Cisplatin and carboplatin are highly active antitumor agents which are curative in combination against some tumors. Major problems with currently available platinum based chemotherapy are the development of clinical resistance and, frequently an unfavorable toxicity profile. We will select from a large number of novel platinum antitumor agents available from several collaborators, compounds to be tested clinically, which are 1) non-cross resistant with the currently available platinum complexes, cisplatin and carboplatin, 2) have a high therapeutic index in experimental systems, 3) have a broad spectrum of activity against experimental solid tumors, 4) have a favorable toxicity profile in large animal toxicology, 5) have a relatively facile synthetic route and 6) are easy to formulate. The best compounds will undergo phase I clinical testing, accompanied by pharmacokinetic studies in which total platinum, non-protein bound platinum and unchanged drug will be measured and correlated with toxicity and pharmacodynamic end points of total cellular platinum and DNA bound platinum in peripheral blood leukocytes and tumor tissue removed at biopsy by the development of pharmacokinetic/pharmacodynamic mathematical models. Cellular glutathione as a parameter of resistance to platinum complexes will also be measured in peripheral blood leukocytes and tumor biopsy. The data will be used to improve drug development and selection of new drugs and combinations for trial. Other approaches to improve platinum chemotherapy will be explored including drug combinations and modulation of toxicity and antitumor efficacy clinically.
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