CIRCUMVENTION OF CISPLATIN RESISTANCE

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Although platinum-based antitumor agents (i.e., cisplatin and carboplatin) play critical roles in the treatment of several cancers, a major impediment 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. This limitation has resulted in a concerted chemical effort to identify platinum analogs that are effective against resistant tumors. Indeed several such analogs (e.g., oxaliplatin and JM216) have entered clinical trials. However, we have little or no knowledge of the effective mode of action of these analogs. Such information is vital for their success and their rational clinical application in the resistant disease setting. Although reduced drug accumulation, increased intracellular glutathione, and increased DNA adduct repair are usually identified as key mechanisms of resistance of cisplatin, they have not provided satisfactory explanations for reversal of resistance by the analogs. Recently we have demonstrated that a loss in p53 activation in response to DNA damage by cisplatin is a fundamental mechanism of resistance to this platinum complex. It is possible for p53 to be activated through an alternative pathway. Thus, the proposed specific aims are designed to investigate the potential of the analogs to induce latent p53. We will examine the consequence of p53 function on the biochemical pharmacology of analogs at the DNA level, investigate recognition of DNA damage by the structurally- diverse analogs, and delineate p53 regulation. To address the specific aims, we will use standard transfection approaches to modulate p53 induction and/or function, and utilize biochemical, pharmacologic, and other molecular techniques to investigate the effect of this modulation on reversal of resistance. The specific techniques will include adduct quantitation, DNA strand breaks, RNA/protein isolation, protein immunoprecipitation, gel electrophoresis, detection by monoclonal/polyclonal antibodies, and flow cytometry. It is likely that our investigations will establish how the analogs reverse cisplatin resistance, and this may provide a basis for designing clinical protocols to treat resistant clinical cancers on a more rational basis.