were performed, 12 bilaterally, with 45 mg of melphalan at 37°C, followed by resection of all palpable PM. Survival was calculated according to the Kaplan-Meier method.. Operative mortality was 0%, and 90-day morbidity was mainly respiratory (grade 3: 42%, grade 4: 2%). After a median follow-up of 24 months (3-63 mo), 18 patients died, two without recurrence. Thirty patients had recurrent disease. Median time to local pulmonary progression was not reached. The 3-year overall survival and disease-free survival were 57% ± 9% and 36% ± 8%, respectively. Lung function data showed a decrease in forced expiratory volume in 1 second and diffusing capacity of the alveolocapillary membrane of 21.6% and 25.8% after 1 month, and 10.4% and 11.3% after 12 months, compared with preoperative values.. Compared with historical series of PM resection without ILuP, favorable results are obtained in terms of local control without long-term adverse effects. These data support the further investigation of ILuP as additional treatment in patients with resectable PM from CRC or sarcoma.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Male; Melphalan; Metastasectomy; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Osteosarcoma; Survival Rate; Young Adult

Surgical resection of lung metastases is a widely accepted procedure but 5-year survival rates remain low and vary between 20% and 50%. Isolated lung perfusion (ILuP) is an experimental technique to deliver a high dose of chemotherapy to the lung, without systemic toxicity. Long-term survival of ILuP has not been reported yet and was determined in a phase I clinical trial.. From May 2001 to December 2004, a phase I clinical trial was conducted to define the maximum tolerated dose (MTD) of ILuP with melphalan. Twenty-nine procedures were performed in 23 patients. The primary tumour was colorectal in 10 patients, renal in eight, sarcoma in four and salivary gland in one. Toxicity results were previously reported and the MTD of melphalan was determined at 45 mg when given at 37°C. Follow-up was updated and long-term survival is reported.. Follow-up was complete, except for one patient who was lost to follow-up after 8 months. After a median follow-up of 62 months, 6 out of 23 patients were alive and free of recurrent disease. One patient died after a subsequent operation. Sixteen patients developed recurrent disease, of whom 11 died. Nine patients had intrathoracic recurrent disease only, one intra- and extrathoracic recurrences each and five extrathoracic only. In one patient, the location of recurrence was not known. Overall- and disease-free 5-year survival rates were 54.8 ± 10.6% and 27.5 ± 9.5%, respectively with an overall median survival time (MST) of 84 months (95% confidence interval (CI): 41-128) and disease-free MST of 19 months (95% CI: 4-34). Lung function and diffusion capacity initially dropped 1 month after perfusion, slightly improving afterwards. Radiographic follow-up with chest computed tomography showed no long-term toxicity from ILuP.. ILuP can be applied without major long-term pulmonary toxicity. Five-year survival rate, overall and disease-free MST in this phase I clinical trial are promising. This is another incentive to perform further studies with ILuP.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Epidemiologic Methods; Female; Forced Expiratory Volume; Humans; Lung Neoplasms; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Reoperation; Total Lung Capacity; Treatment Outcome

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Humans; Hyperthermia, Induced; Longitudinal Studies; Lung Neoplasms; Melphalan; Preoperative Care

Isolated lung perfusion (ILuP) with melphalan was performed under normo- and hyperthermic conditions combined with pulmonary metastasectomy for patients with resectable lung metastases. We present the results of pharmacokinetic analysis of a phase I and extension trial.. Twenty-one procedures of ILuP with melphalan were performed in the phase I trial according to a dose-escalation schedule under normothermic and hyperthermic conditions followed by surgical resection of pulmonary metastases. In an extension trial 8 additional procedures with 15 and 45 mg melphalan were performed under hyperthermic conditions. Samples of serum, perfusate, lung, and tumor tissue were obtained.. High perfusate concentrations of melphalan were recorded in contrast to low systemic concentrations. Marked interindividual variability was observed in melphalan concentrations in perfusate, tumor, and lung tissue. Statistically significant correlation between melphalan dose, and perfusate area under the concentration-time curve (R(2) = 0.578, P = 0.001) and lung tissue concentrations (R(2) = 0.459, P = 0.028) were noted. No significant correlation between melphalan dose and tumor tissue concentrations could be established.. Isolated lung perfusion effectively delivers high doses of melphalan to the lung and tumor tissues with minimal systemic levels. Significant correlation between perfused melphalan dose, perfusate area under the concentration-time curve and lung tissue melphalan concentrations were observed.

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

Current 5-year survival after complete resection of pulmonary metastases is 20% to 40%, and many patients develop intrathoracic recurrences. Isolated lung perfusion is an experimental technique to deliver high-dose chemotherapy to the lung without systemic exposure. A phase I trial of isolated lung perfusion with melphalan (MN) combined with pulmonary metastasectomy for resectable lung metastases was conducted to define the dose-limiting toxicity and maximum tolerated dose.. From May 2001 to August 2003, 16 patients underwent isolated lung perfusion with MN, followed by surgical resection of lung metastases. Patients were treated with increasing MN doses (15, 30, 45, and 60 mg). For each dose level, normothermia (37 degrees C) and hyperthermia (42 degrees C) were evaluated (n = 3 per level). Serum samples were obtained during the procedure. Pulmonary, hematologic, and nonhematologic toxicities were recorded. The primary tumor was colorectal in 7 patients, renal in 5, sarcoma in 3, and salivary gland in 1. Isolated lung perfusion was performed unilaterally in 11 patients, and staged bilaterally in 5.. In total, 21 procedures of isolated lung perfusion with complete metastasectomy were performed without technical difficulties. Operative mortality was 0%, and no systemic toxicity was encountered. Grade 3 pulmonary toxicity developed at a dose of 60 mg of MN at 37 degrees C in 2 of 3 patients at this dose, terminating the trial.. Isolated lung perfusion with MN combined with pulmonary metastasectomy is feasible. Dose-limiting toxicity occurred at a dose of 60 mg of MN at 37 degrees C, and the maximum tolerated dose was set at 45 mg of MN at 42 degrees C.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Female; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Melphalan; Middle Aged; Pulmonary Surgical Procedures; Salivary Gland Neoplasms; Sarcoma

Despite reports that i.v. melphalan is active in the settings of conditioning regimens utilizing high-dose chemotherapy for autologous bone marrow transplantation and in isolated limb perfusion for the treatment of malignant melanoma, its activity at conventional doses has never been defined in this disease. We conducted a phase II study of conventional-dose i.v. melphalan (30 mg/m2) in 17 patients with metastatic melanoma. All patients were previously untreated with chemotherapy with performance status 0, 1 or 2. Forty-seven cycles were given with a median of two cycles. One patient was not evaluable due to early death. There were no responses in the 16 patients, resulting in a 0% response rate (95% confidence interval = 0-17%). We conclude that conventional-dose melphalan by i.v. administration has no appreciable activity in patients with metastatic malignant melanoma.

Topics: Adrenal Gland Neoplasms; Adult; Aged; Antineoplastic Agents, Alkylating; Brain Neoplasms; Dose-Response Relationship, Drug; Female; Gastrointestinal Neoplasms; Hematologic Diseases; Humans; Liver Neoplasms; Lung Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Soft Tissue Neoplasms; Treatment Outcome

Current treatments for metastatic breast cancer are not associated with significant survival benefits despite response rates of over 50%. High-dose therapy with autologous bone marrow transplantation (ABMT) has been investigated, particularly in North America, and prolonged survival in up to 25% of women has been reported, but with a significant treatment-related mortality. However, in patients with haematological malignancies undergoing autologous transplantation, haematopoietic reconstruction is significantly quicker and mortality lower than with ABMT, when peripheral blood progenitor cells (PBPCs) are used. In 32 women with metastatic breast cancer, we investigated the feasibility of PBPC mobilisation with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) after 12 weeks' infusional induction chemotherapy and the subsequent efficacy of the haematopoietic reconstitution after conditioning with melphalan and either etoposide or thiotepa. PBPC mobilisation was successful in 28/32 (88%) patients, and there was a rapid post-transplantation haematopoietic recovery: median time to neutrophils > 0.5 x 10(9) l-1 was 14 days and to platelets > 20 x 10(9) l-1 was 10 days. There was no procedure-related mortality, and the major morbidity was mucositis (WHO grade 3-4) in 18/32 patients (56%). In a patient group of which the majority had very poor prognostic features, the median survival from start of induction chemotherapy was 15 months. Thus, PBPC mobilisation and support of high-dose chemotherapy is feasible after infusional induction chemotherapy for patients with metastatic breast cancer, although the optimum drug combination has not yet been determined.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Central Nervous System Neoplasms; Chi-Square Distribution; Confidence Intervals; Diarrhea; Disease-Free Survival; Etoposide; Female; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Herpes Zoster; Humans; Liver Neoplasms; Lung Neoplasms; Melphalan; Middle Aged; Neoplasm Staging; Survival Rate; Thiotepa; Treatment Outcome

Experimental, and more recently, clinical data have suggested the influence of hemostasis in the spread of malignant disease.. To complete research in this type of coagulation and cancer, a multicentric randomized clinical trial was performed, including 303 patients with small cell lung cancer (SCLC), treated by the addition of aspirin at 1 g/day (a dosage at which aspirin is considered to be a platelet aggregation inhibitor) to combined chemotherapy.. Survival was not increased in the aspirin-treated group (P = 0.90). The analysis according to the extent of disease (limited or extensive disease) did not modify that conclusion.. This result does not confirm the hypothesis that, in SCLC, aspirin (a platelet aggregation inhibitor) reduces metastasis formation and local tumor thrombogenesis.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aspirin; Carcinoma, Small Cell; Cyclophosphamide; Doxorubicin; Etoposide; Female; Humans; Lomustine; Lung Neoplasms; Male; Melphalan; Middle Aged; Platelet Aggregation; Prednisone; Survival Rate

One hundred patients with non-small cell lung cancer were entered by members of the Northern California Oncology Group into a randomized Phase II trial of i.v. melphalan versus i.v. melphalan with concomitant oral misonidazole. The patients had not received prior chemotherapy. Eighty-five patients were evaluable for assessment of response and 89 were evaluable for toxicity analysis. The melphalan/misonidazole group had a superior response rate (two complete and four partial responses among 42 patients or 14%) compared to the melphalan group in which there were no responses among 43 patients (p = 0.024, two-sided Fisher exact test). Since hematological toxicity was equivalent in the two groups, there was an improvement in therapeutic index. Data from 12 patients undergoing pharmacological studies demonstrated that the plasma concentration of melphalan was 25% higher in the misonidazole group, a difference that is not statistically significant. Although the mechanism of interaction has not been fully established, this randomized trial demonstrates that a chemosensitizer can enhance the clinical antitumor activity of an alkylating agent and suggests that chemosensitizers in combination with alkylating agents should be investigated in further clinical trials.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Drug Evaluation; Female; Humans; Lung Neoplasms; Male; Melphalan; Middle Aged; Misonidazole

A total of 241 patients with early breast cancer had serial bone scans and chest radiographs during the first two years of follow-up after primary treatment. Each patient had had a modified radical mastectomy and been found to have involved axillary nodes. They were part of a prospective randomized trial testing the use of L-phenylalanine mustard L-PAM as adjuvant chemotherapy. During the two years, these patients had a total of 832 serial bone scans and 1091 serial chest radiographs. Twenty-five patients (10.4 per cent) had bone metastases detected on sequential scanning, only 13 of whom, however, were asymptomatic at the time of the positive scan. Twelve (5 per cent) patients were found to have pulmonary metastases on routine sequential chest radiography of whom only 8 were asymptomatic at the time of the positive chest radiograph. It is concluded from this study that, apart from their usefulness in the monitoring of clinical trials, serial bone scans and chest radiographs cannot be recommended routinely in the follow-up of asymptomatic patients because of the low yield and high cost involved.

Topics: Adult; Aged; Bone Neoplasms; Breast Neoplasms; Follow-Up Studies; Humans; Lung Neoplasms; Melphalan; Middle Aged; Prospective Studies; Radiography; Radionuclide Imaging; Time Factors

The therapeutic effects of adriamycin and of melphalan in patients with advanced carcinoma of the ovary were tested in a prospective randomized study. Complete and partial remission occurred in eight of 19 patients treated with adriamycin and in four of 20 patients given melphalan. The difference, however, is not statistically significant. The median duration of complete and partial remissions was slightly longer after treatment with melphalan than with adriamycin. The number of cycles required to produce the initial regression state was less in the patients in the group given adriamycin as compared with those in the group treated with melphalan. No cross resistance was observed between the two drugs. These data indicate that, in patients with carcinoma of the ovary, the therapeutic efficacy of adriamycin is competitive with that of the most effective conventional agents, such as melphalan.

Topics: Adenocarcinoma; Carcinoma; Clinical Trials as Topic; Doxorubicin; Drug Evaluation; Endometriosis; Female; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms; Remission, Spontaneous

Topics: Adolescent; Adult; Aged; Bone Marrow; Bone Neoplasms; Carcinoma; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Dactinomycin; Drug Synergism; Female; Fluorouracil; Gastrointestinal Neoplasms; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Mitomycins; Parotid Neoplasms; Sarcoma; Urogenital Neoplasms; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemoradiotherapy; Etoposide; Humans; Infant; Kidney Neoplasms; Lung Neoplasms; Male; Melphalan; Wilms Tumor

Topics: Antineoplastic Agents, Alkylating; Female; Humans; Lung Neoplasms; Male; Melphalan; Radiosurgery

Topics: Antineoplastic Agents, Alkylating; Female; Humans; Lung Neoplasms; Male; Melphalan; Radiosurgery

For treatment of metastatic lung lesions there was used the method of isolated chemoperfusion in combination with metastasectomy. The study included 74 patients (mean age 43 ± 13.4 years). There were performed 99 normothermic isolated chemoperfusions of the lung: with melphalan (39) and cisplatin (60). During surgery there were no lethality outcomes. In the immediate postoperative period it was recorded 1 (1.4%) death developed in 3 days after surgery. The cause of this death was postperfusion lung edema accompanied by increase of signs of respiratory insufficiency. There were following complications after isolated chemoperfusions of the lung: anemia--23 (23.1%), nausea--13 (13.1%), vomiting--5 (5.1%), atrial fibrillation--10 (10.1%), pneumonia-2 (2.0%), pulmonary infarction--2 (2.0%), chylothorax--1 (1.0%), pneumothorax--29 (29.3%), emphysema of soft tissues of the chest wall 73 (73.7% ). Thus isolated chemoperfusion of the lung with melphalan or cisplatin is a procedure reproducible and relatively safe.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Chemotherapy, Cancer, Regional Perfusion; Chylothorax; Cisplatin; Female; Humans; Lung Neoplasms; Male; Melphalan; Metastasectomy; Middle Aged; Nausea; Pneumothorax; Respiratory Insufficiency; Subcutaneous Emphysema; Treatment Outcome

Topics: Adult; Breast Neoplasms; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Crizotinib; Drug Resistance, Neoplasm; Female; Gene Rearrangement; Humans; Immunoglobulin G; Lung Neoplasms; Melphalan; Oncogene Proteins, Fusion; Pyrazoles; Pyridines; Skin Neoplasms

Melphalan is a widely used cytotoxic agent in cancer treatments. This phenylalanine analog has been shown an effective drug in the treatment of breast cancer, multiple myeloma and melanoma of the extremities. A good knowledge of the drug's degradation and metabolism are crucial for understanding its activity during cancer treatments.. The formation of hydrolysis products of melphalan is studied using ultra-performance liquid chromatography (UPLC) tandem mass spectrometry (MS/MS). Aqueous melphalan solutions were incubated at elevated temperatures and analyzed by UPLC/MS/MS. Two previously described hydrolysis products, mono- and dihydroxymelphalan (MOH and DOH), were formed in vitro and could be characterized during MS/MS and high-resolution experiments.. Novel compounds with m/z values >500 Da were discovered. Comparison of the fragmentation patterns of these new molecules with those of MOH and DOH show great similarities. The higher masses are explained by the presence of two or more melphalan units. In total, more than 15 new hydrolysis products were found. Experiments were set up to study the formation and the chemical structures of these molecules.. The hydrolysis of melphalan is studied in the scope of a phase II clinical trial (isolated lung perfusion, ILuP). Patient samples were screened for the presence of all documented and novel melphalan hydrolysis products. This study reports the formation of a new class of oligomeric compounds in both in vivo and in vitro samples.

