Potentiation of Adriamycin Cytotoxicity by Dipyridamole Against HeLa Cells in Vitro and Sarcoma 180 Cells in Vivo

Dipyridamole (DP) is clinically prescribed for its vasodilating and antiplatelet effects. DP also inhibits nucleoside transport and enhances cytostatic activity of antimetabolites. We obtained evidence for augmentation of the cytocidal effect of Adriamycin (ADM) by DP, both in vitro and in vivo. Nontoxic levels of DP enhanced the cytotoxicity of ADM against HeLa cells, and the 50% effective concentration of ADM was decreased 2.4-fold by DP. DP also increased the activity of ADM in clonogenic assays. Intracellular levels of ADM in the case of concomitant exposure to ADM and DP were 1.5-fold higher than in the case of exposure to ADM alone, determined using high-performance liquid chromatography. Incorporation of ADM into the cells pretreated with DP was also increased (1.4-fold), while the efflux was little affected. The growth of Sarcoma 180 tumors was prominently suppressed by the combination of ADM and DP, compared to findings with ADM alone. DP also prolonged the survival of Sarcoma 180 tumor-bearing mice, when given in combination with ADM. While the enhancement of cytostatic activity of antimetabolites has been attributed to a decrease in utilization of the salvage pathway by DP, our data show that the synergic effects of DP with ADM were the result of increased intracellular levels of ADM.