The approval of Taxol by the FDA for ovarian, breast and lung carcinomas has an important advance in the treatment of human malignancies. However, there are serious problems with Taxol; its lack of therapeutic activity in many tumors, its aqueous insolubility, its toxicities such as peripheral neuropathies and neutropenia and its propensity to induce drug resistance. The advent of four new natural products whose chemical structures are highly diverse but whose mechanism of action is similar to that of Taxol, is an exciting and challenging prospect. The three specific objectives of this grant will provide information for the selection of drugs for clinical trials. 1) Determine the effects of Taxol and other compounds that stabilize microtubules, on signaling pathways and cell cycle progression. Investigate the relationship between the effects of Taxol on the microtubule cytoskeleton and on signaling pathways that lead to cell death. Identify among the epothilones, discodermolide and eleutherobin compounds that block or stimulate signaling pathways. 2) Examine the sensitivity of epothilone, discodermolide and eleutherobin in a series of Taxol-resistant cell lines whose mechanisms of resistance vary. Develop cell lines that are resistant to these drugs and incorporate the use of quantitative expression analysis that will allow scoring expression levels of several thousand genes simultaneously in the analysis of their drug resistant phenotypes. Study the relationship of caveolin-1, that we have shown to be upregulated in some drug-resistant cells, to the development of drug resistance. 3) Define the structure activity relationships (SAR) for the epothilones, discodermolide and eleutherobin using analogs to determine the structural requirements for biological activity. Use this information for defining a pharmacophore, that is common to these drugs and Taxol, that will help in the design of new drugs which will be structurally simpler than Taxol.
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