Topics: Antineoplastic Agents; Cardiovascular Surgical Procedures; Chromatography, High Pressure Liquid; Clinical Trials, Phase II as Topic; Hot Temperature; Humans; Hydrolysis; Lung; Lung Neoplasms; Melphalan; Perfusion; Tandem Mass Spectrometry

Amyloidosis is a systemic disease caused by abnormal deposition of amyloid material that is detected with Congo red staining and is difficult to diagnose. Involvement of the tracheobronchial tree is rare and is a challenge for pulmonologists because of the wide differential diagnosis of this disease. We present two cases where tracheobronchial affectation has been observed: in one of them as a primary disease, and in another as secondary affectation. The use of bronchoscopic techniques is essential for the diagnosis of tracheobronchial involvement. In the absence of an effective drug therapy, local management of this disease with endoscopic techniques for bronchial repermeabilization is able to provide clinical improvement and expand the treatment options and prognosis in this disease.

Topics: Airway Obstruction; Amyloidosis; Biopsy; Birefringence; Bone Marrow; Bronchial Diseases; Bronchial Neoplasms; Bronchoscopy; Coloring Agents; Combined Modality Therapy; Congo Red; Diagnosis, Differential; Female; Hemoptysis; Humans; Laser Therapy; Lung; Lung Neoplasms; Male; Melphalan; Middle Aged; Prednisone; Tracheal Diseases

Cyclooxygenase (COX)-2 plays an important role in tumorigenesis and has been implicated to be a critical factor for invasion and metastasis of lung cancer. Tetramethylpyrazine (TMP), an effective component of the traditional Chinese medicine Chuanxiong, has been traditionally used in treating neurovascular and cardiovascular diseases. Recently TMP has been reported to have beneficial effect in cancer patients. However, the function and the mechanism of TMP in lung cancer have not been elucidated to date. In this study, we investigated the in vitro and in vivo effect of TMP in tumorigenesis and whether COX-2 is a molecular target of TMP. We showed that TMP exhibited a dose- and time-dependent inhibition on A549 cell proliferation by suppressing cell cycle progression. In vitro treatment of A549 cells with TMP resulted in a significant inhibition of invasion, associated with reduced activities of COX-2 and MMP-2/TIMP-2. Furthermore, in vivo experiments showed that TMP significantly suppressed metastatic growth of A549 cells and COX-2 expression in metastatic nude mouse model. This preclinical study provides the first evidence for the novel anti-tumor effects of TMP as a COX-2 pathway inhibitor in human adenocarcinoma cell line A549. These studies suggest that TMP may serve as an effective agent for the treatment and chemoprevention of non-small cell lung cancer.

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclooxygenase 2 Inhibitors; Dinoprostone; Female; Humans; Immunoglobulin G; Lung Neoplasms; Matrix Metalloproteinase 2; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Pyrazines; Xenograft Model Antitumor Assays

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

The Italian Sarcoma Group and the Scandinavian Sarcoma Group designed a joint study to improve the prognosis for patients with Ewing's family tumors and synchronous metastatic disease limited to the lungs, or the pleura, or a single bone.. The study was opened in 1999 and closed to the enrollment in 2008. The program consisted of intensive five-drug combination chemotherapy, surgery and/or radiotherapy as local treatment, and consolidation treatment with high-dose busulfan/melphalan plus autologous stem cell rescue and total-lung irradiation.. During the study period, 102 consecutive patients were enrolled. The median follow-up was 62 months (range 24-124). The 5-year event-free survival probability was 0.43 [standard deviation (SD) = 0.05] and the 5-year overall survival probability was 0.52 (SD = 0.052). Unfavorable prognostic factors emerging on multivariate analysis were a poor histological/radiological response at the site of the primary tumor [relative risk (RR) = 3.4], and incomplete radiological remission of lung metastases after primary chemotherapy (RR = 2.6). One toxic death and one secondary leukemia were recorded.. This intensive approach is feasible and long-term survival is achievable in ∼50% of patients. New treatment approaches are warranted for patients responding poorly to primary chemotherapy.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Etoposide; Female; Humans; Ifosfamide; Lung Neoplasms; Male; Melphalan; Myeloablative Agonists; Neoplasm Metastasis; Prognosis; Sarcoma, Ewing; Stem Cell Transplantation; Vincristine; Young Adult

The patient was a 48-year-old male with a right subclavicular tumor. The pathological diagnosis showed primitive neuroectodermal tumor(PNET)because of the rosette formation and the positive neurogenic marker.Radiation was administered at a total dose of 50 Gy, because surgical resection would induce the loss of right arm function. CT examination demonstrated a reduction of the primary tumor and new multiple lung metastases. The patient received intravenous AI regimen(ADM and IFM). After the 7th course, both the primary tumor and multiple lung metastases decreased. AI regimen might be effective for PNET.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Boronic Acids; Bortezomib; Doxorubicin; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Melphalan; Middle Aged; Mitolactol; Mitomycins; Neuroectodermal Tumors, Primitive; Pyrazines; Salvage Therapy; Suicide; Tomography, X-Ray Computed

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

Topics: Adult; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Equipment Design; Female; Humans; Lower Extremity; Lung Neoplasms; Lymphatic Metastasis; Male; Melphalan; Middle Aged; Retrospective Studies; Sarcoma; Treatment Outcome

In order to design the agents with improved antitumor activity of 3,5-bis(thienylidene)piperid-4-one type, E,E-N-phosphoryl-3,5-bis(thienylidene)piperid-4-ones 6a-c and E,E-N-omega-phosphorylalkyl-3,5-bis-(thienylidene)piperid-4-ones 7a-c were obtained via the direct phosphorylation of the parent NH-3,5-bis(thienylidene)piperid-4-one and by condensation of preformed N-phosphorylalkyl substituted piperidones with thiophene 2-carbaldehyde, respectively. The structures of the compounds were elucidated by (1)H, (31)P, (13)C NMR along with a single crystal X-ray diffraction analysis. Under the action of visible light thermodynamically more stable E,E-isomers slowly undergo photochemical conversion in CDCl(3) solution to the corresponding E,Z-isomers and E,Z-N-methyl-3,5-bis(thienylidene)piperid-4-one 5 was isolated in individual state. The importance of phosphorylation for cytotoxic properties of 3,5-bis(thienylidene)piperid-4-ones towards human carcinoma cell lines Caov3, Scov3, and A549 and influence of olefin configuration on antitumor activity were demonstrated.

Topics: Antineoplastic Agents; Cell Line, Tumor; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Female; Humans; Lung Neoplasms; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Nitrogen; Ovarian Neoplasms; Phosphorylation; Piperidones; Structure-Activity Relationship; Thiophenes

In previous research, we focused on the discovery of K-ras biomarkers, and effects of genotoxic carcinogens on their expression were investigated in this study. It is well-known that mutated K-ras gene is involved in approximately 30% of human cancers such as lung cancer. To search for K-ras oncogene-induced modulators in lung tissues of K-ras transgenic mice, we analyzed K-ras-specific genes and proteins related to cancer development, signal transduction, inflammation as well as tumor suppression in a previous study. In this study, we investigated the modulating effects of genotoxic carcinogen treatment on expression of K-ras-dependent modulated genes and proteins in lung tissues of K-ras Tg mice. In order to evaluate candidate K-ras markers modulated by genotoxic stress and to investigate whether a genotoxic carcinogen would enhance or inhibit carcinogenesis in lung tissues of the K-ras Tg mice, the anti-cancer drug melphalan was intraperitoneally injected into K-ras Tg mice every two days for four weeks. RT-qPCR and proteomics analyses were performed in order to confirm whether K-ras-specific biomarkers would be modulated by melphalan treatment in K-ras Tg mice. The decreased adenomas were histopathologically observed and K-ras expression was suppressed in melphalan-treated K-ras Tg mice. Melphalan also recovered the expression of K-ras-dependent modulated biomarkers. These results suggest that melphalan inhibits carcinogenesis via modulating K-ras-specific genes and proteins expressed in the lung tissues of K-ras Tg mice.

Topics: Adenoma; Animals; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Cell Proliferation; Cluster Analysis; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, ras; Humans; Lung Neoplasms; Male; Melphalan; Mice; Mice, Transgenic; Models, Biological

HPV oncoproteins are selectively retained and expressed in HPV infected carcinoma cells. The E7 oncoprotein interacts with the tumour suppressor Rb, and leads to the progression of oncogenesis. In a previous study, E7 biomarkers were identified in E7 Tg mice. In this study, in order to investigate whether a genotoxic carcinogen would modulate carcinogenesis in the E7-Tg mice, an anticancer drug, melphalan, was intraperitoneally injected into E7-Tg mice for eight weeks at two-day intervals and then genes and proteins were analysed using Omics approaches and RT-qPCR. RT-qPCR was performed to confirm whether E7 biomarkers would be modulated by melphalan treatment in E7-Tg mice, revealing that up-regulated E7 markers such as cyclin B1, CD166, and actin alpha1 were down-regulated, whereas expression of down-regulated E7 markers such as vimentin was restored by melphalan treatment. These results suggest that melphalan inhibits carcinogenesis via modulating E7-specific genes and proteins expressed in the lung tissues of E7 Tg mice.

Topics: Actins; Activated-Leukocyte Cell Adhesion Molecule; Animals; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Cyclin B1; Down-Regulation; Female; Injections, Intraperitoneal; Lung; Lung Neoplasms; Male; Melphalan; Mice; Mice, Transgenic; Papillomavirus E7 Proteins; Papillomavirus Infections; Reverse Transcriptase Polymerase Chain Reaction

Sunitinib demonstrating efficacy in pancreatic islet cell carcinomas will pave the way for further trials in other neuroendocrine tumor types such as carcinoid, poorly differentiated neuroendocrine disease, and several other endocrine tumors that are dependent on VEGF/VEGFR for angiogenesis. In addition, other drugs with distinct mechanisms of action, such as mTOR inhibitors, currently investigated in phase III trials, may also supply novel options in those diseases to control tumor growth and metastasis.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoid Tumor; Cell Line, Tumor; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Indoles; Kidney Neoplasms; Lung Neoplasms; Melphalan; Neovascularization, Pathologic; Neuroendocrine Tumors; Pancreatic Neoplasms; Procarbazine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyrroles; Sunitinib; Vinblastine; Xenograft Model Antitumor Assays

In patients with unresectable lung cancer or pulmonary metastases, isolated lung perfusion (ILP) has been described as an alternative method to deliver high-dose chemotherapy to the lungs, thereby minimizing systemic toxicity. Pharmacokinetics of ILP have not been extensively investigated. Therefore, we studied the feasibility of ILP with melphalan in a pig model with emphasis on pharmacokinetics and acute lung damage.. Five pigs underwent ILP with melphalan. Blood and tissue samples were obtained for determination of melphalan levels. Tissue biopsies were taken for microscopic evaluation of lung damage.. During ILP, no hemodynamic effects of importance were noted. No systemic leakage of melphalan was observed in any of the animals. Compared with normal lung tissue, microscopic examination of lung tissue after perfusion without melphalan showed pulmonary edema. Directly after melphalan perfusion additional hemorrhagic areas were seen; however, electron microscopy displayed no irreversible endothelial damage.. This study on pigs proved to be a well reproducible model for ILP with melphalan. Pharmacokinetics show a safety profile with no systemic toxicity, which could justify further patient studies, necessary to determine its effect on pulmonary metastases in humans, especially in case of adjuvant therapy after surgical resection or in unresectable disease.

Topics: Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Lung Neoplasms; Melphalan; Swine

Plasmacytoma is an uncommon tumor and is rarely encountered as a primary pulmonary neoplasm. Herein we describe the conventional radiographic and computed tomographic findings in a patient with a primary pulmonary plasmacytoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bronchoscopy; Cyclophosphamide; Female; Hemoptysis; Humans; Immunoenzyme Techniques; Lung; Lung Neoplasms; Melphalan; Middle Aged; Plasmacytoma; Prednisone; Remission Induction; Tomography, X-Ray Computed

Efficacy studies of isolated lung perfusion (ILuP) with melphalan showed superior results compared to intravenous therapy. However, the influence of pharmacokinetic parameters on the final melphalan lung concentration (FMLC) is unknown. In this study, we studied the impact of three different perfusion parameters on the FMLC in different areas of the lung.. Fifty-four rats were randomized into nine groups. Each group underwent ILuP with variation of perfusion duration (15, 30, and 60 min), the flow (0.125, 0.25, and 0.5 ml/min), concentration (8.3, 16.7, 33.3, 66.7, and 133.3 microg/ml) and the resulting dose (maximum 4 mg/kg). Lung samples were taken from the hilum and at the periphery of the lung (apex, base). Additional samples were taken to evaluate wet-to-dry ratio (W/D-ratio). Multiple linear regression and Student's t test were used for analysis. Significance was defined as a P

Topics: Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; In Vitro Techniques; Linear Models; Lung; Lung Neoplasms; Male; Melphalan; Rats; Tissue Distribution

Isolated lung perfusion (ILuP) is an experimental technique currently tested to increase the 5-year survival of 40% after surgical resection of pulmonary metastases from certain solid tumors. The standard technique of anterograde perfusion was compared with retrograde isolated lung perfusion in which the drug is introduced through the pulmonary veins while the effluent is collected from the pulmonary artery. Since the lung has a dual arterial circulation through the pulmonary artery and bronchial circulation, perfusion through the pulmonary veins can result in a more homogeneous distribution throughout the lung with subsequent higher melphalan concentration.. We randomized 20 rats into two groups. Group one underwent anterograde isolated left lung perfusion while group two underwent retrograde isolated left lung perfusion. A dose of 2 mg/kg melphalan (MN) was administered to the lung at a flow of 0.5 mL/min during 30 min, followed by a 5-min washout with buffered hetastarch (BHE). The final melphalan lung concentration (FMLC) was determined in the hilum, at the apex, the mid-periphery and the base of the lung. Statistical analysis was done with an unpaired student's t-test.. Retrograde left ILuP resulted in a higher FMLC in the hilum (P<0.0001) and in the base of the lung (P=0.03), while anterograde ILuP induced a higher concentration at the apex of the lung (P=0.04). No difference was seen in the mid-peripheral area of the lung (P=0.92).. In this experimental study, retrograde perfusion seems to increase final melphalan lung concentration in hilar and basal regions of the lung compared to anterograde perfusion.

