Cellular pharmacology of Vinca alkaloid resistance and its circumvention.

Vinca alkaloid-resistant human leukemic cells express the multiple drug-resistant phenotype, characterized by cross resistance to natural product compounds of unrelated structure and action. While there are also distinct biochemical lesions associated with this phenotype, their role(s) in the expressions of resistance is not known at this time. More clear, however, is our understanding of the pharmacologic determinants of this resistance--apparent decreased drug uptake and decreased drug retention. This latter phenomenon has been attributed to the workings of an active efflux pump, but data presented here and elsewhere permit an alternative explanation--that of altered drug binding to an as yet unidentified target(s). Elucidation of the mechanism of multiple drug resistance is important in the design of new chemotherapeutic strategies to overcome it. In this regard, calcium channel blocking agents and calmodulin inhibitors can cause an apparent reversal of resistance by enhancing the cytotoxic effectiveness of the anticancer drugs, possibly by increasing the amount of drug retained by the tumor cells. The basis for this enhanced retention and cytotoxicity is not presently known, but it may be related to cellular calcium fluxes, calmodulin content or membrane fluidity and permeability. The meaning of these findings is unclear at the present time, but they may provide new insights into the mechanism of action and ultimate cellular target(s) for Vinca alkaloids. Whether these modifying drugs sensitize the cells to the action of the alkaloids or potentiate the oncolytic drug effect in the cell remains to be determined. Regardless of the mechanism, calcium channel blocking agents may have a role in the combination chemotherapy of the leukemias with Vinca alkaloids.