DEVELOPMENTAL PHARMACOLOGY OF NEW ANTICANCER AGENTS

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This Program encompasses a wide variety of pharmacologic, cellular, biochemical and molecular procedures basic not only to an understanding of the mechanism of action of the new anticancer agents, but also to provide important input into the design of clinical protocols. Pharmacology studies will define pharmacokinetics in mice as well as serum binding characteristics, drug distribution and metabolism in normal and tumor tissues. We have a state-of-the art instrumentation laboratory available for metabolite identification. Cellular pharmacokinetics will define the uptake, efflux and intracellular distribution of agents under study. The cellular and biochemical studies are primarily directed at determining whether the compound acts by any of the 6 standard mechanisms: alkylation, DNA binding, topoisomerase inhibition, protein synthesis inhibition, antimetabolite action or antimitotic effect. Cellular studies will define dose-response relationships in vitro as well as age-response characteristics for both cytotoxicity and progression delay. We have a sophisticated flow cytometry Core within our Cancer Center fully capable of these and other studies including cyclin level determination and quantitation of expression of mitotic proteins. A series of biochemical assays will examine drug effects on macromolecular synthesis inhibition loci. Molecular studies are directed at DNA effects examining binding as well as damage and repair kinetics; the latter assessed by alkaline elution. In addition, direct effect on topoisomerase enzymes will be assessed. Both standard and newer pulse- field electrophoresis techniques provides us with the ability to assess drug cytotoxicity mediated through an apoptotic mechanism. Newer assays directed at drug effects on membrane structures will be assessed by a variety of fluorescent probes. Presently available resistant lines as well as specifically developed lines resistant to the new agent will be used to determine mechanism of drug action and patterns of cross resistance.