Topics: Animals; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Lung Neoplasms; Male; Melphalan; Models, Animal; Pulmonary Artery; Pulmonary Veins; Random Allocation; Rats; Rats, Inbred Strains

Isolated lung perfusion is an experimental technique for the treatment of lung metastases. Single-agent isolated lung perfusion does not result in complete remission. We studied the in vivo and in vitro efficacy of combinations of gemcitabine, cisplatin, and melphalan.. In vitro, using the sulforhodamine B assay, CC531s cells were incubated with cisplatin, gemcitabine, or melphalan or with a combination of these drugs. One drug was added at concentrations causing 25% growth inhibition, whereas the second drug was added at variable concentrations. In vivo, left pulmonary metastases were induced in Wag/Rij rats by means of intravenous injection of CC531s adenocarcinoma cells. At day 7, rats underwent left isolated lung perfusion with gemcitabine (n = 7), cisplatin (n = 9), melphalan (n = 7), gemcitabine-cisplatin (n = 6), melphalan-gemcitabine (n = 6), and cisplatin-melphalan (n = 7). Death by means of metastatic disease was the end point. Survival and differences in survival were assessed by using Kaplan-Meier and log-rank testing.. In vitro synergistic activity was observed for melphalan-gemcitabine, whereas other combinations showed additive or antagonistic activity. In vivo treated rats lived longer compared with control animals ( P < .0001). In isolated lung perfusion melphalan resulted in longer survival compared with gemcitabine ( P = .0016) and cisplatin ( P = .046). Isolated lung perfusion with melphalan-gemcitabine resulted in 67% survival of the rats after 90 days versus 0% in other groups.. Isolated lung perfusion monotherapy or combination therapy with gemcitabine, cisplatin, or melphalan resulted in significantly longer survival compared with that seen in control animals. Isolated lung perfusion combination therapy with melphalan-gemcitabine resulted in the best survival either in vitro or in vivo.

Topics: Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Colorectal Neoplasms; Deoxycytidine; Dose-Response Relationship, Drug; Gemcitabine; In Vitro Techniques; Inhibitory Concentration 50; Lung Neoplasms; Male; Melphalan; Rats; Rats, Inbred Strains; Tumor Cells, Cultured

Two to three percent of the patients with extremity melanoma develop in-transit metastases in the course of their disease. When local treatments fail, isolated limb perfusion (ILP) is a reasonable option, but is generally only applied to patients without evidence of distant metastases. We assessed the value of ILP in stage IV melanoma patients with symptomatic unresectable limb melanoma at our institutions.. A computerized database, containing all patient, tumor, ILP, and follow-up data of 505 ILPs performed in 451 patients between 1978 and 2001, allowed the selection of eight (1.8%) stage IV patients who underwent a palliative ILP for unresectable melanoma lesions on the limbs. All patients had high tumor burden limb disease, according to the combined Fraker and Rossi criteria.. The overall tumor response rate was 88%, with 13% complete and 75% partial response rates. One patient did not respond to ILP. Three partial responding patients attained a complete remission (CR) after excision of the remaining limb lesions. The median duration of hospital stay was 12 days and acute regional toxicity was mild with slight erythema and edema in six and no signs of reaction in two patients. The median limb recurrence-free interval after CR was 6 months and the median duration from the time of distant metastases to death was 15 months. Overall ILP leads to the desired palliative effect in six patients (75%).. ILP should be considered as a palliative treatment in selected stage IV melanoma patients with symptomatic advanced limb disease.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Catheter Ablation; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Humans; Length of Stay; Lung Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Palliative Care; Remission Induction; Skin Neoplasms; Soft Tissue Neoplasms; Tourniquets; Tumor Burden; Tumor Necrosis Factor-alpha

Pleuropulmonary blastoma (PPB) is a rare and aggressive malignant tumor of the lung. Approximately 80 cases of PPB have been published, and in only three cases high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) was applied. A 5-year-old girl presenting with cough, fever, and shortness of breath was referred to the authors in March 1999. A computed tomography scan of the chest showed a tumor mass in the left hemithorax. The lesion was biopsied and the histopathologic report suggested the diagnosis of PPB. The patient received chemotherapy comprising vincristine, actinomycin D, and cyclophosphamide with only a minor response, and treatment was switched to ifosfamide, carboplatin, and etoposide, which produced a partial response. Tumor resection was performed, but margins were positive for PPB. Due to the high risk of recurrence, the authors elected to administrate high-dose chemotherapy using melphalan, etoposide, and carboplatin, followed by autologous HSCT. The patient achieved complete hematologic recovery, and reimaging after HSCT showed no evidence of disease. She relapsed 4 months later and died about 9 months after the completion of high-dose therapy. The role of high-dose chemotherapy and autologous HSCT is likely to be limited in PPB.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child, Preschool; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lung Neoplasms; Melphalan; Pulmonary Blastoma; Radiography; Transplantation, Autologous; Treatment Outcome

Isolated lung perfusion (ILuP) with melphalan (MN) is superior to intravenous infusion for the treatment of pulmonary carcinoma and sarcoma metastases. However, it is unknown whether a bolus injection of MN into the perfusion circuit or ILuP with a fixed concentration of MN will result in the highest lung levels.. ILuP with 0.5 mg MN was performed in Wag-Rij rats for 30 minutes either by a single-pass system (SP) (fixed concentration) (n = 10) or by reperfusion (RP) (bolus injection) (n = 10). In a separate experiment, rats were perfused with blood as the perfusate. In a third experiment, tumor levels were compared between SP, RP, or intravenous therapy with a dose of 0.5 mg. For induction of pulmonary metastases, 0.5 x 10(6) single adenocarcinoma cells were injected intravenously and therapy was given on day 30. For comparison of drug concentrations, unpaired Student's t test was applied. Statistical significance was accepted at p less than 0.05.. Lung perfusion studies were succesfully performed without systemic leakage. Temperature of perfusate and rats was 34 degrees C to 37 degrees C. A significantly higher hematocrit (mean 27.9) compared with buffered starch (mean 2.5) did not result in higher MN lung levels or lower wet-to-dry ratio. Tumor levels were significantly higher after ILuP compared with intravenous therapy. However, no difference in tumor and lung levels was seen between single-pass and reperfusion.. Both ILuP techniques resulted in significantly higher MN lung levels than after intravenous therapy. Because no difference was seen between single-pass and recirculating perfusion, MN can be injected as a bolus into the closed perfusion circuit.

Topics: Adenocarcinoma; Animals; Biological Availability; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Infusions, Intra-Arterial; Infusions, Intravenous; Lung; Lung Neoplasms; Male; Melphalan; Neoplasm Transplantation; Rats; Rats, Inbred Strains; Tumor Cells, Cultured

Children with Wilms tumor who have a particular risk of failure at relapse or at primary diagnosis were treated with high-dose chemotherapy (HDC) and autologous peripheral blood stem cell rescue in order to improve their probability of survival. From April 1992 to December 1998, 23 evaluable patients received HDC within the German Cooperative Wilms Tumor Studies. Nineteen were given melphalan, etoposide and carboplatin (MEC); the others received different regimens. The dose of carboplatin was adjusted according to renal function. Indications for HDC were high-risk relapse in 20 patients, bone metastases in two patients and no response in one patient. Fourteen of 23 patients are alive after a median observation time of 41 months, 11 of 14 in continuous complete remission, three in CR after relapse post HDC. The estimated survival and event-free survival for these patients are 60.9% and 48.2%. Twelve children relapsed after HDC; nine of them died within 12 months and three are surviving from 20 to 33 months after relapse. The main toxicities were hematologic, mucositis and renal (tubular dysfunction; intermittent hemodialysis in one patient). There were no toxic deaths. About half of the children suffering from Wilms tumor with very unfavorable prognostic factors survive disease-free after HDC for over 3 years. Besides hematological toxicity, mucositis and infections, renal function is at risk during HDC. With dose adjustment on glomerular filtration rate, however, no permanent renal failure was observed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Etoposide; Female; Germany; Hematologic Diseases; Humans; Ifosfamide; Infant; Kidney Diseases; Kidney Neoplasms; Life Tables; Lung Neoplasms; Male; Melphalan; Peripheral Blood Stem Cell Transplantation; Prognosis; Stomatitis; Survival Analysis; Thiotepa; Transplantation, Autologous; Wilms Tumor

The time-dependent dose-response relationships for the induction of DNA double-strand breaks (DSB) assessed by pulsed-field gel electrophoresis (PFGE) and for viability (evaluated by the MTT cytotoxicity test) were investigated in order to discriminate between genotoxic and cytotoxic mechanisms of DNA fragmentation. Cultured human lung epithelial cells (A549) were treated (i) with the aldehydes formaldehyde or glutaraldehyde and (ii) with the DNA-DNA interstrand crosslinkers melphalan, diepoxybutane or diepoxyoctane. Induction of DSB by formaldehyde and glutaraldehyde was seen only after cell viability was reduced to less than about 60% of the control values, indicating that DSB were the consequence of extragenomic damage and viability loss. Melphalan, diepoxybutane and diepoxyoctane induced DSB by a genotoxic mode with concentrations that did not affect cell survival: 8 h after treatment initiation both heat-labile crosslinks and DSB could be detected. Cells were not able to repair the crosslinks induced by diepoxybutane, the crosslinker with the shortest chain length. In contrast, with melphalan and diepoxyoctane, which have a longer crosslinking property considerable repair of crosslinks was observed. The molecular size distribution of the produced DNA fragments supported this mechanistic distinction. The DNA fragments generated by diepoxides were initially large, their concentration decreasing monotonously from 7 Mbp to less than 1 Mbp and were converted to smaller fragments by 72 h in the course of cell death. In contrast, DNA fragments induced by formaldehyde peaked below 1 Mbp, implicating activation of DNA-degrading enzymes.

Topics: Aldehydes; Alkylating Agents; Carcinogenicity Tests; Carcinogens; Cell Line; Cell Survival; DNA Damage; Electrophoresis, Gel, Pulsed-Field; Epithelial Cells; Epoxy Compounds; Formaldehyde; Glutaral; Humans; Lung; Lung Neoplasms; Melphalan; Mutagenicity Tests; Mutagens; Tumor Cells, Cultured

Survival after isolated lung perfusion (ILuP) with melphalan was tested in a model of unilateral pulmonary adenocarcinoma.. On day 0, rats were randomized into four groups: Group 1 (n = 9) received tumor cells intravenously for induction of bilateral lung metastases, whereas groups 2-4 (n = 21) underwent a 10-min occlusion of the right pulmonary artery during tumor cell injection for induction of unilateral left lung metastases. On day 7, groups 1 and 2 received no treatment. Group 3 underwent left ILuP with melphalan (2.0 mg/kg) while group 4 received melphalan intravenously (0.5 mg/kg). The end point of the study was death from metastatic disease.. Median survival of ILuP-treated animals (81 +/- 12 days) was significantly longer compared to group 1 (18 +/- 1 days; p = 0.0001), group 2 (28 +/- 3 days; p = 0.0002) and group 4 (37 +/- 6; p = 0.0004).. ILuP with melphalan prolongs survival in the treatment of experimental metastatic pulmonary carcinoma.

Topics: Adenocarcinoma; Animals; Chemotherapy, Cancer, Regional Perfusion; Disease Models, Animal; Lung Neoplasms; Male; Melphalan; Neoplasm Transplantation; Pilot Projects; Rats; Rats, Inbred Strains; Survival Rate

We evaluated the cytotoxic effects of a cell-permeable ceramide (Cer), N-hexanoyl-D-sphingosine (C6-Cer) and of two related sphingoid bases, sphingosine (So) and dihydrosphingosine (sphinganine; Sa) on human melanoma cell lines and on soft tissue sarcoma lines recently established from fresh surgical biopsy specimens. These cell lines ranged from high susceptibility (939 melanoma) to strong resistance (A2058 melanoma and all three sarcomas) to tumour necrosis factor (TNF), an inducer of elevated intracellular Cer levels. However, all the cell lines demonstrated a dose-dependent susceptibility to C6-Cer with protracted cytotoxic kinetics, with the C8161 melanoma being the most sensitive and A2058 the least. Protein kinase C (PKC) antagonizes Cer-dependent apoptosis, and chelerythrine chloride, So and Sa, which inhibit PKC, caused extremely rapid cytotoxicity of melanoma cell lines, irrespective of their relative sensitivity to C6-Cer. So-mediated cytotoxicity was extensive even after only 90 min of treatment, within the time frame of limb perfusion. So and Sa only slightly potentiated the cytotoxic responses to TNF, C6-Cer or melphalan. Sphingolipid-driven intracellular pathways may offer opportunities for therapy of these tumours.

Topics: Alkaloids; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzophenanthridines; Carboxylic Acids; Cell Survival; Ceramides; Dose-Response Relationship, Drug; Fumonisins; Histiocytoma, Benign Fibrous; Humans; Lung Neoplasms; Melanoma; Melphalan; Phenanthridines; Protein Kinase C; Sarcoma; Signal Transduction; Sphingosine; Time Factors; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Ultraviolet (UV)-irradiation has been shown to induce jun N-terminal kinase activity via aggregation-mediated activation of tumor necrosis factor receptor 1 (TNFR1) but the role of TNFR1 in mediating UV-induced apoptosis has not been explored. Using p53-null cells, we demonstrate that UV-stimulated ligand independent activation of TNFR1 plays a major role in mediating the apoptotic effects of UV-irradiation. UV-irradiation and TNF alpha acted in a synergistic manner to induce apoptosis. UV-irradiation stimulated the aggregation-mediated activation of TNFR1 which was coupled with activation of caspase 8, the most proximal caspase in TNF alpha signaling pathway. CrmA and the dominant negative versions of FADD, caspase 8 and caspase 10, that block the apoptotic axis of TNFR1 at different levels, also independently inhibited the UV-induced apoptosis. The engagement of the membrane initiated events was specific for UV-irradiation since neither CrmA nor the dominant negative FADD, caspase 8 or caspase 10 blocked the ionizing radiation-induced apoptosis. Cisplatin and melphalan, the UV-mimetic agents known to elicit UV-type DNA damage, also induced apoptosis but differed from UV in that both of the former agents engaged the caspase cascade at a level distal to FADD. Consistent with these findings cisplatin also did not stimulate TNFR1 aggregation. Together these results indicate that DNA damage per se was not sufficient to activate the membrane TNFR1. Based on our results we propose that the plasma membrane initiated events play a predominant role in mediating UV-irradiation-induced apoptosis and that UV-irradiation appears to engage the apoptotic axis of TNFR1 and perhaps those of other membrane death receptors to transduce its apoptotic signals.

