Role of mismatch repair in the induction of chromosomal aberrations and sister chromatid exchanges in cells treated with different chemotherapeutic agents

Purpose: The mismatch repair (MMR) system plays a major role in mediating the cytotoxicity and clastogenicity of agents generating O-6-methylguanine in DNA. Loss of MMR has also been associated with tumor cell resistance to the cytotoxic effects of 6-thioguanine and cisplatin and with hypersensitivity to N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU). The aim of the present investigation was to elucidate the role played by the MMR system in the generation of chromosomal damage in cells exposed to 6-thioguanine, cisplatin or CCNU. Methods: The MMR-proficient cell lines TK6 and HCT116/3-6, and their MMR-deficient counterparts MT1 and HCT116, were treated with 6-thioguanine, cisplatin or CCNU, and analyzed for cell growth inhibition and chromosomal damage. As a control, similar experiments were performed with the methylating agent temozolomide. Results: Cytotoxicity, chromosomal aberrations and sister chromatid exchanges induced by 6-thioguanine and temozolomide were significantly reduced in the MMR-deficient cell lines with respect to their MMR-proficient counterparts. In contrast, although conferring some protection against cytotoxicity, the loss of MMR did not affect cytogenetic damage induced by cisplatin. CCNU produced comparable levels of cytotoxicity, chromosomal aberrations and sister chromatid exchanges in both MMR-proficient and MMR-deficient cell lines. Conclusions: The MMR system is involved in the generation of chromosomal damage in cells exposed to 6-thioguanine. The system does not play a relevant role in the generation of chromosomal damage in cells treated with CDDP and does not confer protection against the clastogenic effects of CCNU, at least in the cell lines investigated.