CELLULAR-RESISTANCE AND HYPERMUTABILITY IN MISMATCH REPAIR-DEFICIENT HUMAN CANCER CELL-LINES FOLLOWING TREATMENT WITH METHYL METHANESULFONATE

Resistance to the cytotoxic effects of S(N)1 alkylating agents such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosoure a (MNU) is well established in mismatch repair-defective cells, howeve r, little is known about the cellular response to S(N)2 alkylating age nts in these cells. Here we describe the cytotoxic response and the mu tagenic response at the hypoxanthine-guanine phosphoribosyl transferas e (HPRT) locus to the S(N)2 alkylating agent methyl methanesulfonate ( MMS) in human cancer cell lines defective in mismatch repair (MMR), Ou r findings suggest that cytotoxicity to MMS is mediated through MMR, a s indicated by an increased resistance to MMS in MMR-deficient cells. Cells in which specific MMR-gene defects were complemented by chromoso me transfer were generally more sensitive to the cytotoxic effects of MMS, Additionally, the induced mutant frequency at HPRT following expo sure to MMS is significantly increased in MMR-deficient lines. These f indings suggest that resistance to S(N)2 alkylation damage is mediated by MMR genes, and that resistance to such damage in MMR-defective cel ls correlates with an increase in genomic mutations. The results are c onsistent with the hypothesis that abasic sites may be substrates for repair involving MMR-gene products inhuman cells. (C) 1998 Elsevier Sc ience B.V.