The Effect of DNA Repair Inhibitors on the Response of Tumors Treated with X-Ray and Alkylating Agents 1

Abstract

In recent years, numerous workers have demonstrated that both bacterial (1-4) and mammalian cells (5-7) have the ability to repair a variety of damaging events to their cellular DNA. The alkylating agents and X-rays used in the therapy of malignant diseases are thought to exert their cytotoxic effect in cells principally as a result of chemical alteration of DNA in the affected cells (8, 9), of precisely the kinds which can be repaired by the DNA repair mechanism (8-12). DNA repair, therefore, may play an important role in the resistance expressed by many tumors towards these agents. Inhibitors of this process greatly enhance the cytotoxic effect of alkylation and radiation damage in in vitro experiments (13-15). Because of this fact, it was of great interest to determine the effect of the repair inhibitors on the response of tumors in vivo to treatment with X-rays and alkylating agents. Earlier work performed in this laboratory has demonstrated that the repair inhibitors, caffeine and chloro-quine, when used in conjunction with Cytoxan or X-rays, were effective in stopping the growth of Cytoxan-resistant plasmacytomas under conditions where the alkylating agents or X-rays alone were ineffective (16).

Because chloroquine binds to melanin (17) and is therefore concentrated in pigmented cells, it was also of interest to determine the effect of this DNA repair inhibitor on the resistance to alkylating agents and X-rays shown by malignant melanomas implanted in golden Syrian hamsters. The experiments reported below demonstrate that the use of chloroquine, in combination with either phenylalanine mustard or X-rays, can stop the growth of malignant melanomas implanted in hamsters; whereas neither drug nor X-ray alone at the usual therapeutic doses, is able to stop such growth.