Antitumor Antimitotics That Reverse Tumor Resistance

描述（由申请人提供）：针对微管蛋白和有丝分裂的抗有丝分裂药物是临床上最成功的抗肿瘤药物之一。长春花生物碱长春新碱和长春花碱以及紫杉醇和紫杉烷是抗微管蛋白剂，用于治疗各种肿瘤，包括白血病、霍奇金氏病、淋巴瘤（长春花生物碱）和乳腺、卵巢和其他实体肿瘤（紫杉醇和紫杉烷）。最近的证据表明，一些抗微管蛋白药物的组合是协同的，目前正在进行这种组合的临床试验。然而，临床肿瘤耐药是治疗失败的主要原因，通常是p -糖蛋白将抗肿瘤药物泵出肿瘤细胞的结果。因此，新的抗有丝分裂药物对耐药肿瘤具有活性是非常令人垂涎的。我们最近发现了一系列新颖的类似物，它们对抗有丝分裂敏感和耐药的肿瘤细胞具有纳米摩尔范围的抗有丝分裂和抗肿瘤活性，它们与微管蛋白上不同于秋水仙碱、vinca生物碱和紫杉醇的位点结合，并且显著地逆转肿瘤对抗有丝分裂药物的抗性。本提案的具体目的是：1)合成先导化合物的类似物，提供结构-活性关系（SAR）研究，以优化抗肿瘤活性和逆转肿瘤对抗有丝分裂药物的抗性的能力；2)评价这些化合物的微管和细胞周期效应；3)评价单药和联合用药的细胞毒性，以及这些化合物的抗多药耐药活性；4)评价先导化合物和所选类似物对抗有丝分裂敏感和耐药肿瘤的体内抗肿瘤活性。这项研究将为未来类似物的设计提供一个全面的SAR，并提供在体外和体内对敏感和耐药肿瘤具有更高抗肿瘤活性的类似物，以及可能在单一药物中增强逆转肿瘤耐药的能力。这些药物可以单独使用或与其他抗有丝分裂或抗肿瘤药物联合使用，并对抗有丝分裂敏感和耐药的肿瘤提供更广泛的活性。该研究还将进一步明确新系列药物的作用机制，为临床提供药物。

DESCRIPTION (provided by applicant): 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 synergistic 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.