Studies in this area have focused on the characterization of mRNA and protein expression of genes involved in the rate-limiting step of nucleotide excision repair (NER) in human ovarian cancer. These studies have been supplemented by studies of NER modulation in vitro. NER can be effectively following in intact cells, by assessing the repair of cisplatin-DNA damage. In intact cells, several transcription factors appear to be important for regulating the level of activity of NER. One such transcription factor is AP1, which has binding sites in the promoter region(s) of each of the major NER genes involved in DNA damage recognition and excision. Dominant negative constructs to AP1 have been developed by Charles Vinson of DBS. These agents are being extensively explored on the preclinical level to determine; which type of construct is most effective in inhibiting AP1 and in shutting down DNA repair, how these constructs can be best interfaced with cisplatin, and what other chemotherapeutic agents may be affected in a positive manner by use of these constructs. Concurrently, we seek to understand the regulation of the NER process in intact cells, and we are seeking to understand the transcription factor profile of these cells under specific conditions relative to cisplatin drug exposures. We are also examining the role(s) of proteasome inhibition as a possible factor that can modulate the platinum sensitivity/resistance phenotype. Early studies show inverse relationships between the level of such inhibition, cisplatin resistance, and cisplatin-DNA adduct repair. As has been reported by our group previously, we have supporting data that ERCC1 can be used as a marker for this very complex, multi-gene process.