Topics: Adaptor Proteins, Signal Transducing; Antigens, CD; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Calcium-Calmodulin-Dependent Protein Kinases; Carrier Proteins; Caspase 10; Caspase 8; Caspase 9; Caspases; Cell Membrane; Cisplatin; DNA Damage; DNA Repair; DNA, Neoplasm; Enzyme Activation; Fas-Associated Death Domain Protein; HeLa Cells; Humans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; Melphalan; Mitogen-Activated Protein Kinases; Neoplasm Proteins; Receptors, Cell Surface; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Serpins; Transfection; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53; Ultraviolet Rays; Viral Proteins

Isolated left lung perfusion with melphalan and human tumor necrosis factor-alpha for pulmonary metastatic adenocarcinoma in the WAG/Rij rat was studied.. Survival was determined for melphalan, human tumor necrosis-alpha. Lung, pulmonary effluent, and serum melphalan were analyzed by chromatography after isolated lung perfusion or intravenous injection. On day 0, rats were injected with 2.0 x 10(6) CC531S cells intravenously. On day 7, rats underwent sham thoracotomy, received melphalan intravenously, or underwent isolated left lung perfusion with saline, melphalan, tumor necrosis factor, and a combination of the latter two. On day 14, tumor nodules were counted.. For the doses of 400 microg tumor necrosis factor, 1,000 microg tumor necrosis factor, or both melphalan and tumor necrosis factor (2 mg + 200 microg), survival rates after contralateral pneumonectomy were 33%, 17%, and 80%, respectively. Survival in all other groups was 100%. Left lung melphalan level was significantly higher after isolated lung perfusion compared to intravenous administration. Significantly fewer left lung nodules were found for 0.5 mg isolated lung perfusion with melphalan (28+/-17) compared to isolated administration (200+/-0) (p = 0.001), and for 1.0 mg intravenous lung perfusion with melphalan (16+/-10) compared to controls (171+/-65) (p = 0.00047). Tumor necrosis factor showed no significant effect.. Isolated lung perfusion with melphalan is an effective treatment for pulmonary metastases from adenocarcinoma in the rat.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Injections, Intravenous; Lung Neoplasms; Male; Melphalan; Pneumonectomy; Rats; Tumor Necrosis Factor-alpha

An elderly patient with extramedullary lung plasmacytoma and subsequent pleural effusion is described. The presence of abnormal plasma cells in the pleural fluid led to diagnosis. Histologically similar conditions such as multiple myeloma and solitary myeloma of bone were ruled out by clinical evaluation. These neoplasms usually occur in the head and neck area and are not characterized by paraprotein accumulation. Few cases in the lung have been reported. We describe a case of extramedullary plasmacytoma of the lung with plasmacytoma-induced pleural effusion and the presence of monoclonal paraprotein in both the serum and urine. Chemotherapy with melphalan was effective in reducing the size of the plasmacytoma, and pleurodesis was used to manage the pleural effusion.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Humans; Lung Neoplasms; Male; Melphalan; Plasmacytoma; Pleural Effusion, Malignant; Pleurodesis

Multidrug resistance (MDR) in human cancer cells is multifactorial. Previously, we reported on the association between expression of P-glycoprotein (Pgp), the multidrug resistance-associated protein (MRP), and the lung resistance protein (LRP) with the MDR phenotype in the NCI panel of 60 human cancer cell lines used for in vitro anticancer drug screening. Eight cell lines from this panel, manifesting widely divergent levels of in vitro drug resistance were chosen to investigate the role of MRP and LRP expression at the molecular level. LRP mRNA levels, as determined by ribonuclease protection assay, varied significantly among the 8 cell lines, and correlated closely with in vitro drug resistance to both MDR and non-MDR related drugs. LRP mRNA expression was determined to be a stronger correlate of drug sensitivity than protein expression. In contrast, MRP mRNA levels were not significantly correlated with drug sensitivity. The rates of newly transcribed LRP or MRP mRNA did not correlate with mRNA levels, indicating that mRNA stability or other features of processing may be important in regulation of LRP and MRP mRNA levels. Using Southern blot analysis, LRP gene amplification was shown not to be associated with LRP overexpression. These data suggest that LRP expression may be an important determinant of the MDR phenotype in cell lines intrinsically resistant to cancer chemotherapeutic agents.

Topics: Amsacrine; Antineoplastic Agents; ATP-Binding Cassette Transporters; Cell Nucleus; Cisplatin; Colonic Neoplasms; Doxorubicin; Drug Resistance, Multiple; Female; Glycoproteins; Humans; Kidney Neoplasms; Leukemia; Lung Neoplasms; Melphalan; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Ovarian Neoplasms; Phenotype; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured; Vault Ribonucleoprotein Particles

In mice bearing immunogenic tumors, adding thymic humoral factor-gamma 2 (THF-gamma 2)1 immunotherapy as an adjunct to anticancer chemotherapeutic regimens not only potentiates the antitumor activity of each drug but also repairs tumor/chemotherapy-induced damage to T-cell populations and functions. The Lewis lung carcinoma (3LL) is a weakly immunogenic, highly metastatic tumor in C57BL/6 mice. To investigate whether the immunoregulatory octapeptide is also effective against a tumor that does not elicit an antitumor immune response, we assessed the effect of combination THF-gamma 2 immunotherapy and chemotherapy in 3LL-bearing mice. The results indicate that THF-gamma 2 combined with either Melphalan or 5-Fluorouracil was more effective in reducing metastatic load than either chemotherapeutic drug alone and was characterized by massive infiltration of lymphatic cells. The combined chemoimmunotherapy treatment also prolonged the survival time in all treated animals and repaired T-cell defects and impaired in vitro cellular immune response parameters, induced either by the tumor or by chemotherapy. THF-gamma 2 immunotherapy reversed the decrease in the number of bone-marrow myeloid colonies (GM-CFU) induced by chemotherapy treatment of tumor-bearing mice, supporting the hypothesis that THF-gamma 2 directly stimulates the proliferation of myeloid stem cells. The overall results imply, that when administered as an adjunct to chemotherapy, THF-gamma 2 immunotherapy is equally effective against immunogenic and nonimmunogenic tumors.

Topics: Animals; Drug Synergism; Drug-Related Side Effects and Adverse Reactions; Erythrocytes; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Immune Sera; Immunity; Immunotherapy; Lipopolysaccharides; Lung Neoplasms; Male; Melphalan; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Experimental; Oligopeptides; Thymus Hormones

Previous research in our laboratories has shown that the immunoregulatory octapeptide, THF-gamma 2, potentiates the efficacy of anticancer chemotherapy in experimental animal models of local plasmacytoma and repairs drug-induced defects in immunocompetence. The highly metastatic, murine D122 lung carcinoma model has been shown to be useful for evaluating the efficacy of experimental antimetastatic therapeutic modalities. The goal of the present study was to determine whether intranasal thymic humoral factor-gamma 2 (THF-gamma 2) immunotherapy, after a single dose of chemotherapy, could inhibit the development of lung metastases, restore immunocompetence, and increase survival in syngeneic C57BL/6 mice bearing highly metastatic Lewis lung carcinoma (D122) solid footpad tumors. Relative to untreated mice and those receiving chemotherapy alone, mice receiving combined chemoimmunotherapy showed the following significant differences: (a) decreased lung metastatic load as assessed by lung weight, (b) prolonged survival time, (c) massive infiltration of lymphoid cells in the lungs, and (d) restoration of impaired immune parameters to normal values in melphalan-treated mice. THF-gamma 2 prevented tumor emboli from colonizing the target tissue, probably by inducing expansion of the lymphoid cell compartment. When used as an adjunct to anticancer chemotherapy, intranasal THF-gamma 2 immunotherapy is a simple and safe treatment modality that seems to be promising for inhibiting lung metastases.

Topics: Adjuvants, Immunologic; Administration, Intranasal; Animals; Carcinoma, Lewis Lung; Combined Modality Therapy; Female; Fluorouracil; Immunotherapy, Active; Lung; Lung Neoplasms; Male; Melphalan; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Oligopeptides; Organ Size; Spleen; Survival Analysis; T-Lymphocyte Subsets; Thymus Hormones

Isolated lung perfusion allows the delivery of high-dose chemotherapy to the perfused lung and is an efficacious modality in the treatment of pulmonary metastases in the rat. Melphalan activity in this model was investigated.. TOXICITY STUDY: Maximum tolerated dose of melphalan delivered by means of isolated lung perfusion was determined by survival after contralateral pneumonectomy. PHARMACOKINETICS STUDY: Nineteen rats were treated with melphalan administered either by isolated lung perfusion (2 mg) or intravenously (2 mg or 1 mg). Lung, pulmonary effluent, and serum melphalan were analyzed by high-pressure liquid chromatography. EFFICACY STUDY: On day 0, 41 rats received an intravenous injection of 5 x 10(6) methylcholanthrene induced sarcoma cells. On day 7, rats either received intravenous melphalan (2 mg [n = 10]; 1 mg [n = 8]) or underwent left isolated lung perfusion with 2 mg of melphalan (n = 12). Isolated lung perfusion with buffered hetastarch in sodium chloride (Hespan, n = 11) was used as control. On day 14, pulmonary nodules were counted.. Maximum tolerated dose of melphalan delivered buy means of isolated lung perfusion was 2 mg.. Left lung melphalan level was significantly higher in the isolated lung perfusion group (62.2 +/- 34.3 microg/gm lung) than in the intravenous treatment groups (6.9 +/- 1.9 microg/gm lung and 3.3 +/- 0.9 microg/gm lung, respectively) (p = 0.0002).. Significantly fewer left lung nodules were found in animals receiving melphalan by means of isolated lung perfusion (7 +/- 10) than in the groups receiving intravenous melphalan (60 +/- 21) or buffered hetastarch by isolated lung perfusion (84 +/- 52) (p = 0.01 and p = 0.0001, respectively).. Isolated lung perfusion with melphalan is safe and effective in the treatment of pulmonary sarcoma metastases in the rat.

Topics: Animals; Antineoplastic Agents, Alkylating; Infusions, Intravenous; Lung Neoplasms; Male; Melphalan; Methylcholanthrene; Perfusion; Rats; Rats, Inbred F344; Sarcoma, Experimental

Cyclocreatine, an analog of creatine, is an efficient substrate for creatine kinase, but its phosphorylated form is a poor phosphate donor in comparison with creatine phosphate. Cyclocreatine was not very cytotoxic upon 24 h of exposure of human SW2 small-cell lung cancer cells to concentrations of up to 5 mM. However, combinations of cyclocreatine (0.5 mM, 24 h) with each of four antitumor alkylating agents, cis-diamminedichloroplatinum(II), melphalan, 4-hydroperoxycyclophosphamide, and carmustine, resulted in additive to greater-than-additive cytotoxicity toward exponentially growing SW2 cells. The greatest levels of synergy were seen at higher concentrations of 4-hydroperoxycyclophosphamide and carmustine as determined by isobologram analysis. In vivo cyclocreatine (0.5 or 1 g/kg) was more effective if given i.v. rather than i.p. The longest tumor-growth delays, up to 10 days, were produced by extended regimens of cyclocreatine. Cyclocreatine was an effective addition to therapy with standard anticancer agents including cis-diamminedichloroplatinum(II), cyclophosphamide, Adriamycin, or 5-fluorouracil. No additional toxicity was observed when 10 days of cyclocreatine treatment was given with full standard-dose regimens of each drug. The resultant increases in tumor-growth delay were 1.7- to 2.4-fold as compared with those obtained for each of the drugs alone. These results indicate that cyclocreatine may be an effective single agent and an effective addition to combination chemotherapy regimens.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Carcinoma, Small Cell; Carmustine; Cell Division; Cell Survival; Cisplatin; Creatinine; Cyclophosphamide; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Humans; Injections, Intraperitoneal; Injections, Intravenous; Lung Neoplasms; Mammary Neoplasms, Experimental; Melphalan; Rats; Rats, Inbred F344; Tumor Cells, Cultured

Relapse after high-dose alkylating agent therapy continues to be an important clinical issue. To begin to understand the characteristics of cells surviving alkylating agent exposure human MCF-7 breast carcinoma cells were exposed to a range of concentrations of melphalan or cis-diamminedichloroplatinum(II) and cell survival determined by colony formation over a time course of 4 weeks. When antitumor alkylating agent exposure killed 3-4 logs of cells as determined by surviving fraction after 1 week of colony formation a progressive increase in surviving fraction was evident over the 4-week course of the experiment. Many attached single cells with abnormal morphology were evident in these dishes; however, the colonies which arose over the 4-week observation time were made up of cells morphologically indistinguishable from the control cells. Cell cycle patterns in the cultures exposed to high concentrations of the antitumor alkylating agents indicated a block in G2/M but by 4 weeks post-drug exposure most had returned to a normal exponential growth pattern. When MCF-7 cells or human SW2 small cell lung cancer cells were exposed to a concentration of melphalan or cis-diamminedichloroplatinum(II) that killed 1-2 logs of cells followed by exposure to a concentration range of the same drug for 24 h or 7 days later resistance to the second drug exposure was evident in both cell lines. Using [14C]melphalan the uptake of the drug into MCF-7 cells pre-treated was compared. Decreased drug uptake did not appear to be a factor in resistance to melphalan observed upon re-exposure to the drug. The potential clinical implications of these findings is discussed.

