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

Silvia Fiumicino, Simone Martinelli, Claudia Colussi, Gabriele Aquilina, Carlo Leonetti, Marco Crescenzi, Margherita Bignami

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Together with tolerance to killing induced by methylating agents, loss of mismatch repair (MMR) has previously been found to be associated with hypersensitivity to the DNA cross-linking agent I-(2-chloroethyl)-3- cyclohexyl-nitrosourea (CCNU) in several human tumor cell lines (Aquilina et al., 1998). Here, we have investigated whether MMR might act as an efficient repair pathway and provide protection against the clastogenicity induced by CCNU and whether the hypersensitivity of MMR-defective cells is extended to other cross-linking agents. An increase in cell killing and in the frequency of micronuclei was observed after CCNU exposure in 2 hPMS2-defective clones (clones 6 and 7) compared with the parental HeLa cells. Introduction of a wild-type copy of chromosome 7 in clone 7 led to re-expression of the hPMS2 protein and brought survival and chromosomal damage upon CCNU exposure to parental levels. Our data indicate that MMR protects against the clastogenic damage induced by this drug. The hPMS2-defective HeLa cells were also hypersensitive to killing by mitomycin C. Mitomycin C sensitivity was confirmed in an hMLH1-defective clone derived from Raji cells and in msh2- defective mouse embryo fibroblasts derived from knock-out mice. hPMS2- defective and parental HeLa cells were transplanted into nude mice, and the animals were treated with mitomycin C. While parental cell growth rate was unaffected, the growth 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.

Original languageEnglish
Pages (from-to)590-596
Number of pages7
JournalInternational Journal of Cancer
Issue number4
Publication statusPublished - 2000

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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