Anthracyclines are among the most widely used antitumor drugs and one of the major limitations to their continued use in cancer chemotherapy could be the emergence of drug resistant tumor cells. Mechanisms of anthracycline resistance has been studied in several in vitro tumor models and the data suggests that energy- dependent drug efflux, which will result in lower retention of drug, is a major factor in cellular resistance; this process can, however, be reversed in resistant cells by co-treatment with either trifluoperazine or verapamil. But, in recent studies, we and others have observed that although the resistant cells are able to retain drug equivalent to (AD 32) or more (daunorubicin) than the level retained in sensitive cells, the cells are yet resistant to drugs which at these concentrations would have been highly toxic to sensitive cells. This suggests that other factors than transport, may contribute to tumor cell anthracycline resistance. Although anthracyclines have been shown to have several mechanisms for induction of cellular toxicity, their interaction with DNA is of utmost importance. Therefore, we have studied the effects of cellular DNA damage and repair in drug exposed adriamycin sensitive and resistant murine leukemic P388 cells and the preliminary data show that (a) there is reduced DNA damage and increased DNA repair in resistant cells, (b) different anthracyclines induced differential DNA damage in resistant cells and (c) that DNA damage in resistant cells cannot be increased to the level seen in sensitive cells by combined exposure to drug transport modulators, although the cellular retention of drug is increased in resistant cells. The primary aim of the proposed studies is to delineate the mechanism(s) of DNA damage and repair in P388 murine leukemic cells and cells derived from human solid tumor xenografts, resistant (melanotic melanoma) and sensitive (squamous cell carcinoma of cervix) to adriamycin, and correlate these effects to drug transport and cytotoxicity. The data obtained from these studies will result in understanding the mechanism of differential toxicity of anthracyclines in tumor cells.
