Antitumor Antimitotics That Reverse Tumor Resistance

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Antimitotic agents that target tubulin and mitosis are some of the most clinically successful antitumor agents. The Vinca alkaloids vincristine and vinblastine as well as Taxol and the taxanes are antitubulin agents used against a wide variety of tumors including leukemias, Hodgkin's, lymphomas (Vinca alkaloids) and breast, ovarian and other solid tumors (Taxol and taxanes). Recent evidence suggests that combinations of some antitubulin agents are synergestic and clinical trials are currently underway with such combinations. Clinical tumor resistance however is a major cause of treatment failure and is most often the result of P-glycoprotein which pumps the antitumor agent out of the tumor cells. Thus novel antimitotic agents that are active against resistant tumors are highly coveted. We have recently discovered a series of analogs that are quite novel in that they possess antimitotic and antitumor activities in the nanomolar range against antimitotic sensitive as well as resistant tumor cells, they bind to a site on tubulin that is different from the colchicine, vinca alkaloid and Taxol sites, and remarkably also reverse tumor resistance to antimitotic agents. The Specific Aims of this proposal are: 1) the synthesis of analogs of the lead compounds to provide a structure-activity relationship (SAR) study to optimize both the antitumor activity as well as the ability to reverse tumor resistance to antimitotic agents; 2) evaluation of the microtubule and cell cycle effects of these compounds; 3) evaluation of the cytotoxicity both as single agents and in combination, and the anti-multidrug resistance activities of these compounds; and 4) evaluation of the in vivo antitumor activity of the lead compounds and selected analogs against both antimitotic sensitive and resistant tumors. This study should provide a comprehensive SAR for the design of future analogs and afford analogs with increased antitumor activity against sensitive and resistant tumors in vitro and in vivo as well as an increased ability to reverse tumor resistance perhaps in single agents. Such agents could be used alone or in combination with other antimitotic or antitumor agents and provide a broader spectrum of activity against both antimitotic sensitive and resistant tumors. The study will also further define the mechanism of action of the novel series and could afford agents for clinical use.