Topics: Breast Neoplasms; Cell Cycle; Cell Size; Cell Survival; Cisplatin; Drug Resistance; Humans; In Vitro Techniques; Lung Neoplasms; Melphalan; Time Factors; Tumor Cells, Cultured

Clinical trials combining paclitaxel with other active chemotherapy agents are currently underway. In vitro preclinical studies may assist in the selection of appropriate drug combinations or sequences for clinical investigation. We have used clonogenic cell survival assays and DNA flow cytometry to examine the effect of paclitaxel combined with melphalan, thiotepa, or cisplatin on the survival and cell-cycle parameters of human lung A549 and breast MCF-7 adenocarcinoma cells. A549 and MCF-7 cells were incubated with paclitaxel for 24 h, followed by a 1 h exposure to cisplatin, melphalan, or thiotepa. Both cell types were also incubated with cisplatin or an alkylator for 1 h followed by a 24 h paclitaxel exposure. When the paclitaxel exposure preceded either melphalan, thiotepa, or cisplatin, the cytotoxicity was additive for both cell lines tested. When cisplatin or alkylator exposure was given prior to the paclitaxel, cytotoxicity was also additive in MCF-7 cells. However, cisplatin or alkylators were antagonistic to paclitaxel cytotoxicity when they preceded the paclitaxel exposure in A549 cells (e.g., 2% survival with 100 nM paclitaxel vs. 7% survival with cisplatin and paclitaxel). Cell-cycle analysis revealed that exposure to 100 nM paclitaxel for 24 h blocked a majority of the cells into the G2/M phase (> or = 80% for A549 cells, 60-65% for MCF-7 cells). However, exposure to alkylators before incubation in paclitaxel reduced the proportion of A549 but not MCF-7 cells in G2/M--e.g., exposure to 30 micrograms/ml cisplatin prior to paclitaxel exposure caused only 25% of A549 and 55% of MCF-7 cells to block in G2/M.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Cycle; Cell Death; Cisplatin; DNA, Neoplasm; Drug Administration Schedule; Flow Cytometry; Humans; Lung Neoplasms; Melphalan; Paclitaxel; Thiotepa; Tumor Cells, Cultured

Metallothionein (MT) shows a protective effect against toxic actions of some antitumor drugs and gamma-irradiation in animals. Preadministration of bismuth subnitrate, an MT inducing drug, significantly reduced side effects of antitumor drugs without affecting antitumor activity of the drugs. This specific effect of bismuth on the toxicity of antitumor drugs appears to be attributable to its specific induction of MT in normal tissues, but not in tumor tissue. Preinduction of MT synthesis in the lung also prevented mice from carcinogenesis caused by cisplatin and melphalan in the lung. On the other hand, zinc compound induced MT synthesis in the tumor, and significantly suppressed the antitumor activity of some antitumor drugs. Propargylglycine (PPG), an inhibitor of cystathionine pathway, significantly inhibited MT induction by zinc in the tumor inoculated in mice, and, consequently, PPG could diminish cisplatin resistance acquired by an increase in the tumor MT levels.

Topics: Alkynes; Animals; Antineoplastic Agents; Bismuth; Cisplatin; Drug Resistance; Female; Glycine; Lung Neoplasms; Melphalan; Metallothionein; Mice; Neoplasms, Experimental; Pargyline

The syntheses and cytotoxic activities of substituted N-phenylacetamido derivatives of doxorubicin and melphalan are described. The derivatives were designed as prodrugs which could be activated in a site-specific manner by monoclonal antibody-penicillin-G amidase (mAb-PGA) conjugates. N-(Phenylacetamido)doxorubicin (2) and N-(phenylacetyl)melphalan (6) were found to be 10- and 20-fold less cytotoxic against H2981 lung adenocarcinoma cells than doxorubicin and melphalan, respectively. When incubated with PGA, the cytotoxicity of 2 and 6 increased and became equivalent to that of the corresponding drugs from which they were made. The poor solubility characteristics of 2 in aqueous solutions provided the basis for the development of the more soluble doxorubicin derivatives, N-(4-aminophenylacetyl)doxorubicin (3) and N-(4-phosphonooxy)phenylacetyl)-doxorubicin (4). In vitro cytotoxicity assays indicated that 3 and 4 were at least 1000-fold less toxic than doxorubicin against H2981 cells. PGA and the mAb conjugate L6-PGA were able to effect the activation of 3 and 6 on H2981 cells (L6-antigen positive). Hydrolysis of the phosphate group of 4 was required prior to activation with PGA or L6-PGA. This was achieved using alkaline phosphatase, or by exposing 4 to phosphatases present in cell culture medium. The activation of 3, 4, and 6 on H2981 cells by L6-PGA occurred in an immunologically specific manner, since activation could be blocked by saturating cell surface antigens with L6 prior to treatment with L6-PGA. These results demonstrate that 3, 4, and 6 are prodrugs that can be specifically activated to release clinically approved anticancer agents by a mAb-PGA conjugate.

Topics: Adenocarcinoma; Antibiotics, Antineoplastic; Doxorubicin; Humans; Lung Neoplasms; Melphalan; Penicillin Amidase; Phenylacetates; Prodrugs; Structure-Activity Relationship; Tumor Cells, Cultured

In order to examine in detail the sensitivity to chemotherapy of tumour cells at various organ sites and at various stages of metastasis, we have used a series of cell lines, all selected from sister subpopulations derived from a single mouse mammary tumour, which can be distinguished and quantitated from normal cells and from each other through growth in selective medium. For the studies described here, we used two lines, 4T07 and 66FAR, which will form colonies in vitro in medium containing 60 microM 6-thioguanine or 330 microM 2,6-diaminopurine, respectively. Both cell lines have similar sensitivity to the test chemotherapeutic agent, melphalan, in vitro. These two tumour cell lines were treated with melphalan in vivo, when growing either in lungs as experimental metastases at various times after cell injection or as palpable tumours growing subcutaneously. Responses to various doses of melphalan were measured by removing lungs or subcutaneous tumours and performing colony-forming assays in selective medium. The data indicate marked shifts in sensitivity as a function of metastatic stage. Analyses of dose-response curves show that both cell lines were similarly sensitive to melphalan at early times (45 min) after cell injection i.v. but became less sensitive at an intermediate time after injection (3 days). Differences between the two lines became apparent at later times after i.v. injection (by day 8 or 9) and in subcutaneous tumours, where a marked reduction in the shoulder of the dose response curve was seen in line 4T07, resulting in sensitivity equal to or greater than the of early times, whereas the dose response parameters of 66FAR remained at those of the intermediate time point. These results show that, in heterogeneous tumours, individual subpopulations of tumour cells may respond differently to chemotherapeutic agents at various disease stages. In vitro measures of tumour sensitivity do not predict these changes in in vivo sensitivity. Model systems similar to the one described here may yield information which will eventually be useful in maximising the efficacy of clinically relevant adjuvant chemotherapy regimens.

Topics: Animals; Cell Division; Dose-Response Relationship, Drug; Female; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Skin Neoplasms; Tumor Cells, Cultured; Tumor Stem Cell Assay

We examined the efficacy of metallothionein induction in the prevention of the carcinogenic action of cis-platinum and melphalan administered repeatedly to mice over a relatively long period. The increased pulmonary metallothionein induced by bismuth or zinc compounds during the period of chemotherapy with cis-platinum or melphalan protected the mice from carcinogenesis of these drugs in the lung. These results suggested the efficacy of metallothionein inducers in suppression of carcinogenicity considered as a secondary effect of anticancer agents in cancer chemotherapy.

Topics: Animals; Anticarcinogenic Agents; Bismuth; Carcinogens; Chlorides; Cisplatin; Female; Lung; Lung Neoplasms; Melphalan; Metallothionein; Mice; Mice, Inbred A; Nitrates; Zinc Compounds

In this study we describe the effects of tamoxifen, toremifene and their 4-hydroxy and N-desmethyl metabolites on the toxicity of a range of drugs to human breast and lung cancer and to Chinese hamster ovary cell lines, determined using a tetrazolium-based semi-automated colorimetric assay. Vinblastine resistance was completely abolished in an mdr1-transfected lung cancer cell line (S1/1.1), indicating that P-glycoprotein-mediated multidrug resistance can be fully reversed by anti-oestrogens. A substantial (14- to 39-fold) enhancement of vinblastine toxicity to highly multidrug-resistant (MCF-7Adr) cells expressing P-glycoprotein was also observed in the presence of tamoxifen, toremifene and their metabolites, while m-amsacrine, cisplatin and melphalan toxicity was unaffected.

Topics: Amsacrine; Animals; Breast Neoplasms; Cell Survival; CHO Cells; Cisplatin; Cricetinae; Dose-Response Relationship, Drug; Drug Resistance; Humans; Lung Neoplasms; Melphalan; Tamoxifen; Toremifene; Tumor Cells, Cultured; Vinblastine

We have studied alterations in glutathione (GSH) levels and glutathione-S-transferase (GST) activity in a series of in vitro derived multidrug resistant and cisplatin resistant sublines of the human lung cancer lines NCI-H69 (small cell), COR-L23 (large cell) and MOR (adenocarcinoma). We have also investigated the effects of ethacrynic acid, a putative inhibitor of GSTs, on levels of GSH and GST activity and on cellular sensitivity to melphalan and to cisplatin. Neither GSH content nor GST activity were significantly greater in the resistant sublines compared with their respective parental lines. The only effects of treating with ethacrynic acid at doses of 1 microgram ml-1 and 3 micrograms ml-1 for 2 h were a reduction in GSH content in the cisplatin resistant subline H69/CPR at the 3 micrograms ml-1 dose, and an increase to over 140% of control at 1 microgram ml-1 and 3 micrograms ml-1 in the MOR parental line (MOR/P) and at 1 microgram ml-1 in the multidrug resistant subline MOR/R. Exposure of parental line COR-L23/P to 3 micrograms ml-1 and 6 micrograms ml-1 of ethacrynic acid for 24 h, however, increased the GSH content to over 300% and 500% of control respectively. Variable effects of ethacrynic acid on GST activity were seen in these cell lines. Doses of 1 microgram ml-1 and 3 micrograms ml-1 reduced activity to 59% and 48% of control respectively in multidrug resistant subline H69/LX4. On the other hand, activity was increased in the cisplatin resistant subline H69/CPR (to 146% and 218% of control) and in MOR/P (to 117% and 137% of control) by 1 microgram ml-1 and 3 micrograms ml-1 respectively of ethacrynic acid. Addition of ethacrynic acid (3 micrograms ml-1) to treatment of the cell lines with melphalan or with cisplatin did not alter the dose-response curves to these agents.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Drug Interactions; Drug Resistance; Drug Screening Assays, Antitumor; Ethacrynic Acid; Glutathione; Glutathione Transferase; Humans; Lung Neoplasms; Melphalan; Tumor Cells, Cultured

Two patients with metastatic spread of unusual tumors responded to treatment with high-dose Melphalan and autologous bone marrow transplant. One patient had adenoid cystic carcinoma of a minor salivary gland and the other had Merkel cell tumor of the scalp. Both patients had undergone prior surgery and radiotherapy, but later relapsed with distant metastases. Both patients had progression of their disease despite conventional and salvage chemotherapy. Treatment with high-dose Melphalan and autologous bone marrow transplant resulted in partial responses for both patients. High-dose Melphalan should be considered for therapy earlier in the course of patients with these unusual cancers.

Topics: Adult; Bone Marrow Transplantation; Carcinoma, Adenoid Cystic; Carcinoma, Merkel Cell; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Male; Melphalan; Salivary Gland Neoplasms; Scalp; Skin Neoplasms

We reported earlier that oncolysate retained in the excision wound of a local tumor inhibits growth of remote tumor in the rat. We further studied this effect on pulmonary metastasis. C57BL/6 mice were given B16 melanoma F10 cells subcutaneously into the gluteal area (Day 0) and then intravenously on Day 10. On Day 14, mice were divided into four groups. Group 1 received a sham operation and no further treatment. Tumors were excised in the remaining mice. Group 2 received tumor excision alone. Groups 3 and 4 received injections of freeze-lysed tumor cells (TC) and lysate modified (PTC) with a hapten, L-phenylalanine mustard (PhM), respectively, into excision wounds. On Day 24, metastases were assessed by determining metastatic burden. Average diameters of excised tumors in repeated experiments ranged from 8.7 to 10.9 mm. In repeat experiments, pulmonary metastatic burden increased by as much as 52 to 181% in the tumor excised group (Group 2) in comparison with those receiving sham surgery (Group 1). However, metastatic burden was always reduced in Group 3. An even greater reduction was seen in Group 4. To study the possible involvement of macrophages, the production of prostaglandin-E2 (PGE2) and cytotoxicity of macrophages in these animals were examined. It was found that tumor excision enhanced PGE2 production by macrophages and suppressed their cytotoxicity, while TC inoculation prevented both of these changes. An even greater prevention was observed with PTC inoculation. These results indicate an association among macrophage cytotoxicity, PGE2 production of macrophages, and metastasis. In order to clarify the mechanism for these reactions, we did experiments using adherent splenic macrophages from the four groups of animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cell Survival; Dinoprostone; Immunization; Lung Neoplasms; Macrophages; Male; Melanoma, Experimental; Melphalan; Mice; Mice, Inbred C57BL; Neoplasm Metastasis

We have derived sublines of three human lung cancer cell lines with acquired resistance to cisplatin. The cisplatin resistant sublines of NCI-H69 (small cell), COR-L23 (large cell), and MOR (adenocarcinoma) show 5.3 fold, 3.1 fold, and 3.8 fold resistance, respectively, determined in a 6-day MTT assay. Although the parent lines show a wide range of glutathione content per cell, the sublines each show similar values to their corresponding parent line. Radiation response curves have been obtained using a soft agar clonogenic assay. Values obtained for the parent lines (95% CL in parentheses) were: NCI-H69: Do = 0.99 Gy (0.87-1.16), n = 2.9 (1.6-5.2), GSH = 14 ng/10(4) cells; COR-L23: Do = 1.23 Gy (1.05-1.49), n = 1.3 (0.7-2.2), GSH = 47 ng/10(4) cells; MOR: Do = 1.66 Gy (1.48-1.88), n = 3.0 (1.9-4.8), GSH = 86 ng/10(4) cells. The cisplatin resistant variants of NCI-H69 and COR-L23 showed 31% and 63% increases, respectively, in Do compared to their parent lines, whereas no change in radiation response was seen in MOR. In this panel of lines, therefore, although there is a correlation between glutathione content and radiosensitivity of the parent cell lines, acquired resistance to cisplatin is not accompanied by increased glutathione content. However, two of the three cisplatin resistant lines do show a significantly reduced radiosensitivity.

Topics: Adenocarcinoma; Carcinoma; Carcinoma, Small Cell; Cisplatin; Dose-Response Relationship, Radiation; Drug Resistance; Glutathione; Glutathione Transferase; Humans; Lung Neoplasms; Melphalan; Radiation Tolerance; Tumor Cells, Cultured

DNA damage was evaluated by flow cytometric (FCM) analysis of cells treated with L-phenylalanine mustard (L-PAM) and stained with anti-DNA monoclonal antibody (MAb) F7-26. DNA damage was rapidly repaired, as indicated by the loss of DNA immunoreactivity after removal of L-PAM. Two types of drug combinations were found to inhibit DNA repair. Combinations containing inhibitors of DNA polymerase (ara-C, aphidicolin) or these inhibitors and hydroxyurea inhibited DNA repair in A2780/PAM and A549 cells. The inhibition of DNA repair by combinations of DNA-damaging agents thioTEPA or cisplatin and DNA polymerase inhibitors is a novel observation based on the specificity of DNA damage assay with MAb F7-26. Combinations containing thioTEPA or cisplatin inhibited DNA repair in A549 but not in A2780/PAM cells. Drug combinations which inhibited DNA repair also significantly enhanced cell killing by L-PAM. Cell survival in cultures treated with L-PAM and efficient inhibitors was 2 to 3 orders of magnitude lower than was expected for additive survival. ThioTEPA and cisplatin play a dual role in combination chemotherapy by inducing DNA damage and inhibiting repair of DNA damage. FCM analysis of DNA repair may be a useful component of drug evaluation and could be applied to determine cell-type specific sensitivity to inhibitors of DNA repair.

