Mitomycin C combination therapy against murine tumor systems. Effectiveness with cyclophosphamide and methotrexate.

Abstract

Mitomycin C (MMC) has been evaluated in combination with several antitumor agents. Full dose response curves were established for all drugs and drug combinations. Synergy was shown with MMC plus either cyclophosphamide (CYC) or methotrexate (MTX). In testing MMC and CYC against P388 leukemia, the combined treatment yielded a 75% rate of long-term survivors at the optimal level, compared to no survivors at the optimal level of the best single agent, CYC, alone. There was no increased toxicity among the combination-treated animals. Large increases in lifespan were obtained against L1210 and B16. Maximally tolerated doses of the single agents could be combined without increased toxicity. The combination of MMC and MTX was synergistic against ip L1210 and P388 leukemias. The responses of mice bearing L1210 to treatment on days 1, 5, and 9 respectively, were 42% ILS for 3.0 mg/kg MMC; 96% ILS for 15 mg/kg MTX; 172% ILS with four out of ten survivors for 3.0 mg/kg MMC plus 15 mg/kg MTX. MMC and adriamycin (ADR) were found to be synergistic against B16 melanoma at one schedule but not against another schedule, or against colon carcinoma 26. No improvements over optimal nontoxic single agent therapy were seen for chlorambucil, 5-fluorouracil, dibromodulcitol, cis-diaminedichloroplatinum or 4-'(9-acridinylamino) methansulfon-M-anisidide. On the basis of these data, recommendations were made for clinical trials for MMC plus either CYC or MTX against lung, breast, and colon tumors.