Mechanism of caffeine modulation of the antitumor activity of adriamycin.
We examined the effects of a combination of adriamycin (ADR) and caffeine on DNA and protein biosynthesis and on the activities of DNA polymerase alpha and beta in normal and tumor tissue. The decrease in DNA and protein biosynthesis in tumor produced by caffeine combined with ADR were 2.5 and 2.4 times greater, respectively, compared with ADR alone. The combination of caffeine and ADR enhanced the decrease in DNA polymerases activities in the tumor which was induced by ADR, the decreases being 1.8 and 1.6 times greater, respectively, than that of ADR alone. In contrast, these ADR-induced changes in normal tissues were not enhanced by the combination with caffeine. The combination with caffeine had no effect on ADR concentration in normal tissues, but in the tumor, it increased the ADR concentration to 2.1 times that of ADR alone. In vitro, ADR efflux from Ehrlich ascites carcinoma cells was significantly inhibited by exposure to caffeine. These findings indicate that the effect of caffeine on ADR concentration in the cell plays an important role in the mechanism by which caffeine enhances ADR antitumor activity.
Sadzuka
Y
Y
School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Mochizuki
E
E
Takino
Y
Y
D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy*; D004256:DNA Polymerase I / Q000187:drug effects / Q000378:metabolism; D004257:DNA Polymerase II / Q000187:drug effects / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects*; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D002110:Caffeine; D004317:Doxorubicin; D004256:DNA Polymerase I; D004257:DNA Polymerase II