REDUCTION OF PIRARUBICIN-INDUCED CELL-KILLING BY CAFFEINE IN MOUSE P388 LEUKEMIA-CELLS

The influence of caffeine was studied on 4'-O-tetrahydropyranyldoxorub icn (pirarubicn)-induced cytotoxicity in exponentially growing mouse P 388 leukemia cells, and the results were compared to those observed af ter treatment with caffeine and doxorubicin. In combination with anthr acyclines in cell culture, caffeine exerts a dramatic reduction in pir arubicin and doxorubicin cytotoxicity in a concentration-dependent way . The reduction was observed significantly at caffeine concentrations in the range of 0.5-20 mM. The reduction of pirarubicin-induced cytoto xicity by caffeine in vitro reflected a decrease in intracellular pira rubicin accumulation. Caffeine reduced the inhibitory effect of piraru bicin on the incorporation of thymidine into DNA and uridine into RNA in cells. However, the antitumor activity of pirarubicn in mice bearin g P388 leukemia was not affected by the administration of caffeine. On the other hand, caffeine reduced the antitumor activity of doxorubici n in mice bearing P388 leukemia by a mechanism that may depend on alte ration of cellular drug levels in vivo. A possible mechanism for this effect may be the reduced ability of cells to accumulate drug in the p resence of caffeine.