Mismatch repair and response to DNA-damaging antitumour therapies

Abstract

Most antitumour therapies damage tumour cell DNA either directly or indirectly. DNA damage responses, and particularly DNA repair, influence the outcome of therapy. Because DNA repair normally excises lethal DNA lesions, it is intuitive that efficient repair will contribute to intrinsic drug resistance. Indeed, in certain circumstances reduced levels of DNA nucleotide excision repair are associated with a good therapeutic outlook (Curr Biol 9 (1999) 273). A paradoxical relationship between DNA mismatch repair (MMR) and drug sensitivity has been revealed by model studies in cell lines. This suggests that connections between MMR and tumour therapy might be more complex. Here, we briefly review how MMR deficiency can affect drug resistance and the extent to which loss of MMR is a prognostic factor in certain cancer therapies. We also consider how the inverse relationship between MMR activity and drug resistance might influence the development of treatment-related malignancies which are increasingly linked to MMR defects.