Topics: Alkylating Agents; Antineoplastic Agents; Aphidicolin; Cell Line; Cell Survival; Cisplatin; Cytarabine; Diterpenes; DNA Damage; DNA Repair; Female; Humans; Lung Neoplasms; Melphalan; Nucleic Acid Synthesis Inhibitors; Ovarian Neoplasms; Thiotepa

To elucidate the mechanism(s) of cisplatin resistance, we have characterized a human non-small cell lung cancer cell line (PC-9/CDDP) selected from the wild type (PC-9) for acquired resistance to cisplatin. PC-9/CDDP demonstrated 28-fold resistance to cisplatin, with cross resistance to other chemotherapeutic drugs including chlorambucil (X 6.3), melphalan (X 3.7) and 3-[(4-amino-2-methyl-5-pyrimidinyl)]methyl-1-(2-chloroethyl)-1-nitros our ea (ACNU) (x 3.9). There was no expression of mdr-1 mRNA in either wild-type or resistant cells. The mRNA and protein levels of glutathione S-transferase (GST) pi were similar in the two lines. A GST-mu isozyme was present in equal amounts and the activities of selenium-dependent and independent glutathione peroxidase and glutathione reductase were unchanged. The mRNA level of human metallothionein IIA and the total intracellular metallothionein levels were reduced in the resistant cells. Significantly increased intracellular glutathione (GSH) levels were found in the resistant cells (20.0 vs 63.5 nmol/mg protein) and manipulation of these levels with buthionine sulfoximine produced a partial sensitization to either cisplatin or chlorambucil. Increased GSH probably also played a role in determining cadmium chloride resistance of the PC-9/CDDP, even though this cell line had a reduced metallothionein level. Also contributing to the cisplatin resistance phenotype was a reduced intracellular level of platinum in the PC-9/CDDP. Thus, at least two distinct mechanisms have been selected in the resistant cells which confer the phenotype and allow degrees of cross resistance to other electrophilic drugs.

Topics: Adenocarcinoma; Blotting, Northern; Cell Survival; Chlorambucil; Cisplatin; Drug Resistance; Glutathione Transferase; Humans; Lung Neoplasms; Melphalan; Nimustine; RNA, Neoplasm; Tumor Cells, Cultured; Tumor Stem Cell Assay

From 1982-1989, 113 hyperthermic limb perfusions were carried out in 102 patients. Ninety-three patients were treated for malignant melanoma and nine for soft tissue sarcoma. 47/93 patients had high-risk stage I melanoma with a 5-year survival rate of 89%. For the 46 patients treated for recurrent and metastatic melanoma the projected 5-year survival rate was 40%. The nine patients with soft tissue sarcoma were perfused for local recurrences or because of anatomically difficult tumor locations. 3/9 patients subsequently developed recurrent disease of the extremity; two of these patients had to be treated by amputation. The rate of major complications was low: no patient died in the postoperative course, an amputation due to toxic reaction was never required. Erythema and oedema (57%), severe skin reaction (6%) and transient nerve palsy (15%) were common side effects of therapy. Only two cases of leucopenia were observed (2%). The favourable results after hyperthermic limb perfusion show the efficacy of this method in the treatment of malignant melanoma and selected cases of soft tissue sarcoma.

Topics: Adolescent; Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Lung Neoplasms; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Postoperative Complications; Sarcoma; Soft Tissue Neoplasms; Survival Rate

Fifteen patients with Stage IV lung cancer both untreated and previously treated were enrolled into a high-dose chemotherapy program with multiple alkylating agents and autologous bone marrow reinfusion. Eight patients received cyclophosphamide at 7.5 gm/m2 over 3 days with thiotepa escalated from levels of 1.8 mg/kg to 6.0 mg/kg over 3 days. Seven patients received the above dose of cyclophosphamide plus thiotepa at 675 mg/m2 and oral melphalan escalated from levels of 0.75 mg/kg to 2.5 mg/kg over 3 days. Both regimens are part of larger Phase I-II clinical studies. The median time to recovery of more than 500 granulocytes and more than 50,000 platelets per microliter was 16 and 27 days, respectively. Two patients died as a consequence of severe, overwhelming infections during their period of aplasia. Of the 13 evaluable patients, no patients achieved a complete response and seven patients (47%) obtained a partial response. The median duration of response was 12 weeks. Other nonhematologic toxicities included nausea/vomiting, diarrhea, mucositis, skin rash, hemorrhagic cystitis, and cardiomyopathy. Since there are substantial toxicities associated with high-dose chemotherapy and responses of such brief duration, further investigation with these drug combinations is not warranted.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carcinoma, Non-Small-Cell Lung; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Lung Neoplasms; Male; Melphalan; Middle Aged; Neoplasm Staging; Thiotepa

Since 1980, 75 patients with small-cell lung cancer (SCLC) have been entered into four consecutive studies of high-dose chemotherapy using autologous bone marrow transplantation (ABMT) to assist haematological recovery. In the first study, 25 patients were treated with cyclophosphamide (160-200 mg/kg) as the sole chemotherapy; in the second (26 patients), the cycle of high-dose cyclophosphamide (with or without 800-1,200 mg/m2 etoposide) was repeated as induction treatment. In the first study, response was high [14 complete responses (CR), 7 partial responses (PR)] but was not increased by repeating the cycle (15 CR, 8 PR), and survival was slightly worse in the second trial. In the third study, 15 patients were treated with doxorubicin, vincristine and etoposide for two cycles and then with 200 mg/kg cyclophosphamide. Although high-dose cyclophosphamide increased the complete response rate, the additional responses were short-lived. In the final study, an attempt was made to increase the initial CR rate by combination chemotherapy using carboplatin (400-600 mg/m2), etoposide (120 mg/m2 x 4) and either high-dose cyclophosphamide (40 mg/kg x 4) or melphalan (140 mg/m2). Although all nine patients responded, none underwent a CR. The long-term survival (up to 7 years) does not appear to be different from that in comparably selected cases treated with conventional chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Carcinoma, Small Cell; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Follow-Up Studies; Humans; Lung Neoplasms; Melphalan; Organoplatinum Compounds; Prognosis; Radiotherapy Dosage; Remission Induction; Vincristine

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

Thirty-seven patients with widely metastatic malignant melanoma were treated with one of three chemotherapy regimens, incorporating high-dose dacarbazine (DTIC). The chemotherapy was followed by autologous bone marrow rescue which was harvested under local anesthesia in 25 of the patients. The three regimens comprised a 24-hour infusion of DTIC (Regimen A for patients less than 45 years of age, 4.3 to 10.5 g/m2; B, if greater than 45 years of age 2.7 to 4.0 g/m2; and later C, if greater than 45 years of age 7.0 to 8.0 g/m2). The second alkylating agent was given at +8 and +16 hours from the start of DTIC. The total doses of the melphalan ranged from 60 to 130 mg/m2 for Regimen A and 30 to 40 mg/m2 for Regimen B. Ifosfamide 5.0 to 8.0 g/m2 was given instead of melphalan in Regimen C. The response rates for the regimens were 81% (25% CR) for A, 27% (11% CR) for B, and 20% (with no complete responders) for Regimen C. There was no statistically significant difference between the three regimens for survival with a median value of 6 months. One of the 16 patients treated with the very high dose Regimen A died of septicemia and three of ten patients in Regimen C died within the first 2 weeks of treatment. There was statistically significant greater myelosuppression, stomatitis, and diarrhea in the very high dosage DTIC and melphalan (Regimen A) compared with the other two regimens. No significant difference in response rate or toxicity was observed for the different dosages escalated within each of the three regimens. Although hematologic and gastrointestinal toxicity were very severe, no unusual side effects were noted except for one episode of severe acute renal failure in the high-dose DTIC and melphalan, Regimen A. Responses occurred mainly in nonvisceral, nodal, and cutaneous sites and occasionally in pulmonary metastases. The Karnofsky performance improved 4 to 6 months after treatment notably with the high-dose DTIC and melphalan therapy. No survival benefit for the combination chemotherapy despite the high dosages was detected and such an approach currently cannot be recommended.

Topics: Adult; Aged; Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Dacarbazine; Humans; Ifosfamide; Lung Neoplasms; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Skin Neoplasms

Topics: Bone Transplantation; Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Male; Melphalan; Middle Aged

A 52-year-old man with a plasmacytoma of the body of T-10 in February 1965 returned 6 months later with multiple myeloma characterized by bone pain, osteolytic lesions, and IgD lambda monoclonal protein in the serum, 6.1 g of Bence Jones protein in the urine, and 21% plasma cells in the bone marrow. The M-protein and bone pain disappeared within 6 weeks after therapy with melphalan and prednisone was started. Therapy was discontinued in December 1974. Immunoelectrophoreses and immunofixations of the serum and urine over the years revealed no monoclonal protein. A mediastinal tumor developed, and the patient died of respiratory insufficiency on October 23, 1986. Autopsy revealed a large bronchogenic carcinoma of the right lung extending to the mediastinum, trachea, and esophagus. There was no evidence of multiple myeloma. This patient had responded rapidly to chemotherapy and had no recurrence of myeloma during a 21-year follow-up.

Topics: Carcinoma, Bronchogenic; Follow-Up Studies; Humans; Immunoglobulin D; Lung Neoplasms; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasms, Multiple Primary; Prednisone; Time Factors

Nineteen patients with metastatic malignant melanoma were treated with 20 courses of high-dose combination alkylating agent chemotherapy and autologous bone marrow support. All 20 treatment courses were evaluable for toxic reactions and 17 of 20 courses were assessable for response. Twelve of the 20 courses were given at the phase 2 dose per square meter of cyclophosphamide (5.625 g), cisplatin (165 mg), and carmustine (600 mg). Marrow reconstitution occurred with a median time to recovery of 21 and 24 days for more than 500 neutrophils and more than 20,000 platelets, respectively. The overall response rate was 65%, with one patient achieving a complete response with chemotherapy alone. Ten additional patients achieved partial responses following chemotherapy, of which three were subsequently rendered disease free by surgical resection of single areas of residual tumor. Two of these patients are alive and disease free more than 22 months following chemotherapy and one remains relapse free. The median survival for responding patients was 15.2 months and 8.6 months for the entire group.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Liver Neoplasms; Lung Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Pelvic Neoplasms; Remission Induction

Pretreatment of mice with low doses of methyl-CCNU was shown to reduce the toxicity of lethal doses of methyl-CCNU or melphalan administered one or two days following the low dose. There was an increase in survival rate, body weight, thymus and kidney wet weight. Tissue morphology was less affected in the primed mice as compared to mice receiving the high dose or a high-low dose combination. In mice implanted s.c. with Lewis lung carcinoma, priming with 5 mg kg-1 methyl-CCNU 2 days before injection of a very high (35 mg kg-1) dose significantly increased the lifespan as compared to treatment with the high dose alone or with high-low dose combination. When the dose of methyl-CCNU was further increased to 40 mg kg-1 toxic death occurred, which was, however, significantly reduced by 'priming' with the low dose given. When low-high dose combination was used twice (the high dose was given on day 7 or 9, and 18 or 20 after tumour inoculation), priming with 5 mg kg-1 (but not with 10 mg kg-1) two days prior to the high dose was beneficial in reducing toxic death (in two experiments) and either increasing lifespan or not significantly increasing it. In no case was there protection of the tumour by the low-high dose combinations.

Topics: Animals; Lung Neoplasms; Male; Melphalan; Mice; Mice, Inbred C57BL; Nitrosourea Compounds; Semustine

Nineteen patients were treated with high dose chemotherapy followed by an autologous bone marrow transplantation. The chemotherapy regimen was an association of BCNU, procarbazine, etoposide, melphalan. Six patients had a progressive disease; 4 short-term complete remissions were observed. In 13 responding patients, 6 maintained complete remissions were noted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carcinoma, Small Cell; Carmustine; Combined Modality Therapy; Etoposide; Humans; Lung Neoplasms; Melphalan; Procarbazine

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

Previous studies with cultured human normal fibroblasts indicated that pretreatment of the cells with zinc for 12 h prior to exposure to the alkylating agent melphalan increased survival by seven- to ninefold over survival values obtained in cultures treated with drug only. Comparable pretreatment of cells derived from a variety of human tumors resulted in an increase in survival of 1.7-fold or less. To determine whether the limited responsiveness to zinc represented a general property of tumor cells (which would be characterized by a lack of highly zinc-responsive subpopulations contained within the parental tumor populations), a series of clones was prepared from the A101D human melanoma line and the A549 human alveolar cell carcinoma line. Cells from each clone were then challenged with melphalan with and without zinc pretreatment. Twenty-five percent of the tumor clones exhibited increased resistance to melphalan following pretreatment with zinc (range of 2.1- to 5.2-fold increase in survival), indicating that the parental tumor lines were highly heterogenous in regard to inducibility to a state of reduced sensitivity to melphalan. There was no evidence of a relationship between zinc-induced reductions in toxicity and induced elevations in total intracellular glutathione content, indicating that the primary effect of zinc is not directed toward elevating intracellular levels of glutathione.

Topics: Cell Survival; Clone Cells; Glutathione; Humans; Lung Neoplasms; Melanoma; Melphalan; Pulmonary Alveoli; Zinc

Both B16 melanoma and Lewis lung carcinoma growing in C57/Bl mice spontaneously metastasize to the lungs and other organs. When the tumors are grown in the mouse tail to a specific volume and amputated, the spontaneously disseminated tumor cells can then be independently treated. The effects of a single dose of cyclophosphamide (200 mg/kg), cis-platinum (6 mg/kg) and melphalan (10 mg/kg) on the appearance of pulmonary and other metastases were measured. The cis-platinum treatment was shown to reduce the number and incidence of metastases of both tumors at various times after treatment. The antimetastatic effectiveness of cis-platinum against these two tumors was increased when 2.4 mg/kg was administered each day for five consecutive days after amputation of the primary. Cyclophosphamide, when administered at two-thirds maximum tolerated dose, had a small promoting effect on the number and incidence of pulmonary metastases of Lewis lung carcinoma, whereas, applied in the same dose, it had efficacy in the treatment of disseminated B16 melanoma and inhibited appearance of both pulmonary and lymph-node metastases. When melphalan was administered in single- and multiple-dose regimens, the number and incidence of metastases of both tumors increased at various times after primary tumor amputation. These data suggest that melphalan can promote the growth of disseminated tumor cells in both the lungs and other sites and that some systemic chemotherapies may result in promotion instead of suppression of metastatic disease.

