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Antitumor Antimitotics That Reverse Tumor Resistance

逆转肿瘤耐药性的抗肿瘤抗有丝分裂药

基本信息

批准号：
7746359
负责人：
ALEEM GANGJEE
金额：
$ 24.79万
依托单位：
DUQUESNE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-24 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7746359
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole ABCC1 gene Antimitotic Agents Binding Binding Sites Biological Breast Cell Cycle Chromosomes Clinical Clinical Trials Colchicine Digit structure Dose Evaluation Excision Future Goals Hodgkin Disease In Vitro Inhibitory Concentration 50 Knowledge Lead Lymphoma Malignant Neoplasms Malignant neoplasm of ovary Mediating Medicine Microtubules Mitosis Modeling Multi-Drug Resistance Ovarian P-Glycoprotein P-Glycoproteins Paclitaxel Parents Pennsylvania Pharmacology Play Process Property Proteins Pump Resistance Role Series Site Solid Neoplasm Structure-Activity Relationship Taxane Compound Toxic effect Treatment Failure Tubulin Tumor Cell Line Universities Vinblastine Vinca Alkaloids Vincristine Work analog antitumor agent base chemotherapeutic agent college cytotoxicity daughter cell design in vitro activity in vivo leukemia neoplastic cell novel overexpression polymerization taxane tumor

项目摘要

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.

靶向微管蛋白和有丝分裂的抗有丝分裂剂是一些临床上最成功的抗肿瘤剂。的长春花生物碱、长春新碱和长春碱以及紫杉醇和紫杉烷类都是抗微管蛋白剂，各种肿瘤包括白血病、霍奇金淋巴瘤、淋巴瘤（生物碱类）和乳腺、卵巢等实体瘤肿瘤（紫杉醇和紫杉烷）。最近的证据表明，某些抗微管蛋白药物的组合具有协同作用，并且目前正在对这种组合进行临床试验。然而，临床肿瘤耐药性是一个主要原因，这是治疗失败的最常见的结果，P-糖蛋白将抗肿瘤剂泵出肿瘤细胞因此，对耐药肿瘤有活性的新型抗有丝分裂剂是高度令人垂涎的。我们最近发现了一系列相当新颖的类似物，因为它们具有抗有丝分裂和抗肿瘤活性，当它们在纳摩尔范围内对抗有丝分裂敏感的以及耐药的肿瘤细胞时，它们结合到微管蛋白上的位点，与秋水仙碱、长春花生物碱和紫杉醇位点不同，还显著逆转了肿瘤对抗有丝分裂剂的耐药性。剂.该建议的具体目的是：1）合成先导化合物的类似物，以提供构效关系（SAR）研究，以优化抗肿瘤活性以及逆转肿瘤的能力对抗有丝分裂剂的抗性; 2）评价这些化合物对微管和细胞周期的影响; 3）评价作为单一药剂和组合的细胞毒性，以及这些化合物;和4）评价先导化合物和所选类似物的体内抗肿瘤活性，抗有丝分裂敏感性和抗性肿瘤。这项研究应提供一个全面的SAR的设计提供了在体外和体内对敏感和抗性肿瘤具有增加的抗肿瘤活性的类似物。以及可能在单一药剂中逆转肿瘤抗性的能力增加。这些药物可以用于单独或与其它抗有丝分裂剂或抗肿瘤剂组合，并提供更广谱的抗抗有丝分裂敏感性和抗性肿瘤。研究还将进一步明确小说的作用机制可为临床提供药物。