Resistance to chemotherapy is a major reason for treatment failure and death from ovarian cancer (this disease causes 12,000-15,000 deaths/year in the USA). The most active drug for ovarian cancer treatment is cisplatin and preliminary evidence in vitro models of resistance indicates that increased DNA repair may be an important mechanism of platinum resistance. The overall goal of this project is to determine if increased DNA repair is a significant reason for treatment failure in ovarian cancer. The determination that DNA repair is an important mechanism of clinical drug resistance would allow treatment approaches to be developed which might limit the onset of this resistance mechanism or reverse resistance if it occurs.
The specific aims of the project are: 1.Develop an assay for total platinum-DNA adducts based on the ability of the UvrABC DNA repair enzyme complex to recognize these lesions. 2.Develop an assay for measurement of repair of platinum damage to genes undergoing transcription (active genes) based on UvrABC recognition of platinum damage. 3.Apply these methods to analyze the role of DNA repair In resistance to cisplatin and platinum analogs in human ovarian cancer cell line models, and to examine the effect of DNA repair inhibitors on platinum cytotoxicity and on DNA repair in these cell lines. Preliminary results indicate the capability of UvrABC to recognize platinum DNA lesions and the ability to measure total platinum bound to DNA. The optimization of these methods will ultimately lead to the capacity to measure platinum damage and repair in clinical material.
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