EFFECTS OF METHYLXANTHINE DERIVATIVES ON ADRIAMYCIN CONCENTRATION ANDANTITUMOR-ACTIVITY

We studied the mechanism whereby caffeine acts as a biochemical modula tor 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 c ells, theophylline, pentoxifylline, and theobromine inhibited this eff lux, while caffeine metabolites did not. The effects of several methyl xanthine derivatives on the antitumor activity of adriamycin and on ad riamycin concentration in tissue were also examined in CDF1 tumor-bear ing mice. Theobromine, which inhibited adriamycin efflux in vitro, inc reased the antitumor activity of adriamycin and the concentration of a driamycin in tumors. The caffeine metabolites, which had no effect on the adriamycin efflux, did not increase antitumor activity. These resu lts 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.