Nucleotide excision repair pathway review I: implications in ovarian cancer and platinum sensitivity

Platinum-based chemotherapy has been the mainstay of treatment for advanced gynecological cancers following cytoreductive surgery and in radiation sensitization of cervical cancer. Despite its initial high overall clinical response rate, a significant number of patients develop resistance to platinum combination therapies. The precise mechanism of platinum-resistance is multifactorial and accumulation of multiple genetic changes may lead to the drug-resistant phenotype. Platinum chemotherapy exerts its cytotoxic effect by forming DNA adducts and subsequently inhibiting DNA replication. It is now clear that the nucleotide excision repair (NER) pathway repairs platinum-DNA adducts in cellular DNA. Evaluation of genetic polymorphisms in cancer susceptibility as one etiology for platinum resistance may help us to understand the significance of these factors in the identification of individuals at higher risk of developing resistance to anti-cancer drug therapies. In this review, we summarized the relevant studies, both in vitro and in vivo, that pertain to NER in ovarian cancer and platinum resistance. It is evident also that there are a few limited studies in genetic polymorphisms of NER and ovarian cancer. These studies reviewed suggest that concurrent up-regulation of genes involved in NER may be important in clinical resistance to platinum-based chemotherapy in ovarian cancer. In the future, larger and well-designed population-based studies will be needed for a more complete understanding of relevant genetic factors that may result in improved strategies for determining both chemotherapy choice and efficacy in patients with advanced ovarian and cervical cancer. Review II will focus on the NER pathway in cervical cancer and platinum sensitivity.