mitolactol and Melanoma

The efficacy and modes of action of dibromodulcitol (DBD) and cisplatin (CDDP) were studied in several model systems. Combination treatments produced a longer survival time in mice bearing P388 solid lymphomas than either of the drugs alone. In the human metastatic melanoma HT-168 xenograft model the combined application of DBD and CDDP was also very effective, inducing a reduction in the number and volume of metastatic nodules. For V79 spheroids, DBD was mainly cytotoxic against the internal, quiescent cells, whereas cisplatin primarily killed cells in the proliferating, external regions of the spheroids. When combined, the drugs appeared to act synergistically throughout the spheroids. Studies on plasmid DNA showed that CDDP primarily generates cross-links, whereas single-strand breaks were dominant after DBD treatment. Upon using an assay for cleavage by restriction nuclease, antagonistic action of DBD and CDDP in combination may occur, nevertheless more strand breaks were always observed in these samples. These results suggest that the efficacy of combined DBD and CDDP is in part a result of 'spatial cooperation' by the drugs (i.e. affecting different cells) and in part the result of DNA damage produced by the combination treatments.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cisplatin; DNA Damage; DNA, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Leukemia P388; Male; Melanoma; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Inbred DBA; Mitolactol; Neoplasm Metastasis; Neoplasm Transplantation; Tumor Cells, Cultured

Topics: Alkaloids; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Humans; Melanoma; Mitolactol; Paclitaxel

Twenty-two patients with metastatic melanoma were treated with a chemotherapy regimen consisting of two cycles of induction therapy with vinblastine, bleomycin, and cisplatin, followed by maintenance therapy with dacarbazine and dibromodulcitol. A 17% response rate was noted in this patient group, with a median survival of 40 weeks. Objective responses were limited to cutaneous, nodal, pulmonary, and one adrenal site of metastatic disease. Toxicity was acceptable and was limited to myelosuppression and nausea with emesis. Further study appears warranted to define the optimal treatment plan for metastatic melanoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Dacarbazine; Drug Evaluation; Female; Follow-Up Studies; Humans; Male; Melanoma; Middle Aged; Mitolactol; Vinblastine

One hundred consecutive patients with cerebral metastases from malignant melanoma were studied in relation to survival from the time of diagnosis of central nervous system (CNS) involvement, response to treatment, characteristics of their primary lesion, and the course of the disease from initial diagnosis to the development of intracranial tumor. After treatment, clinical and investigational evidence of objective regression of cerebral lesions was demonstrable in ten patients who survived with a median of 11.5 months from diagnosis of CNS involvement. In 11 additional patients, CNS disease remained clinically stable for a median period of 7 months. Median survival for the entire group of 100 patients was 2.5 months. However, eight patients (8%) survived longer than 1 year from the time of diagnosis of cerebral metastases, four of whom (4%) survived longer than 2 years; the longest survivor being disease-free and incomplete neurologic remission at more than 82 months. Patients with malignant melanoma metastatic to the brain should be informed of the therapeutic options available for their disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Combined Modality Therapy; Dexamethasone; Evaluation Studies as Topic; Humans; Hydroxyurea; Lomustine; London; Melanoma; Mitolactol; Prognosis; Radioisotope Teletherapy

In this Eastern Cooperative Oncology Group (ECOG) phase II study, dibromodulcitol (DBD) and a combination of actinomycin D, hydroxyurea, and cyclophosphamide (AHC) were compared with methyl-CCNU, the current ECOG standard, in patients who had received no prior chemotherapy for disseminated malignant melanoma. The response rates were 6% (3/50) for AHC, 9% (3/34) for DBD, and 14% (7/49) for methyl-CCNU. Median survival times were 4, 5, and 6 months, respectively. Neither regimen appears to offer any advantage over methyl-CCNU as front-line therapy for patients with disseminated melanoma.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dactinomycin; Drug Evaluation; Female; Humans; Hydroxyurea; Male; Melanoma; Middle Aged; Mitolactol; Semustine

A combined clinical and pharmacokinetic phase I study of the substituted hexitol dibromodulcitol (DBD), administered as a single oral monthly dose, has been performed. Twenty-three patients with advanced neoplasms received DBD doses ranging from 600 to 1,800 mg/m2 body surface area (BSA). The dose-limiting toxicity was myelosuppression, with both significant granulocytopenia and thrombocytopenia occurring at dose levels of 1,500 to 1,800 mg/m2. The average pharmacokinetic parameters for DBD, calculated on the basis of a one-compartment model with first-order absorption and elimination, include the elimination constant, .005 +/- .002/min; absorption constant, .012 +/- .009/min; and an apparent volume of distribution, 1.03 +/- .4 L/kg. The area under the drug concentration curve (AUC) and the peak drug level (Cmax) were linearly related to the dose administered (P less than .001). The mean AUC was 18.7 +/- 6.1 mmol/L min, and the mean Cmax was 47.1 +/- 16.8 mumol/L when normalized to a DBD dose of 1 gm/m2. The elimination constant was significantly reduced in patients with abnormal hepatic function (P less than .01). The elimination constant was not correlated with renal function. The half-life of DBD in plasma (158 minutes) was considerably shorter than the four-to eight-hour half-life of total radioactivity in plasma measured by previous investigators following the administration of radiolabeled DBD.