Topics: Cisplatin; Cyclophosphamide; Drug Administration Schedule; Humans; Lung Neoplasms; Lymphatic Metastasis; Melanoma, Experimental; Melphalan; Neoplasm Metastasis; Neoplasms, Experimental

Drug sensitivity assays were performed using a variation of a colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)] assay on V79, CHO-AuxB1, CHRC5, NCI-H460, and NCI-H249 cell lines following optimization of experimental conditions for each cell line. Results from this assay were compared with data assimilated simultaneously by clonogenic assay and by dye exclusion assay. Good correlation was observed using the CHO-AuxB1 cell line and the pleiotropic drug-resistant mutant CHRC5, with similar degrees of relative resistance observed with both the MTT and clonogenic assays. Good correlation was observed between the clonogenic and MTT assays for 1-h drug exposures, although the MTT assay was more sensitive to vinblastine. In general, the clonogenic assay was more sensitive when continuous drug exposures were utilized, although this was primarily related to the increased drug exposure time. While the use of the MTT assay in drug sensitivity testing of primary tumor samples is limited, since contaminating normal cells may also reduce the tetrazolium, the MTT assay can be semiautomated, and therefore it offers a valid, simple method of assessing chemosensitivity in established cell lines.

Topics: Animals; Antineoplastic Agents; Autoanalysis; Cell Line; Cisplatin; Clone Cells; Colorimetry; Coloring Agents; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance; Humans; In Vitro Techniques; Lung Neoplasms; Melphalan; Tetrazolium Salts; Thiazoles; Vinblastine

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

A method based on detection of drug-induced cell cycle perturbation by flow cytometric DNA analysis has previously been described in Ehrlich ascites tumors as a way to estimate chemosensitivity. The method is extended to test human small-cell carcinoma of the lung. Three tumors with different sensitivities to melphalan in nude mice were used. Tumors were disaggregated by a combined mechanical and enzymatic method and thereafter have incubated with different doses of melphalan. After incubation the cells were plated in vitro on agar, and drug induced cell cycle changes were monitored by flow cytometric DNA analysis. Melphalan produced a dose-related S phase accumulation in the two sensitive tumors, whereas no changes in the cell cycle distribution were found in the resistant tumor. The size of S phase accumulation correlated to the chemosensitivity in vivo. For low concentrations of melphalan, the S phase accumulation was accompanied by G2 + M accumulation. The results indicate that the method may be extended to sensitivity testing of human solid tumors, including screening for new agents.

Topics: Animals; Carcinoma, Small Cell; Cell Cycle; DNA; Dose-Response Relationship, Drug; Drug Resistance; Flow Cytometry; Humans; Interphase; Lung Neoplasms; Melphalan; Mice; Mice, Nude; Neoplasm Transplantation

Four human small cell carcinomas of the lung grown in nude mice were exposed to melphalan. Two of the tumors were derived from subpopulations isolated by in vitro cloning from the same tumor biopsy. The chemosensitivity of the tumors was determined by calculating the specific growth delay. Drug-induced changes in the cell cycle were detected by flow cytometric DNA analysis. The specific growth delay of the tumors was very different with the greatest differences between the two subpopulations originating from the same tumor. Melphalan induced a dose-related S phase accumulation in three sensitive tumors, whereas no changes were seen in a resistant tumor. Furthermore, the amount of S phase accumulation reflected the sensitivity to melphalan. The results suggest that heterogeneity in chemosensitivity is an important reason for chemotherapy failures.

Topics: Animals; Carcinoma, Small Cell; Cell Cycle; Cell Line; DNA; Dose-Response Relationship, Drug; Drug Resistance; Flow Cytometry; Growth; Humans; Lung Neoplasms; Melphalan; Mice; Mice, Nude; Neoplasm Transplantation

Thirty-six patients with lung cancer, 24 with prior chemotherapy and 12 without prior chemotherapy, received iv melphalan at doses ranging from 20 to 40 mg/m2 of body surface area. Patients who showed moderate myelosuppression and remained in the study were also investigated to determine if cyclophosphamide (300 mg/m2) administered 1 week before the identical dose of i.v. melphalan modified the hematopoietic toxicity of melphalan (cyclophosphamide priming). In this study, the activity of melphalan was minimal, four minor responses with no partial or complete responses. Three of these minor responses were in previously untreated patients. The major toxicity was hematopoietic and the maximum tolerated i.v. dose was 20 mg/m2 in the patients previously treated with chemotherapy and 30 mg/m2 in those without prior chemotherapy. Cyclophosphamide priming did not reduce the myeloid toxicity. Myelosuppression was more severe in the course that included cyclophosphamide. Recovery, however, appeared to be similar in both courses. I.v. melphalan at these doses has minimal activity in lung cancer. Cyclophosphamide administered 1 week before i.v. melphalan does not decrease the myelosuppression but should be investigated further for its effect on the rate of wbc and neutrophil count recovery.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Bronchogenic; Cyclophosphamide; Female; Hematologic Diseases; Humans; Leukocyte Count; Lung Neoplasms; Male; Melphalan; Middle Aged; Nausea; Neutrophils; Platelet Count

The patient was a 26-year-old male. He was admitted to our hospital with a chief complaint of hemoptysis, cough and left scrotal mass on May 9,1984. Chest X-ray film, LAG and CT revealed multiple lung, lymph node and cerebral metastases. Based on a diagnosis of testicular neoplasm, orchiectomy was performed on May 14,1984. PVB chemotherapy (Cis-diamminedichloro-platinum, Vinblastine and Pepleomycin) was administered. Because he got worse, however, he was treated with another combination chemotherapy, consisting of Methotrexate (MTX, 100 mg/m2 intravenous push (i.v.), 200 mg/m2 12-h infusion, day 1. The dose of MTX was increased with each course. Maximum dose of MTX was 900 mg/m2/day), Vincristine (1.0 mg/m2 i.v. day 1.) Actinomycin D (10 micrograms/kg i.v. days 3.4.5), Cyclophosphamide (600 mg/m2 i.v. day 3.), Adriamycin (30 mg/m2 i.v. day 8.) and Melphalan (6 mg/m2 p.o. day 8.). After 6 courses of this regimen, distant metastases disappeared or were reduced to under one tenth, and complete remission was obtained without severe side effects. The patient was in good health on March 30, 1985.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Choriocarcinoma; Cyclophosphamide; Dactinomycin; Doxorubicin; Drug Administration Schedule; Humans; Lung Neoplasms; Male; Melphalan; Methotrexate; Testicular Neoplasms; Vincristine

Several different drug retreatment protocols were employed to examine the emergence of resistance to MeCCNU in Lewis lung tumours. Previous studies suggested that although the majority of cells in untreated Lewis lung tumours were sensitive to MeCCNU, there was a very small proportion of resistant cells (approximately 0.001%) that limited "tumour cure' with that drug. If such cells were inherently drug resistant then it should be possible to derive highly resistant tumours by repeated drug treatment. In the first experiment tumours were treated with a single high dose of MeCCNU (35 or 40 mgkg-1) and on regrowth, transplanted into fresh mice and tested for drug sensitivity. Using both excision cell survival and growth delay endpoints, only approximately 25% of tumours were significantly resistant to the test dose, suggesting that many tumours resist the effects of the drug for reasons other than the presence of inherently drug resistant cells. One of the tumours (R4), that regrew after the initial treatment and appeared to be resistant to the test treatment, was retreated with a further 30 mgkg-1 MeCCNU and became more resistant. This line, designated R4/1, was cross-resistant to the other nitrosoureas, BCNU and CCNU, but not to cyclophosphamide, melphalan, cis-platinum or ionising radiation. The effect of treatment dose on the kinetics of MeCCNU resistance development was also studied in a retreatment regimen where the tumours were allowed to regrow and then transplanted into fresh hosts for the next treatment. Resistance developed more quickly at an intermediate dose of 15 mgkg-1 than at 7.5 mgkg-1 where the selective pressure was lower, or at 30 mgkg-1 where there was probably extinction of partially resistant cells. Resistance to MeCCNU developed even more quickly when tumours were retreated several times in the same host, although in a similar experiment with cyclophosphamide no resistance occurred.

Topics: Animals; Carmustine; Cell Line; Cell Survival; Cisplatin; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Resistance; Lomustine; Lung Neoplasms; Melphalan; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Nitrosourea Compounds; Semustine; Time Factors

We investigated the synergistic anti-tumor effects of K-18 (conjugate of human gamma-globulin and melphalan) and concomitantly administered hyperthermia on Lewis lung carcinoma in mice. The antitumor effect of a subeffective dose of K-18 or an equivalent dose of melphalan alone was enhanced by local hyperthermia. K-18 administration demonstrated a greater potentiation for inhibition of tumor growth than that of melphalan alone. Local hyperthermia plus K-18 reduced the dose of melphalan required for tumor growth inhibition by melphalan alone. The combined application of K-18 and hyperthermia for treating cancer warrants further study.

Topics: Animals; Carcinoma; Combined Modality Therapy; Drug Combinations; Female; gamma-Globulins; Humans; Hyperthermia, Induced; Immunotoxins; Lung Neoplasms; Melphalan; Mice; Tissue Distribution

To clarify the role of standard chest radiography in prostatic adenocarcinoma, the pulmonary manifestations of 198 patients with Stage D disease were evaluated. All patients were treated with chemotherapeutic protocols allowing for adequate clinical and radiographic correlation. Retrospective interpretation of serial chest radiographs revealed that 35% of our patients had visible intrathoracic abnormalities; however, only 24% of the patients had abnormalities attributable to intrathoracic metastases. Twenty-two percent of patients had pleural effusions, 16% reticular opacities, 3.5% reticulonodular opacities, 8% isolated or discrete pulmonary nodules, and 4.5% adenopathy. Etiologies of these opacities included metastatic disease in 93.5% of those with adenopathy and nodular or reticulonodular opacities, but 39% of pleural effusions and 52% of reticular opacities were best attributed to concomitant processes. Four patients had intrathoracic metastases without bone metastases. Standard chest radiography is a valuable screening procedure that should be correlated with clinical data to differentiate metastases from concomitant processes.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Fluorouracil; Humans; Lung; Lung Neoplasms; Lymphatic Metastasis; Male; Melphalan; Methotrexate; Middle Aged; Pleural Effusion; Prednisone; Prostatic Neoplasms; Radiography; Retrospective Studies; Vincristine

The ability of the in vitro sister chromatid exchange (SCE) assay to predict in vivo tumor drug sensitivity was investigated using a spontaneous hepatocarcinoma in C3Hf/Kam mice and 3 chemotherapeutic agents: melphalan; cis-platinum; and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). For hepatocarcinoma cells grown in monolayer culture, melphalan was the most efficient at inducing SCEs, and BCNU, the least. cis-Platinum induced a range in SCEs that overlapped those of BCNU and melphalan, suggesting that hepatocarcinoma is not a homogeneous population with intermediate sensitivity, but is a mixture of cis-platinum-sensitive and -resistant cells. According to in vitro cell survival curves, hepatocarcinoma was most sensitive to melphalan, less sensitive to cis-platinum, and essentially resistant to BCNU. The relative antineoplastic effects of melphalan, cis-platinum, and BCNU in vivo were compared by the response of artificial and spontaneous pulmonary metastases and solid tumors to these agents. For artificial metastases, there was a dose-dependent decrease in the number of lung nodules in mice treated with melphalan or cis-platinum, with melphalan being the more effective. BCNU had no effect. Spontaneous pulmonary metastases generated from hepatocarcinoma leg tumors were reduced in those mice treated with melphalan, unaffected by cis-platinum, and increased by BCNU. In hepatocarcinoma leg tumors (5 to 6 mm in diameter), melphalan induced the longest growth delay, and BCNU the least. Therefore, the relative effects produced by these three drugs in vivo were the same as predicted by SCE induction in vitro. The SCE assay may thus have potential clinical application.

Topics: Animals; Carmustine; Cell Survival; Cisplatin; Colony-Forming Units Assay; Liver Neoplasms, Experimental; Lung Neoplasms; Male; Melphalan; Mice; Mice, Inbred C3H; Sister Chromatid Exchange; Tumor Stem Cell Assay

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

Inherent and induced resistance was investigated in human small-cell lung cancer xenografts. Specimens from three patients were established in immune suppressed mice; the sensitivity of the xenografts to cyclophosphamide, MeCCNU and melphalan was determined using the growth delay end-point. Clinical chemosensitivity data were available in two cases and inherent differences in sensitivity were noted both in the xenografts and clinically. Radioactively labelled melphalan uptake studies were performed with these two xenografts. A number of different strategies to induce resistance were explored. Only one method proved to be successful and in only one of the xenografts; this was with cyclophosphamide. The induced resistant line was characterised in terms of the time course of its production, the degree of induced resistance, the growth rate, the cross-resistance pattern and stability of the phenotype; the possibility of altered antigenicity was also examined.

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Carcinoma, Small Cell; Cyclophosphamide; Drug Resistance; Female; Humans; Lung Neoplasms; Melphalan; Mice; Mice, Inbred CBA; Semustine; Time Factors; Vincristine

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

Treatment of mice (some bearing Lewis Lung tumors), with penicillin (PEN) at 500 mg/l drinking water for one week prior to treatment with misonidazole (MIS), resulted in: the elimination of their anaerobic cecal flora; a decrease in MIS-induced neurotoxicity; an increase in pharmacological exposure to MIS; a decrease in MIS chemopotentiation; a probable increase in MIS radiosensitization; an increase in MIS induced hypothermia. Assuming no chemical interaction between PEN and MIS, these observations indicate that the intestinal microflora can influence the activity of MIS in vivo. Therefore their influence should be considered in all sensitizer-related studies in vivo. The observed reduction in the neurotoxic but not the radiosensitizing potential of MIS following PEN treatment indicates a therapeutic benefit.

