NEW ANTIMICROTUBULE AGENTS FROM MARINE ORGANISMS

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Although agents for the effective treatment of leukemias and lymphomas are available, little progress has been made toward the development of new drugs useful for the treatment of clinically important solid tumors. Currently, a major target for cancer chemotherapy is inhibition of mitotic spingle formation by disruption of their mechanism of action. The vinca alkaloids cause microtubule depolymerization, while the diterpene paclitaxel and its derivative taxotere stabilize microtubule. The recent discoveries that been met with enormous enthusiasm from organic chemists as well as cancer researchers. Thorough a collaborative program between Utah State University and the Cancer Research Center of Hawaii, we have discovered that the sponge- derived macrolides laulimalide and isolaulimalide are potent cytotoxins with paclitaxel-like anti-microtubule-stabilizing activity. Laulimalide induces the dose-dependent reorganization or cellular microtubule, the formation of abnormal mitotic spindles, and microtubule. Laulimalide is a potent inhibitor of cellular proliferation with an IC/50 in the low nanomolar range. Significantly, in contrast to paclitaxel, both laulimalide inhibited the proliferation of SKVLB-1 cells, a P- glycoprotein over-expressing multi-drug resistant cell line, suggesting that is poor substrate for transport by P-glycoprotein. Incubation of MDA-MD-435 cells with laulimalide resulted in mitotic arrest and activation of the caspase cascade of proteolytic enzymes that accompany apoptotic cell death. Furthermore, in NCI's 60 cell line assay, laulimalide demonstrated interesting profiles of activity toward breast and prostate cell lines, resulting in a request from the NCI for additional laulimalide with which to begin in vivo evaluation. These compounds represent a new class of microtubule-stabilizing agents with activities that may prove therapeutically useful. The long-term goal of this project is to advance laulimalide or a laulimalide analog as a potential anti-cancer chemotherapeutic agent. To achieve this goal we propose to do the following: 1) supply the NCI with sufficient laulimalide for in vivo evaluation using a two-pronged approach involving both recollection/reisolation and chemical synthesis, 2) investigate structure-activity-relationships for laulimalide by preparing analogs, 3) screen laulimalide analogs for microtubule- stabilizing activity and for cytotoxicity toward drug-resistant cell lines, 4) submit active analogs to the NCI for screening in the 60-cell line assay and for in vitro evaluation, when warranted, and 5) obtain patent coverage for promising laulimalide analogs.