mitolactol and Neoplasms

Three hexitol derivatives, dibromomannitol (DBM), dibromodulcitol (DBD), and dianhydrogalactitol (DAG), originally investigated in Hungary, have been evaluated as anticancer agents in the United States. Their principal mechanism of action is attributed to alkylation via actual or derived epoxide groups. Their preclinical spectrum includes activity against murine leukemias and against the murine ependymoblastoma, which is particularly noteworthy for DAG. Dibromomannitol trials were targeted to chronic myelogenous leukemia but no advantage over busulfan therapy was demonstrable. Dibromodulcitol and DAG were sequentially evaluated for their usefulness against a wide variety of tumors. The activity of DBD against breast cancer has stimulated several continuing trials in this disease. On the other hand, DAG was disappointing in breast cancer and in several other malignancies, but some activity has been noted against lung cancer. Both DBD and DAG are being investigated for possible usefulness in the management of patients with intracranial neoplasms. The present clinical experience does not allow firm judgment on the advantage of one analogue over another. Such comparative analysis does point out the desirable direction of future studies as well as the limitations of current preclinical systems for the selection of analogues.

Topics: Animals; Clinical Trials as Topic; Dianhydrogalactitol; Dogs; Humans; Kinetics; Mannitol; Mice; Mitobronitol; Mitolactol; Neoplasms; Sugar Alcohols

Topics: Animals; Bone Marrow; Chemical Phenomena; Chemistry; Clinical Trials as Topic; DNA, Neoplasm; Drug Resistance; Female; Humans; Immunity; Mitolactol; Neoplasms; Neoplasms, Experimental

Three hexitol derivatives, dibromomannitol (DBM), dibromodulcitol (DBD), and dianhydrogalactitol (DAG), originally investigated in Hungary, have been evaluated as anticancer agents in the United States. Their principal mechanism of action is attributed to alkylation via actual or derived epoxide groups. Their preclinical spectrum includes activity against murine leukemias and against the murine ependymoblastoma, which is particularly noteworthy for DAG. Dibromomannitol trials were targeted to chronic myelogenous leukemia but no advantage over busulfan therapy was demonstrable. Dibromodulcitol and DAG were sequentially evaluated for their usefulness against a wide variety of tumors. The activity of DBD against breast cancer has stimulated several continuing trials in this disease. On the other hand, DAG was disappointing in breast cancer and in several other malignancies, but some activity has been noted against lung cancer. Both DBD and DAG are being investigated for possible usefulness in the management of patients with intracranial neoplasms. The present clinical experience does not allow firm judgment on the advantage of one analogue over another. Such comparative analysis does point out the desirable direction of future studies as well as the limitations of current preclinical systems for the selection of analogues.

Topics: Animals; Clinical Trials as Topic; Dianhydrogalactitol; Dogs; Humans; Kinetics; Mannitol; Mice; Mitobronitol; Mitolactol; Neoplasms; Sugar Alcohols

Topics: Animals; Bone Marrow; Chemical Phenomena; Chemistry; Clinical Trials as Topic; DNA, Neoplasm; Drug Resistance; Female; Humans; Immunity; Mitolactol; Neoplasms; Neoplasms, Experimental

SNF4435C and D, novel immunosuppressants produced by a strain of Streptomyces spectabilis, were examined for their reversing effects in vitro on various multidrug-resistant (MDR) tumor cells overexpressing P-glycoprotein. These two compounds in the range of 3-10 microM completely reversed the resistance of MDR variant cells, mouse leukemia P388 cells [vincristine (VCR)-resistant P388/VCR and adriamycin (ADM)-resistant P388/ADM], human myelogenous leukemia K562 cells (VCR-resistant K562/VCR and ADM-resistant K562/ADM) and human ovarian cancer A2780 cells (ADM-resistant AD(10)), against VCR. Both compounds moderately potentiated the sensitivity of the MDR cells to ADM but the reversal was not complete. SNF4435C and D significantly increased the intracellular accumulation of VCR in AD(10) cells as potently as verapamil, cyclosporin A (CysA) and FK506, whereas the compounds exerted no effect on the accumulation of VCR in the drug-sensitive parent cells. Moreover, SNF4435C improved the chemotherapeutic efficacy of VCR in the treatment of P388/VCR-bearing mice. When 10 mg/kg SNF4435C was administered intraperitoneally to the mice concurrently with 0.2 mg/kg VCR for every 5 days, a treated/control (T/C) value of 143% was obtained. These results suggest that the compounds are useful candidates or tools for MDR modification in cancer chemotherapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Inhibitory Concentration 50; Mice; Mitolactol; Mitomycins; Neoplasm Transplantation; Neoplasms; Nitro Compounds; Pyrones; Tumor Cells, Cultured; Vincristine

