DESCRIPTION: Cytovia has discovered a new class of antimitotic agents which are potent inducers of apoptosis and strong inhibitors of tumor cell growth. Preliminary experiments indicate that these compounds block mitosis by inhibiting the polymerization of tubulin, disrupting microtubule function, and triggering G2/M arrest. They can also inhibit the in vitro growth of multidrug resistant cell lines, which suggests that they may prove useful in the treatment of drug-resistant cancers. Because these compounds are small synthetic organic molecules, rather than natural products like the conventional antimitotic agents, they can be synthesized and modified readily to produce a wide variety of analogs. The current grant application proposes to characterize the in vivo properties of these novel agents using the athymic nude mouse cancer model. The application also proposes to design and synthesize analogs of these compounds, in a search for next-generation antimitotic agents with optimized chemical and biological properties. The results of the proposed experiments will provide critical information about the chemistry and pharmacology of these antimitotic agents and will help identify candidates for detailed pre-clinical testing and clinical trials. PROPOSED COMMERCIAL APPLICATION: The antimitotic agents that we propose to study in this application appear to have properties that are superior to other anticancer drugs, including other antimitotic agents. If successfully developed, these novel agents may capture a substantial portion of the market for antimitotics cancer drugs, which for the taxanes alone may exceed $2 billion in the year 2000.