Cisplatin and carboplatin are currently being used in the applicant's institution for the treatment of a variety of solid tumors. The goal of this application is to initiate laboratory research which will complement the ongoing funded clinical trials with these agents. The laboratory research will be to: a) investigate the role of DNA repair in the resistance of human tumors to platinum containing regimens; b) determine if the level of DNA repair and/or intratumor platinum DNA adduct levels correlate both with each other and with disease response and c) improve our understanding of how the resistance of human tumor to platinum containing regimens can be overcome. One important outcome relates to the development of preclinical assays which can predict a patients response prior to chemotherapy. At this time assays which measure platinum adducts require treatment before a correlation between response and adduct formation can be determined. The applicants wish to determine if the tumor capacity for DNA repair, which ultimately determines the final platinum adduct level in any tissue type, can also be correlated with tumor response. This approach if successful, would allow clinicians to optimize chemotherapy on an individual basis. The applicant states that another important outcome of this research may be the identification of mechanisms by which the resistance to either cisplatin or carboplatin can be overcome. They state that this is particularly important for patients who are either inherently resistant to the proposed therapy or who have developed resistance to platinum as a result of previous treatment.
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