Dianhydrogalactitol (DAG), labelled with 3H, was administered in single intravenous or oral doses to six patients (three in each group) with cancer. Kinetic parameters were calculated for the unchanged DAG and its biotransformation products. Elimination of the drug by metabolism and excretion was described by a catenary model. In order to elucidate the role of DAG as a mediator of the alkylating action of the cytostatic drug dibromodulcitol (DBD), the pharmacokinetic parameters of DAG and DBD were compared. The mean residence time for pharmacologically active molecules in the body was six times shorter for DAG (1.9 hr) than for DBD (11.4 hr). Alkylating action and metabolic degradation proceeded about 8-9 times faster for DAG than for DBD. The process of DBD alkylation implies a slow solvolytic conversion of the parent drug into the more reactive bromoepoxide and DAG. The preformed DAG would be rapidly consumed by intracellular alkylation and degradation, while unchanged DBD could form a depot in the cells and exert its cytostatic activity through the epoxides released in situ by solvolytic activation. Thus DBD entering the cells in unchanged form may have a more important role in its therapeutic effects than had been assumed earlier.

Topics: Adult; Aged; Alkylation; Biotransformation; Dianhydrogalactitol; Female; Humans; Kinetics; Male; Middle Aged; Mitolactol; Models, Biological; Neoplasms; Pleural Effusion; Protein Binding; Sugar Alcohols

Topics: Alopecia; Amenorrhea; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Cystitis; Doxorubicin; Drug Eruptions; Female; Fluorouracil; Heart; Humans; Methotrexate; Mitolactol; Mitomycins; Neoplasms

Topics: Animals; Antineoplastic Agents; Chemical Phenomena; Chemistry; Dianhydrogalactitol; DNA Replication; Drug Evaluation; Female; Humans; Male; Mice; Mitolactol; Neoplasms; Neoplasms, Experimental; Structure-Activity Relationship; Sugar Alcohols

Dibromodulcitol (DBD), labelled with [3H] at position C-1, was administered orally to 6 patients in a single dose of 15 mg/kg. Kinetic parameters were calculated for the effective drug (DBD + BrEpG + DAG), protein-bound hexitol moieties and free metabolites. Approximate values were estimated for the oral bioavailability of DBD. Disposal of the drug by metabolism and excretion was described by a simplified catenary model. The results indicated that 8-20% of the drug became firmly bound to macromolecules, probably by alkylation. The slow rate of alkylation in vivo (half-life 14 hr) may imply conversion of DBD into epoxides and their alkylating interaction with the target nucleophiles. The long retention of the firmly bound hexitol moieties in the body may be an indicator of the cumulative potency of DBD and must be taken into consideration by developing dosage schedules.

Topics: Administration, Oral; Half-Life; Humans; Kinetics; Mitolactol; Neoplasms

Pilot studies to obtain drug dosages for the combinations of dibromodulcitol (DBD) and BP-16, DBD and AMSA, and DBD, VP-16 and AMSA were carried out to levels of acceptable clinical toxicity. Myelosuppression was the dose-limiting toxicity in all combinations. While regressions were few in this group of heavily pretreated patients, we feel the drug combinations need further study in central nervous system, breast, and lung cancers.

Topics: Aged; Aminoacridines; Amsacrine; Drug Evaluation; Drug Therapy, Combination; Etoposide; Female; Humans; Male; Middle Aged; Mitolactol; Neoplasms; Pilot Projects; Podophyllotoxin

Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Mitolactol; Neoplasms; Remission, Spontaneous

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

Adriamycin is a new anticancer antibiotic with a wide spectrum of activity against solid tumours. The results obtained with this agent in 159 patients with histologically confirmed advanced metastastic malignancies are reported. Encouraging results were obtained in patients with sarcomas of bone and soft tissue (12/22). Response was also seen in mesothelioma (3/9) and lung cancer (5/15). A variety of other neoplasms was also treated and results obtained in neuroblastoma, testicular tumours, stomach carcinoma, breast cancer and nephroblastoma are reported. Treatment is discussed, with reference to response rates and toxicity. Results in 72 patients with advanced breast cancer, who received adriamycin in combination with other chemotherapeutic agents, are presented. Seventeen patients with primary liver cancer were also treated with adriamycin. To date, this is the only chemotherapeutic agent that appears to significantly improve survival times in patients with this resistant form of cancer. The prophylactic use of adriamycin against osteogenic sarcoma is also discussed.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Infant; Liver Neoplasms; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Mitolactol; Neoplasm Metastasis; Neoplasms; Pleural Neoplasms; Sarcoma

Topics: Antineoplastic Agents; Azacitidine; Breast Neoplasms; Chemical Phenomena; Chemistry; DNA Replication; DNA, Neoplasm; Doxorubicin; Drug Therapy, Combination; Humans; Leukemia, Lymphoid; Lymphoma; Male; Mitolactol; Neoplasms; Nitrosourea Compounds; Testicular Neoplasms; Thyroid Neoplasms