COMBINATION CHEMOTHERAPY INVOLVING ORALLY-ADMINISTERED ETOPOSIDE AND JM-216 IN MURINE TUMOR-MODELS

Purpose: Orally administered VP-16 (etoposide) was evaluated in combin ation with an orally administered platinum analog, JM-216 [ammine/cycl ohexylamine diacetatodichloride Pt(IV)], in mice bearing murine tumors , for therapeutic synergy, Methods: The treatment schedules used invol ved two courses of therapy, each course consisting of administration e very day for 5 days beginning on either day 4 or day 5 posttumor impla ntation, and again on day 11 or day 12 postimplantation. Result: The a mounts of each drug tolerated in the combination treatment setting wer e much less than their individual maximum tolerated doses (MTDs). Thus , to be used safely, each drug's dose had to be greatly reduced from t he amount tolerated when the drugs were given individually. Multiple e xperiments using a staged P388 leukemia model implanted intravenously yielded confirmatory data supporting the existence of a therapeutic sy nergy for the drug combination. Identical regimens applied in the stag ed M5076 sarcoma model implanted subcutaneously, however, were not con sidered to have yielded data indicative of therapeutic synergy. Conclu sions: A clinical phase I study using this combination chemotherapy ca n be recommended on the basis of the results obtained in the leukemia model.