RESISTANCE TO 6-THIOGUANINE IN MISMATCH REPAIR-DEFICIENT HUMAN CANCERCELL-LINES CORRELATES WITH AN INCREASE IN INDUCED MUTATIONS AT THE HPRT LOCUS

Although the resistance to the cytotoxic response of certain DNA damag ing agents has been well characterized in cells deficient in mismatch repair, little is known about how such resistance affects mutagenesis. Using human cancer cell lines defective in mismatch repair (MMR) and complementary cell lines in which the MMR defects were corrected by ch romosome transfer, we present the cytotoxic effect and the mutagenic r esponse at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus following exposure to the chemotherapeutic agent, 6-thioguanine (6-TG). Upon exposure to 6-TG, there was a differential cytotoxic resp onse. The MMR-deficient cells were resistant to 6-TG exposure up to 5 mu M, whereas the MMR-proficient cell lines were significantly more se nsitive at the same levels of exposure. Furthermore, the mutagenic res ponse at HPRT induced by 6-TG was substantially increased in the MMR-d eficient lines relative to the MMR-proficient cell lines. These findin gs support the notion that cytotoxicity to 6-TG is mediated through fu nctional MMR and that resistance to the cytotoxic effects of 6-TG is d irectly associated with an increase in induced mutations in MMR-defect ive cells. These data suggest that the use of 6-TG as a chemotherapeut ic agent may result in the selection of MMR-defective cells, thereby p redisposing the patient to an increased risk for developing secondary tumors.