Effects of Methylxanthine Derivatives on Adriamycin Concentration and Antitumor Activity

We studied the mechanism whereby caffeine acts as a biochemical modulator of adriamycin, and examined various methylxanthine derivatives to determine whether they would be of value as biochemical modulators. In an in vitro study of adriamycin efflux in Ehrlich ascites carcinoma cells, theophylline, pentoxifylline, and theobromine inhibited this efflux, while caffeine metabolites did not. The effects of several methylxanthine derivatives on the antitumor activity of adriamycin and on adriamycin concentration in tissue were also examined in CDF(1) tumor‐bearing mice. Theobromine, which inhibited adriamycin efflux in vitro, increased the antitumor activity of adriamycin and the concentration of adriamycin in tumors. The caffeine metabolites, which had no effect on the adriamycin efflux, did not increase antitumor activity. These results suggest that the metabolism of caffeine may weaken its effect as a biochemical modulator, and that pentoxifylline and theobromine would be of value as biochemical modulators of adriamycin.