Topics: Absorption; Administration, Oral; Adult; Aged; Bone Marrow Transplantation; Carcinoma; Dianhydrogalactitol; Dose-Response Relationship, Drug; Drug Evaluation; Female; Half-Life; Humans; Kinetics; Male; Melanoma; Middle Aged; Mitolactol; Neoplasm Metastasis; Sarcoma; Time Factors

Thirty-seven fully assessable patients with metastatic malignant melanoma were administered DTIC, actinomycin-D, and dibromodulcitol (DBD) on a q 3- to 4-week schedule. Doses of actinomycin-D and DTIC were 1.25 mg/m2 and 750 mg/m2, respectively, on day 1. DBD was progressively escalated in five dose levels in succeeding patients from an initial 90 mg/m2 daily, days 3-7, to a dose-limiting 230 mg/m2. Two complete and nine partial responses were observed for an overall response rate of 30%. Median duration of response was 18 weeks. Major toxicities observed were hematologic and gastrointestinal. Median survival of all patients was 30 weeks and did not differ significantly from our earlier trials of DTIC and actinomycin-D +/- chlorozotocin. Although the observed objective response rate was higher than our previous efforts in this disease, the addition of DBD failed to significantly impact on the survival of the entire treatment group. Further investigation of this chemotherapy combination does not appear warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Dactinomycin; Drug Evaluation; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Male; Melanoma; Middle Aged; Mitolactol

The Central Pennsylvania Oncology Group conducted a phase II study of mitolactol in advanced metastatic melanoma to determine the overall survival rate and duration of response to this agent. The starting dose was 100 mg/m2/day orally. If no hematologic toxicity was noted on weekly blood cell counts, the dose was increased to 130 mg/m2/day on Day 35, and, if still tolerated, to 160 mg/m2/day on Day 70. Six of 25 evaluable patients (24%) had objective partial response. The median duration of response was 20 weeks, with a range of 10-66 weeks. Six of 25 patients (24%) had stable measurable disease, with a median duration of 9 weeks. The median survival from date of entry in this study was 21 weeks in responding or stable patients compared to 7 weeks in nonresponders. Hematologic toxicity was the dose-limiting factor. This study shows that mitolactol has moderate activity against advanced melanoma, and the drug deserves further study in combination with nonmyelotoxic drugs.

Topics: Adult; Aged; Bone Marrow; Drug Evaluation; Female; Hemoglobins; Humans; Leukocyte Count; Male; Melanoma; Middle Aged; Mitolactol; Neoplasm Metastasis; Platelet Count

Topics: Adult; Aged; Drug Evaluation; Female; Humans; Male; Melanoma; Middle Aged; Mitolactol; Neoplasm Metastasis; Skin Neoplasms

Dibromodulcitol (DBD) and BCNU were administered to 20 patients with metastatic malignant melanoma who had not received prior chemotherapy. One complete and three partial responses were noted; duration of response was short. Dose limiting toxicity was thrombocytopenia. DBD and BCNU do not appear to improve response over single agent therapy for disseminated melanoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Drug Evaluation; Female; Humans; Male; Melanoma; Middle Aged; Mitolactol; Neoplasm Metastasis; Skin Neoplasms

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Dacarbazine; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Melanoma; Middle Aged; Mitolactol; Neoplasm Metastasis; Vinblastine

Twenty-four patients were evaluated in a non-randomized study to assess the effectiveness of dibromodulcitol (DBD) in Stage IV melanoma. Patients received 100 mg/m2 of DBD orally for 35 days. The dose was escalated to 130 mg/m2 and then to 160 mg/m2 if no significant hematologic toxicity occurred. There were no objective responses, including six patients who had had no prior chemotherapy. Five patients (21%) remained stable. Median survival was 151 days. Survival favored females, nonvisceral involvement pretherapy, and patients with a disease-free interval (DFI) of greater than 1 year. None of these advantages was statistically significant. Toxicity was predominantly hematologic, but nausea, vomiting, shortness of breath, and diarrhea were also seen. Oral DBD, using this dose and schedule, does not appear efficacious in advanced disseminated melanoma.

