DIPYRIDAMOLE MODULATES MULTIDRUG-RESISTANCE AND INTRACELLULAR AS WELLAS NUCLEAR-LEVELS OF DOXORUBICIN IN B16 MELANOMA-CELLS

Simultaneous occurrence of resistance to many chemotherapeutic agents, termed multidrug resistance (MDR), is a complex phenotype. MDR occurs due to several reasons, including over-expression of a 170-kDa membra ne-bound protein, called P-glycoprotein (P-gp), which apparently parti cipates in active drug efflux. Multidrug-resistant cells also frequent ly exhibit an altered pattern of intracellular drug distribution, resu lting in a reduction in the nuclear level of drugs such as a doxorubic in (DOX). In this study, the effect of dipyridamole (DP) on drug resis tance and on intracellular as well as nuclear levels of DOX in multidr ug-resistant melanoma cells has been examined. For this purpose, drug- sensitive murine melanoma cells (B16V) and their multidrug-resistant v ariant cells, (B16VDXR; selected for resistance to DOX) which over-pro duce P-gp, were employed. B16VDXR cells were cross-resistant to severa l anti-cancer agents including etoposide (VP-16) and mitoxantrone (Mit ox). DP (10 mu M) significantly potentiated the cytotoxicity of DOX, V P-16 and Mitox towards multidrug-resistant B16VDXR cells but not in pa rental drug-sensitive B16V cells. The presence of DP resulted in a 3.7 -fold increase in the total cellular level and a 4.2-fold increase in the nuclear content of DOX in the resistant cells. Isobologram analysi s indicates that DP at several pharmacologically relevant concentratio ns synergistically potentiates the activity of DOX in B16VDXR cells. ( C) 1994 Wiley-Liss, Inc.