EFFECTS OF DEX-VERAPAMIL ON DOXORUBICIN CYTOTOXICITY IN P388 MURINE LEUKEMIA-CELLS

Resistance-modifying agents (RMAs) such as Verapamil have been proved to be effective in reversing multi-drug resistance (MDR) in many in vi tro assays. In this study we have investigated the efficacy of Dex-Ver apamil, the R-isomer of Verapamil, as a chemosensitizer in a murine le ukemia cell line (P388) and in its resistant counterpart (P388/Dx) exp ressing a typical MDR phenotype. We have examined in vivo the effect o f the co-administration of Dex-Verapamil and Doxorubicin in mice trans planted with P388 or P388/Dx cells. Mice treated with the combination of Doxorubicin plus RMA had a significant increase in survival rate as compared to controls; however, the effect was modest. On the contrary , in vitro Dex-Verapamil can enhance Doxorubicin cytotoxicity in P388/ Dx cells with a much greater effect depending on the treatment scheme used, by increasing the intracellular content of drug. Taken together our data indicate that Dex-Verapamil can indeed increase the sensitivi ty to Doxorubicin in resistant cells, but the limited efficacy shown i n vivo demonstrates that this phenomenon is strongly dependent on the treatment scheme used and on the maintenance of constantly elevated se rum levels.