Topics: Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Melanoma; Mitolactol; Skin Neoplasms

In vitro tests of tumor cell drug sensitivity have been suggested as a means of selecting more appropriate clinical strategies against human cancer and improving preclinical drug development. The lack of biotransformation in these in vitro assays precludes the meaningful assessment of several major chemotherapeutic agents, including dacarbazine and cyclophosphamide. In vivo drug exposure of tumor cells in agar diffusion chambers placed in mice offers a possible solution to problems of drug biotransformation and pharmacokinetics. We have prospectively used this system as an assay for sensitivity of clonogenic human melanoma cells. Tumor cells were tested fresh, cryopreserved, and/or cultured in vitro before or after clinical use of dacarbazine, semustine, and mitolactol in 41 patient-drug combinations in which a clinical correlation could be made. Tumor cell drug sensitivity in the assay using fresh or cryopreserved tumor cells was highly correlated with clinical response and resistance with clinical nonresponse. Cultured melanoma cells exhibited enhanced plating efficiency in comparison to both fresh and cryopreserved cells of the same tumor. Cultured cells also showed increased drug sensitivity which did not correlate with drug sensitivity of the same fresh or cryopreserved tumor or with clinical response. Tumor cell drug sensitivity assays carried out in vivo provide a possible basis for preclinical evaluation of drugs which are unsuitable for in vitro testing.

Topics: Animals; Biological Assay; Biotransformation; Cell Survival; Clone Cells; Dacarbazine; Drug Evaluation; Drug Tolerance; Humans; Kinetics; Melanoma; Mice; Mitolactol; Nitrosourea Compounds; Semustine; Specimen Handling

Topics: Adult; Aged; Drug Evaluation; Female; Humans; Male; Melanoma; Middle Aged; Mitolactol; Neoplasm Metastasis

Twenty-six patients with disseminated malignant melanoma received an oral regimen of mitolactol and semustine (methyl-CCNU). Sixteen patients had received prior systemic therapy, and 16 had visceral involvement. There were no objective regressions among ten patients receiving the drugs as initial systemic therapy. However, one of 16 patients having prior systemic treatment did have an objective response. Hematologic and gastrointestinal toxic effects were well-tolerated.

Topics: Aged; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Leukocyte Count; Leukopenia; Male; Melanoma; Middle Aged; Mitolactol; Neoplasm Metastasis; Nitrosourea Compounds; Pilot Projects; Platelet Count; Semustine; Skin Neoplasms; Thrombocytopenia

Twenty-five patients with measurable metastatic melanoma refractory to DTIC and a nitrosourea were treated with dibromodulcitol (DBD). DBD was administered orally at bedtime at a dose of 100 mg/m2/day until hematologic toxicity (a greater than or equal to 50% decrease in the wbc or platelet count) was induced. Five patients experienced clinically useful objective remissions; responding lesions included both soft tissue metastases and visceral metastatic disease. It is concluded that DBD is useful in the treatment of patients with metastatic melanoma and thus joins DTIC and the nitrosoureas as single agents which are active against this malignancy.

Topics: Adult; Aged; Bone Marrow; Dacarbazine; Drug Evaluation; Drug Resistance; Female; Humans; Male; Melanoma; Middle Aged; Mitolactol; Neoplasm Metastasis; Nitrosourea Compounds; Remission, Spontaneous; Triazenes

Co-operative investigation of clinical therapy for cancer is used to test hypotheses developed in single institutions and in animal research laboratories. The present studies in a large co-operative organization, the Central Oncology Group, are being conducted in seven major solid tumors in adults; in these studies patients with a poor surgical prognosis are being treated with preoperative or postoperative chemotherapy, preoperative radiotion therapy of these modalities. Results of studies currently underway or recently completed in 1,278 patients are summarized. In most instances, the research has demonstrated little or no apparent improvement in the disease free interval or the survival time from adjuvant therapy, although only on of the studies has been completed and fully evaluated thus far. In carcinoma of the colon and rectum and melanoma, mild toxicity from drug therapy has been associated with statistically significant improvement in survival times. These studies have produced base line information on disease free intervals, time to progression and survival time in patients with cancer who are seen in the participating institutions. These observations are expected to useful in the planning of future adjuvant studies.

Topics: Adult; Altretamine; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Carmustine; Colonic Neoplasms; Cyclophosphamide; Dacarbazine; Doxorubicin; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Lomustine; Lung Neoplasms; Male; Melanoma; Mitolactol; Neoplasms; Osteosarcoma; Pancreatic Neoplasms; Rectal Neoplasms; Vincristine