MODULATION OF VINBLASTINE CYTOTOXICITY BY DILANTIN (PHENYTOIN) OR THEPROTEIN PHOSPHATASE INHIBITOR OKADAIC ACID INVOLVES THE POTENTIATION OF ANTI-MITOTIC EFFECTS AND INDUCTION OF APOPTOSIS IN HUMAN TUMOR-CELLS

Cellular insensitivity to vinca alkaloids is suggested to be primarily due to drug efflux by P-glycoprotein (P-gp). The anti-epileptic pheny toin (DPH), which does not bind to P-gp, can selectively enhance vincr istine (VCR) cytotoxicity in wild-type (WT) or multidrug-resistant (MD R) cells. We now demonstrate that the protein phosphatase inhibitor ok adaic acid (OKA) can mimic the effect of DPH by selectively enhancing cytotoxicity of vinblastine (VBL), but not taxol and doxorubicin, in h uman leukaemia HL-60 cells. Both DPH and OKA potentiate the anti-mitot ic effects of VBL by enhanced damage to the mitotic spindle, resulting in prolonged growth arrest. Also, unlike VBL alone, in human leukaemi a or non-small-cell lung carcinoma cells treated with VBL plus DPH, re covery from damage to the mitolic spindle is compromised in drug-free medium and cell death by apoptosis in interphase ensues. Since protein phosphatases are involved with the regulation of metaphase to anaphas e transit of cells during the mitotic cycle, enhanced VBL cytotoxicity in the presence of DPH or OKA may involve effects during metaphase on the mitotic spindle tubulin leading to growth arrest and apoptosis in interphase. These novel results suggest that DPH or OKA could be powe rful tools to study cellular effects of vinca alkaloids and possibly f or the development of novel therapeutic strategies.