REVERSAL OF DOXORUBICIN RESISTANCE IN MULTIDRUG-RESISTANT MELANOMA-CELLS IN-VITRO AND IN-VIVO BY DIPYRIDAMOLE

The occurrence of multidrug resistance (MDR) decreases the clinical ut ility of several anticancer agents, including doxorubicin (DOX). A tra nsmembrane efflux pump, P-glycoprotein (P-gp), is frequently implicate d in the development of MDR in tumor cells. Dipyridamole (DP), a clini cally used antiplatelet drug, enhances the cytotoxicity of the antican cer drugs affected by MDR, Although this aspect has been studied exten sively in cell culture models, the effectiveness of DP to overcome mul tidrug resistance has not been investigated using in vivo models of mu ltidrug-resistant solid tumors. Therefore, the objective of this study was to evaluate the role of DP in the reversal of resistance to DOX i n tumor-bearing mice in the context of its anti-MDR activity in vitro. For this purpose, drug-sensitive murine melanoma cells (B16V) and the ir DOX-selected MDR variant, B16VDXR cells, were used In vitro, the re versal of DOX resistance of B16VDXR cells by DP was determined using c lonogenic assays, and the influence of DP on the transport of DOX was evaluated by measurement of steady-state accumulation as weil as efflu x of DOX in B16VDXR cells. Antitumor activity of different treatments was assessed by monitoring tumor growth. Pharmacokinetics of DOX, with or without DP, were evaluated in C57BL/6 mire bearing B16V or B16VDXR tumors. DP produced a 6.4-fold reversal of resistance to DOX in vitro ; this was accompanied by an increase (3.6-fold) iii the steady-state intracellular accumulation of DOX and a marked reduction in the efflux of DOX from B16VDXR cells. Furthermore, a linear correlation was obse rved between the EC50 values and the steady-state intracellular levels of DOX in the multidrug-resistant cells. In the in vivo experiments, similar growth patterns were seen for the DOX alone and the DOX+DP gro ups for B16V tumors. The results with B16VDXR tumors were in sharp con trast. The DOX+DP treatment caused a significant delay in the growth o f B16VDXR tumors compared to treatment with DOX alone or controls. DP did not alter the plasma pharmacokinetics of DOX in C57BL/6 mice but r esulted in a significant increase in the intratumoral accumulation of DOX.