[DNA repair and drug resistance: enhancement of the effects of anticancer agents by DNA repair inhibitors].

Recently, it has been revealed that anticancer effects are increased by the inhibition of DNA repair of cancer cells. Methylxanthine is the drug which block DNA repair. In this study we discussed the combined effects of CDDP and caffeine or pentoxifylline using human osteosarcoma cells (OST strain). When 2 mM caffeine was added before 1 hr exposure of CDDP or caffeine and CDDP was added simultaneously for 1 hr, no synergistic effect was shown. On the other hand, marked synergistic growth inhibition was observed when caffeine or pentoxifylline was added continuously after 1 hr exposure of CDDP. The addition of caffeine from 24 hr to 48 hr after 1 hr exposure of CDDP also showed synergistic effects as the doubling time of OST cells was about 30 hrs. Further more we treated three patients with advanced osteosarcomas by the combination of CDDP, ADM, and caffeine (p.o.) or that of CDDP and caffeine. A nine-year-old boy with multicentric osteosarcoma treated by the combination of CDDP, ADM, and caffeine showed partial response, and caffeine did not increase the side effects of anticancer agents. Hence the study on overcoming drug resistance by the inhibition of DNA repair will be promising.