Topics: Animals; Bacteria; Body Temperature; Combined Modality Therapy; Drug Synergism; Female; Intestines; Lung Neoplasms; Melphalan; Mice; Misonidazole; Nitroimidazoles; Penicillins; Radiation-Sensitizing Agents

Carminomycin, a new antibiotic made in the USSR, was used in the treatment of 21 patients aged 5 to 15 years with extended osteogenic sarcoma. As a result of the treatment the number of the patients with lifetime prolonged for 1-2 years increased from 7.6 to 46 per cent. It was shown that the drug might be used for the prophylaxis of the localized forms of the disease in children.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carubicin; Child; Child, Preschool; Combined Modality Therapy; Daunorubicin; Drug Evaluation; Follow-Up Studies; Humans; Lung Neoplasms; Lymphatic Metastasis; Melphalan; Osteosarcoma; Time Factors; Vincristine

Topics: Adolescent; Bone Marrow Transplantation; Bone Neoplasms; Humans; Lung Neoplasms; Male; Melphalan; Sarcoma, Ewing

Topics: Adolescent; Bone Neoplasms; Child; Female; Humans; Lung; Lung Neoplasms; Lymphoma, Non-Hodgkin; Male; Melphalan; Sarcoma, Ewing; Time Factors; Whole-Body Irradiation

As a result of total-local irradiation of the lung combined with polychemotherapy in patients with solitary metastases to the lungs, a 3-year survival in children was 52.7 +/- 12.1%, after local irradiation of the lungs and chemotherapy 30 +/- 11.8% of the patients. Combined treatment was well tolerated by pediatric patients. The results of the study have shown that radiation therapy of metastases of Ewing's sarcoma to the lungs with simultaneous polychemotherapy does not disturb external respiratory function even in a later period, the clinical manifestations of lung radiation reactions were seldom observed.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carubicin; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Gamma Rays; Humans; Lung Neoplasms; Melphalan; Methotrexate; Orotic Acid; Prednisolone; Radiotherapy Dosage; Sarcoma, Ewing; Time Factors; Vincristine

Serum vitamin A and retinol-binding protein (RBP) concentrations were measured in patients comprising 53 myeloma and 28 epithelial cell cancer cases. Vitamin A levels in these patients were found to be significantly lower than those in the 30 healthy subjects, the effect being more marked in the patients with cancer of epithelial origin. The serum concentrations of retinol-binding protein (RBP) fell in parallel with vitamin A in the epithelial cancer patients, while the RBP concentrations remained unaffected in the patients with myeloma, suggesting that the underlying factor for resulting low vitamin A levels may be different in these two groups of patients.

Topics: Adult; Aged; Breast Neoplasms; Female; Humans; Lung Neoplasms; Male; Melphalan; Middle Aged; Multiple Myeloma; Retinol-Binding Proteins; Urinary Bladder Neoplasms; Uterine Neoplasms; Vitamin A

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

The in vivo response of B16 melanoma and Lewis lung carcinoma to combinations of hyperthermia and graded doses of CCNU or Melphalan was studied. To obtain dose-response curves and quantitative comparisons of different treatments, an agar-colony assay was used to measure survival of cells from excised tumours. For heating experiments, the use of 2 tumours per animal, one heated and one not, allowed all other factors to be kept constant. When tumours were immersed in a water-bath at 43 degrees C for 1 h, Thermal Enhancement Ratios (TER) measured from the slopes of the dose-response curves were up to 1.6 for CCNU and 2.4 for Melphalan. Direct heat killing of about 1 decade was seen for 1 h at 43 degrees C. The anaesthetic Saffan also enhanced drug cell kill; the largest Dose Modifying Factor (2.7) was measured for Melphalan in the Lewis lung tumour. The duration of heating, and waterbath temperature, both influenced the enhancement of cell killing by CCNU, as did the time of excision of tumours between 0 and 3 1/2 h after treatment. There was no difference in effect between 3 1/2 and 24 h. The interaction between heat and CCNU varied if the interval between them was altered. The maximum effect was found if the heat and drug were given in close sequence.

Topics: Animals; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Hot Temperature; Lomustine; Lung Neoplasms; Male; Melanoma; Melphalan; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Nitrosourea Compounds; Temperature; Time Factors

Ultrasonic energy can generate controlled, local hyperthermia (42 degrees C--43 degrees C), and ultrasonic hyperthermia results in increased cytotoxicity of chemotherapeutic drugs for the treatment of cancer. Human breast (MX-1) and lung (LX-1) tumors implanted subcutaneously in athymic nude mice were treated with a single application of ultrasonic (670 kHz, peak intensity of 5 watts/cm2) hyperthermia (43.0 degrees C +/- 0.5 degrees C) for 30 minutes in combination with suboptimal doses of cyclophosphamide, melphalan, or procarbazine. Delays in the tumor growth rate and temporary tumor regression were observed. Comparison of the tumor growth rate with single modalities, ie, drug or hyperthermia alone, shows evidence of synergistic effects of the combination of ultrasonic hyperthermia and melphalan on MX-1 and of hyperthermia and procarbazine on LX-1 tumors.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cyclophosphamide; Drug Synergism; Female; Hot Temperature; Humans; Lung Neoplasms; Melphalan; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Procarbazine; Transplantation, Heterologous; Ultrasonic Therapy

The effect of melphalan on the growth of 4 different lines of human lung-tumour xenografts has been established. The oat-cell carcinoma was the most sensitive, whereas the adenocarcinoma was the most resistant. Two lines of large-cell anaplastic carcinomas were intermediate in sensitivity. The differences in sensitivity were not reflected in the gross uptake of drug into the tumours. There was, with the exception of the adenocarcinoma line, a marked decrease in uptake per g tumour with increasing tumour size. This was partly caused by a decrease in the vascular supply in the same tumours with increasing tumour size. Extravasation of plasma proteins increased with increasing tumour size in all tumours, but was much less pronounced in the adenocarcinoma than in the other tumour lines. The extracellular volume of the various tumour lines did not vary with tumour size.

Topics: Adenocarcinoma; Animals; Capillary Permeability; Carcinoma, Small Cell; Cell Line; Erythrocyte Volume; Extracellular Space; Humans; Lung Neoplasms; Male; Melphalan; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Neoplasms, Experimental; Plasma Volume; Transplantation, Heterologous

A transplantable non-immunogenic murine carcinoma of spontaneous origin, WHT Carcinoma N-C (Hewitt), was used to assess the effectiveness of melphalan (Ml) and/or methotrexate (Mx) for treatment of occult metastatic disease following surgical excision of primary tumors. Early surgical excision alone cured 66% of mice; later excision gave no cures. Maximum sublethal doses of chemotherapy rarely cured mice of metastases but did extend their survival time by up to 66% as compared with mice subjected to excision only. The influence of excision and chemotherapy on the frequency of local recurrence or pulmonary metastasis is discussed. Extrapulmonary metastases were 2.5 times more frequent in long-term than in short-term survivors, independently of treatment.

Topics: Animals; Drug Therapy, Combination; Female; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Melphalan; Methotrexate; Mice; Neoplasm Metastasis; Neoplasm Recurrence, Local

Topics: Animals; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Lung Neoplasms; Melphalan; Mice; Neoplasms, Experimental; Peptichemio

Efficacy of local treatment of neoplastic pleural effusions may be related to the administered drugs, as judged by our series of 225 patients. The evaluation of the local improvement--which did not interfere with the evolution of the primary cancer--showed good (45.9%) or satisfactory (48.6%) results in a series of 148 patients treated with peptichemio. This local improvement was practically devoid of any adverse side-effect even when the treatment was particularly prolonged. This survey deals with 15 years of therapeutical experience concerned with neoplastic pleural effusions from malignant epithelial tumours.

Topics: Dose-Response Relationship, Drug; Humans; Lung Neoplasms; Melphalan; Peptichemio; Phagocytosis; Pleural Effusion

Topics: Adenocarcinoma; Amino Acids; Animals; Antineoplastic Agents; Copper; Drug Therapy, Combination; Female; Intestinal Neoplasms; Lung Neoplasms; Mammary Neoplasms, Experimental; Melphalan; Mice; Neoplasms, Experimental; Rumen; Sarcoma 37; Uterine Cervical Neoplasms

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

Metastatic tumor incidence in BALB/C X DBA/8F1 female mice was examined in the presence and absence of adjuvant chemotherapy. Following surgical removal of spontaneous mammary adenocarcinomas, phenylalanine mustard, adriamycin, and 5-fluorouracil (PAF) were administered at 4, 2, and 50 mg/kg, respectively, once a week for six injections. Recurring tumors and new tumors developing in other breasts over the next 6 months were noted and surgically removed to allow time for originally undetectable pulmonary metastases to develop or to regress completely. This regimen of PAF significantly decreased original tumor recurrences from 58% in controls to 36% in treated mice. New tumor development also was significantly reduced during the 5 weeks of PAF therapy and for 8 weeks thereafter. However, the incidence of pulmonary metastasis was unaffected by the chemotherapy, being 42% in controls and 37% in PAF-treated mice. About 30% of these metastases would have been undetectable at the time of original surgery. The findings stress the importance of developing agents and/or schedules that will specifically affect metastatic cells when administered early to minimal numbers of tumor cells. This system represents a stringent clinimimetic model for evaluating adjuvant chemotherapy in this regard.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary

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

Recent advances in the use of chemotherapy for treatment of osteosarcoma have altered out pessimism in this disease. Results are presented from 3 groups of investigators using different agents as adjuvant chemotherapy following immediately upon amputation of the primary. The Roswell Park Memorial Institute began a regime, immediately after amputation, of adriamycin 30 mg/M2 for 3 doses and given every 4-6 weeks. This study was subsequently expanded in a cooperative group (ALGB) and the results on 20 patients analyzed. At 19 months approximately 75 per cent are free of any pulmonary metastases compared with 10-25 per cent expected from amputation alone. Similar results have been obtained by other Centers using different chemotherapeutic agents. In Boston Children's Hospital high dose Methotrexate with citrovorum factor is used. In 12 of these patients local control of the primary by surgery was obtained and of these only 1 developed pulmonary metastases during an observation time of 23 months. At the M. D. Anderson Hospital multi-drug combinations were used including Cyclophosphamide, Vincristine, L-Phenylalamine Mustard and Adriamycin. They reported a survival rate of 55 per cent (10 out of 18). All of these neoplastic agents have toxic side effects but when carefully used these effects are minimized and the quality of life is quite good. Many questions must be answered by future controlled long term follow-up studies.

Topics: Amputation, Surgical; Bone Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Humans; Lung Neoplasms; Melphalan; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Vincristine

Differences in cytostatic sensitivity between subcutaneously transplanted Lewis lung carcinomas and metastases from them were studied in vitro. Sensitivity to vinblastine sulphate and melphalan was determined as the reduction of the incorporation of H3-thymidine into drug-treated cells compared with control cells. The main result of the present study is that tumor cells obtained from pulmonary metastases are more sensitive to cytostatic drugs in vitro than are the cells obtained from the corresponding subtaneous tumors. When cells from pulmonary metastases are transplanted subcutaneously, the sensitivity of the resulting tumor closely resembles that of other subcutaneous tumors. However, when the tumor cells have been passed through many cycles where the pulmonary metastases from subcutaneous tumors were re-transplanted subcutaneously and then allowed to metastasize again, a selection of tumor cells has apparently occurred: they have become more sensitive even when grown subcutaneously. Different explanations of this phenomenon are discussed.

Topics: Animals; Cells, Cultured; Lung Neoplasms; Melphalan; Mice; Mitosis; Neoplasm Metastasis; Neoplasms, Experimental; Vinblastine

Topics: Adult; Antineoplastic Agents; Choriocarcinoma; Colchicine; Dactinomycin; Daunorubicin; Female; Flavonoids; Humans; Lung Neoplasms; Melphalan; Mercaptopurine; Methotrexate; Middle Aged; Mitomycins; Neoplasm Metastasis; Olivomycins; Pneumonectomy; Pregnancy; Uterine Neoplasms; Vinblastine

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

Three patients with multiple myeloma who developed a plasma cell sarcoma during apparently successful chemothapy are described. It is postulated that the chemotherapy induced the sarcomatous change.

Topics: Aged; Bence Jones Protein; Bone Marrow; Cyclophosphamide; Female; Humans; Immunoelectrophoresis; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Lung Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Multiple Myeloma; Nitrogen Mustard Compounds; Pleural Neoplasms; Time Factors

Topics: Adenocarcinoma; Fallopian Tube Neoplasms; Female; Humans; Lung Neoplasms; Melphalan; Middle Aged; Neoplasm Metastasis; Radiography

Topics: Bone Neoplasms; Child; Child, Preschool; Cyclophosphamide; Dose-Response Relationship, Radiation; Female; Humans; Lung Neoplasms; Male; Melphalan; Neoplasm Metastasis; Prognosis; Radiotherapy Dosage; Sarcoma, Ewing; Time Factors; Vinblastine

Topics: Aged; Carcinoma, Squamous Cell; Female; Humans; Lung Neoplasms; Melphalan; Middle Aged; Pulmonary Artery; Pulmonary Fibrosis; Pulmonary Veins; Recurrence; Vascular Diseases

Topics: Animals; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Female; Leukopenia; Lung Neoplasms; Lymphoma, Non-Hodgkin; Melphalan; Mice; Neoplasm Metastasis; Ovarian Neoplasms; Peritoneal Neoplasms; Rats; Sarcoma 180; Sarcoma, Experimental; Thiotepa; Triazines

Topics: Adolescent; Adult; Dysgerminoma; Humans; Leukopenia; Lung Neoplasms; Lymphatic Metastasis; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Teratoma; Testicular Neoplasms; Vinblastine

Topics: Bone Neoplasms; Humans; Lung Neoplasms; Male; Melphalan; Middle Aged; Multiple Myeloma

Topics: Adrenalectomy; Aged; Antineoplastic Agents; Breast Neoplasms; Bronchial Neoplasms; Cortisone; Cyclophosphamide; Drug Synergism; Ethinyl Estradiol; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Hydrazines; Hypophysectomy; Kidney Neoplasms; Lung Neoplasms; Male; Melanoma; Melphalan; Mesothelioma; Methotrexate; Middle Aged; Nandrolone; Neoplasm Metastasis; Ovarian Neoplasms; Podophyllin; Sarcoma; Thiotepa; Vinblastine

Topics: Adult; Aged; Antitubercular Agents; Cyclophosphamide; Humans; Lung Neoplasms; Male; Melphalan; Multiple Myeloma; Neoplasms, Multiple Primary; Skin Neoplasms; Urethane

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: Adult; Cyclophosphamide; Dysgerminoma; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Melphalan; Mesothelioma; Middle Aged; Neoplasm Metastasis; Peritoneal Neoplasms; Radiotherapy Dosage; Sertoli-Leydig Cell Tumor; Teratoma; Testicular Neoplasms

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; Lung Neoplasms; Lymphatic Metastasis; Melphalan; Neoplasm Metastasis; Neoplasm Transplantation; Rats; Sarcoma, Experimental; Tail; Thiotepa; Vitamin B 12

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; Carcinoma 256, Walker; Carcinoma, Hepatocellular; Chemistry, Pharmaceutical; Leukemia; Leukemia, Experimental; Liver Neoplasms; Lung Neoplasms; Melphalan; Neoplasms, Experimental; Nitrogen Mustard Compounds; Pharmacology; Phenylalanine; Research; Skin Neoplasms

Topics: Humans; Lung Neoplasms; Male; Melphalan; Patient Discharge; Phenylalanine; Testicular Neoplasms