In vitro antagonistic cytotoxic interactions between platinum drugs and taxanes on bone marrow progenitor cell CFU-GM

We have designed and used an in vitro bone marrow cell culturing system for investigating pharmacodynamic interactions between platinum anti-cancer dr ugs and taxanes. With this system, in which the bone marrow progenitor cell CFU-GM is proliferating and differentiating into granulocytes and monocyte s, we could show a strong antagonistic cytotoxicity of the combination carb oplatin and Taxotere, in three different schedules, and of the combination cisplatin and Taxol, in two out of the three schedules tested. Modulation o f intracellular platinum drug accumulation in granulocytes and monocytes do es not seem to be a plausible explanation for the observed antagonism. In v itro coincubation of granulocytes/monocytes with the combination carboplati n and Taxotere did not reveal an effect of Taxotere on intracellular platin um accumulation. Although Taxol reduced intracellular cisplatin levels by 1 2%, this effect was not significantly different from the co-incubation of c isplatin with Cremophor EL, the solvent for paclitaxel in Taxol. The toxici ty data obtained in this study seem to be in accordance with recent clinica l trials where combination therapies with platinum drugs and taxanes result ed in marked reductions in myelosuppression in patients. Therefore, these t ypes of assays could be useful as to the assessment of bone marrow toxiciti es of clinically important drug combinations, [(C) 1999 Lippincott Williams & Wilkins.].