Development of drug resistance is major drawback in the clinical use of cisplation. To achieve further antitumor response, a high dose level with its inherent severe toxicity becomes a necessary compromise. The goal of this grant proposal is to study the ability of selected mixed amine ligands coordinated to platinum (II) nd platinum (IV) complexes to increase the therapeutic index, specifically by circumventing cisplatin-induced resistance and reducing host toxicity. Such an undertaking will involve broad aspects of cytotoxic, biochemical, pharmacological, and toxicological evaluations, which we believe to be essential in assessing the clinical potential of these compounds. Platinum complexes bearing the mixed amine ligands will be synthesized, and their cytotoxicity and antitumor efficacy evaluated against rodent and human cell lines resistant to cisplatin. Antitumor activity will also be assessed against diaminocyclohexane (DACH)-sulfatoplatinum (II)- or DACH-carboxypthalatoplatinum (II) resistant cells which lack cross-resistance to cisplatin. Platinum induced DNA interstrand and intrastrand cross-links will be determined to ascertain the potential of mixed amine ligands to modulate the kinetics of these critical lesions. Equally important will be an evaluation of the target organ toxicity of these agents: In particular, in vivo renal handling of platinum complexes will be ssessed and correlated with their potential to induce renal damage. In vitro (i.e., cellular) pharmacokinetics of these compounds will be similarly correlated to cytotoxic and biochemical observations. These studies will ascertain the ability of mixed amine groups to modulate the spectrum of antitumor activity, toxicity and biochemical pharmacology of platinum complexes. The data will also be vital in selecting an analog for possible clinical development.
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