The theme of this proposal is the clinical development of new therapeutic regimens for solid tumors based on modulation of enzymes involved in DNA damage and repair metabolism. Several inhibitors of enzymes involved in DNA damage and repair metabolism have recently entered clinical evaluation and are available for phase I development both as individual cytotoxic agents as well as modulators of established DNA damaging agents. This program brings together a strong interactive team of biochemists, clinical pharmacologists and clinicians to conduct pharmacokinetic and pharmacodynamic guided phase I trials to optimize the use of these new agents. Initial studies will focus on the clinical development of modulators of topoisomerase I and O6-alkylguanine alkyltransferase both as individual agents and in combination with established anticancer drugs whose cytotoxicity is mediated through effects on DNA metabolism. Pharmacokinetic guided phase I trials will be designed to optimize the administration of the topoisomerase I inhibitors 9-aminocamptothecin and topotecan. Novel therapeutic regimens based on combining cisplatinum with inhibitors of topoisomerase directed DNA repair will be developed. Novel strategies based on modulation of O6-alkylguanine alkyltransferase directed DNA repair will be developed to potentiate the cytotoxicity of chloroethylnitrosoureas such as BCNU. Agents which deplete O6-aklylguanine alkyltransferase either through initiation of methyladducts at the O6- position of guanine, for example temozolomide, or through direct inhibition of the enzyme, for example O6-benzylguanine, will be evaluated. Tissue biopsies will be obtained from patients entered on these trials to assess expression of biochemical targets in metastatic cancers and to monitor success of the desired modulation. The strategy developed for these pharmacokinetic and pharmacodynamic guided trials will be followed in the evaluation of new agents that become available for study during the course of this cooperative agreement. Agents which cause cytotoxicity by affecting DNA metabolism or that modulate an enzyme involved in response to DNA damage will be given priority. The identification, design and prioritization of phase I studies for new agents will be based on laboratory evaluation in preclinical models conducted at the CWRU/Ireland Cancer Center and developed in collaboration with staff of the Clinical Trials Evaluation and Development program of the National Cancer Institute.
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