In late 1997 - early 1998 a novel trinuclear platinum compound, BBR3464, will enter Phase 1 clinical trials, the first genuinely new platinum agent not based on the classical cisplatin structure to do so. The profile of preclinical activity mirrors its unique structure and is characterized by activity in human tumor (e.g. ovarian) xenografts resistant to cisplatin and alkylating agents; a high activity in a broad spectrum of human tumors commonly insensitive to chemotherapeutic intervention (e.g. non-small-cell lung, gastric) and characterized as p53-mutant. The p53 protein is recognized as playing a critical role in cellular response to drug-induced DNA damage. Loss of normal p53 function can lead to intrinsic drug resistance as a result of reduced cell ability to engage an apoptotic response. Thus, a clinical drug acting independently of the p53 pathway can offer outstanding clinical promise for chemotherapy in over 50 percent of solid human tumors with defective p53. This proposal will explore the hypothesis that these new agents, in comparison to other clinical agents, exert their cytotoxicity and antitumor activity in a p53-independent manner through differential repair traceable to a unique array of DNA adducts, different in scope and effect to any of the DNA-damaging currently agents used in the clinic. This proposal will therefore delineate the types of adducts formed and begin to examine the structural consequences thereof with respect to protein recognition and DNA repair.
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