Sensitivity to DNA cross-linking chemotherapeutic agents in mismatch repair-defective cells in vitro and in xenografts

Together with tolerance to killing induced by methylating agents, loss of m ismatch repair (MMR) has previously been found to be associated with hypers ensitivity to the DNA cross-linking agent 1-(2-chloroethyl)-3-cyclohexyl-ni trosourea (CCNU) in several human tumor cell lines (Aquilina et al., 1998). Here, we have investigated whether MMR might act as an efficient repair pa thway and provide protection against the clastogenicity induced by CCNU and whether the hypersensitivity of MMR-defective cells is extended to other c rosslinking agents. An increase in cell killing and in the frequency of mic ronuclei was observed after CCNU exposure in 2 hPMS2-defective clones (clon es 6 and 7) compared with the parental HeLa cells. introduction of a wild-t ype copy of chromosome 7 in clone 7 led to re-expression of the hPMS2 prote in and brought survival and chromosomal damage upon CCNU exposure to parent al levels. Our data indicate that MMR protects against the clastogenic dama ge induced by this drug, The hPMS2-defective HeLa cells were also hypersens itive to killing by mitomycin C, Mitomycin C sensitivity was confirmed in a n hMLH1-defective clone derived from Raji cells and in msh2-defective mouse embryo fibroblasts derived from knock-out mice. hPMS2-defective and parent al HeLa cells were transplanted into nude mice, and the animals were treate d with mitomycin C, While parental cell growth rate was unaffected, the gro wth of MMR-defective tumor was significantly reduced. Our results indicate that the in vitro hypersensitivity to mitomycin C conferred by loss of MMR is paralleled in vivo and may have implications for the chemotherapy of MMR -defective tumors. Int. J, Cancer 85:590-596, 2000, (C) 2000 Wiley-Liss, In c.