PREDICTORS OF VINCA ALKALOID PHARMACOKINETICS

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DESCRIPTION: (Applicant's Abstract) This proposed research will increase our understanding of the biochemical basis for the antitumor efficacy and the dose-limiting toxicities of vinca alkaloids. The ultimate goal is to provide a rationale for the design of chemotherapeutic agents that are both more effective and less toxic. Vinca alkaloids have become the mainstay of numerous chemotherapy protocols over the past thirty years; however, only four vinca alkaloids are currently available in the U.S. and Europe. The drug receptor is tubulin, the major component of microtubule spindle fibers essential in cell division. Vincas disrupt microtubule dynamics essential for mitosis and induce the formation of nonmicrotubule spiral polymers. Drugs with very similar chemical structures, such as vincristine and vinblastine, have very different toxicity profiles and unique, as well as overlapping antitumor efficacies. The reasons for these drug differences have eluded researchers and without this knowledge rational drug design has been hampered. An understanding of the energetics of drug-receptor interactions is essential for interpreting pharmacokinetic and pharmacodynamic data. Until now it has not been possible to obtain reliable estimates of vinca alkaloid binding affinities (drug-induced tubulin spiraling potential) for structure-function comparisons. Improved technology in recent years has made analytical ultracentrifugation a useful method for readily collecting the multiple data sets necessary for quantitative binding studies. The applicant has completed a thermodynamic analysis of eight vinca alkaloids using sedimentation velocity. It is her hypothesis that cellular drug uptake together with the magnitude of tubulin spiral formation correlate with drug retention by cells and cytotoxicity. The applicant proposes to identify how chemical modifications that enhance or inhibit spiral formation influence vinca alkaloid effects in vitro and in cells. The specific aims of this research are to systemically assay the effect of chemical modifications of eight vinca alkaloids on 1) cell proliferation, 2) drug uptake and retention by cells, 3) in vitro microtubule assembly and 4) individual microtubule dynamics. These data will be compared with the previously determined overall drug binding affinities (potential for inducing tubulin spirals). This work will derive in vitro criteria to predict drug pharmacokinetics and will contribute to understanding drug cytotoxic effects.