Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy

Abstract

Clinical studies performed by several groups suggest that platinum-DNA adduct--measured in malignant or non-malignant cells from cancer patients--may be an important marker for clinical biological effect of platinum-based chemotherapy. DNA repair is clearly an important effector of resistance to platinum-based DNA-damaging agents in tissue culture, although its role in effecting clinical resistance to these agents is not completely clear. In recent years, it has become apparent that DNA repair is an extremely complex process. Processes within DNA repair that may contribute to one or more drug resistance phenotypes include 0-6-alkytransferase activity, base excision repair, mismatch repair, nucleotide excision repair (NER), and gene specific repair. Clearly, several of these processes may concurrently show increased activity within any single cell, or tumor, at any one time. For platinum compounds, in vitro data clearly show that NER is the DNA repair pathway responsible for the repair of cisplatin-DNA damage. One critical gene within NER is ERCC1. Data exist in human ovarian cancer and in human gastric cancer that ERCC1 may be a useful marker for clinical drug resistance when platinum-based systemic chemotherapy is utilized. Although the data suggest that the relative ERCC1 mRNA level may be a good marker for NER activity in human ovarian cancer, it is unclear whether expression of this gene has any relationship to other pathways of DNA repair.