Carboplatin and paclitaxel interact antagonistically in a megakaryoblast cell line - a potential mechanism for paclitaxel-mediated sparing of carboplatin-induced thrombocytopenia

Purpose: Clinical observation has shown that paclitaxel ameliorates the ant iplatelet toxicity of carboplatin when the two drugs are combined, although antitumour activity and white cell toxicity are at least additive. We hypo thesized that this is due to an interaction between the two drugs at the le vel of the platelet precursor. Methods: We measured inhibition of growth of the megakaryoblast cell line MEG-01 following exposure to paclitaxel and c arboplatin singly or combined. Drug interaction was assessed by median effe ct analysis. Results: An antagonistic interaction was observed, and this wa s most marked at drug concentrations giving a low level of growth inhibitio n (P < 0.002, sign test). The interaction was not sequence-dependent. There was no significant difference in whole-cell accumulation of platinum or th e amount of platinum adducts on DNA following combined treatment in compari son with carboplatin alone. Conclusions: These results provide the first ev idence of an antagonistic interaction between paclitaxel and carboplatin in a platelet precursor and provide an explanation for the platelet-sparing e ffect of the combination of these chemotherapeutic agents. While the mechan isms underlying the interaction described in this report are yet to be full y elucidated, this study provides evidence that the antagonism between pacl itaxel and carboplatin in MEG-01 cells is not due to reduced platination of DNA.