MECHANISTIC DEVELOPMENT OF PLATINUM BASED DRUGS

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DESCRIPTION: (Applicant's Abstract) Ovarian cancer, which results in higher mortality than any other gynecologic malignancy, is the fourth leading cause of cancer deaths in women in the United States. According to the American Cancer Society, ovarian cancer was responsible for 15,000 deaths and was diagnosed in 27,000 women in 1997. Although, platinum-based antitumor agents (i.e. cisplatin and carboplatin) play critical roles in the treatment of this disease, a major impediment concerns relapse in a majority of patients, who fail subsequent challenge with the platinum agent due to the onset of drug resistance in their tumor cells. Reduced drug accumulation, increased intracellular glutathione, increased adduct tolerance and increased DNA adduct repair are usually identified as key mechanisms of resistance to cisplatin in ovarian and other cancers. An A2780-derived cisplatin-resistant ovarian tumor model in the applicant's laboratory typifies these mechanisms. However, he has found that the resistant model, in contrast to the sensitive line, lacks expression of p53 tumor suppressor gene when challenged with cisplatin. A platinum analog, however, can induce p53 in both lines. The applicant believes that the cell's inability to increase p53 protein in response to DNA damage by cisplatin is a fundamental mechanism of its resistance to this platinum complex. The proposed specific aims are designed to characterize the ability of the analog to induce p53 and reduce the threshold of DNA adduct tolerance. He will also establish the importance of p53 induction for cell death, and explore whether p53 is induced by up-regulation at the transcriptional or post-translational level. He will utilize transfection approaches to modulate p53 induction and/or function to test his hypothesis. Other specific aims will be accomplished through biochemical, pharmacologic, and molecular techniques involving RNA/protein isolation, protein immunoprecipitation, gel electrophoresis, detection by monoclonal/polyclonal antibodies, flow cytometry, DNA strand breaks, etc. It is likely that his investigations will establish how the analog restores inducibility of p53 and circumvents cisplatin resistance, and may provide an opportunity to treat refractory ovarian cancers on a more rational basis.