Selective enhancement of vincristine cytotoxicity in multidrug-resistant tumor cells by dilantin (phenytoin)

Tumor cell resistance to chemotherapeutic agents of diverse structure and mechanism of action is thought to be due to efflux of drug by P-glycoprotein, which is overexpressed in tumor cells with the multidrug-resistant phenotype. Agents generally associated with the multidrug-resistant phenotype include inhibitors of topoisomerase II, e.g., doxorubicin, etoposide, and the microtubule poisons such as vinblastine, vincristine (VCR), and taxol. The antiepileptic drug phenytoin (DPH), an inhibitor of tubulin polymerization, potentiates (P < 0.05) the cytotoxicity of the chemotherapeutically useful microtubule poison VCR in tumor cells with the wild-type or multidrug-resistant phenotype. Among agents associated with the multidrug-resistant phenotype, the modulation of cytotoxicity by DPH was selectively effective with the microtubule poison VCR but not the topoisomerase II inhibitor doxorubicin. The potentiation of vincristine cytotoxicity by DPH was not due to binding to P-glycoprotein or by increasing VCR accumulation. We thus propose a novel mechanism for the modulation of resistance based on evidence that DPH at noncytotoxic concentrations can selectively enhance the cytotoxic potential of vincristine without interfering with P-glycoprotein function. Thus, studies with phenytoin could assist in characterizing other molecular determinants of multidrug resistance and the design of trials to modulate drug efficacy.