MECHANISM OF ACTION OF CRYTOPHYCINS

描述：此应用程序的总体目标是定义 一种新的抗微管剂--隐霉素的启动机制 细胞凋亡或程序性细胞死亡。隐膜蛋白是一个新的家族 微管蛋白结合剂有望最终用于 人类肿瘤疾病的治疗。他们有独特的活动， 与长春花碱和紫杉醇不同，长春花碱和紫杉醇具有抗耐药性的活性 在体外和体内模型中的肿瘤。最近，对癌症的研究 化疗药物的发现使化疗药物发生了革命性的变化 不同的主要靶点和结合部位启动细胞凋亡。这些研究 将研究药物作用的分子机制和信号 隐孢子菌素引发的导致细胞凋亡的信号转导事件。这个 隐孢子菌素过早激活细胞周期调控假说 将对导致细胞凋亡的蛋白质进行测试。 初步数据表明，Bcl-2的磷酸化可能是一个关键 事件和研究人员提出的检验假设的建议 隐孢霉素诱导的磷酸化和失活 细胞凋亡。癌症化疗药物的启动能力 细胞凋亡可能是治疗反应的重要决定因素。 关于这一新类别的行动机制的信息 这些药物将与其他微管活性药物和 还可以深入了解它们的具体行动机制。一个 第二个目标是使用不同的隐孢子素类似物来确定 隐孢子素三个亚基的构效关系 分子与特定的生物效应有关。中美之间的差异 同系物的生物反应将决定它们之间的关系 在生物事件和启动细胞凋亡的终极能力之间。

DESCRIPTION: The overall goal of this application is to define the mechanisms by which cryptophycin, a new antimicrotubule agent, initiates apoptosis or programmed cell death. The cryptophycins are a new family of tubulin-binding agents that show promise for the eventual use in the treatment of human neoplastic diseases. They have unique activities and, unlike the vinca alkaloids and taxol, are active against drug-resistant tumors in both in vitro and in vivo models. Recently, the study of cancer chemotherapeutic agents was revolutionized by discoveries that agents with diverse primary targets and binding sites initiate apoptosis. These studies will investigate the molecular mechanism of drug action and the signal transduction events initiated by cryptophycin that lead to apoptosis. The hypothesis that cryptophycin prematurely activates cell cycle regulatory proteins that lead to the initiation of apoptosis will be tested. Preliminary data suggest that the phosphorylation of Bcl-2 could be a key event and the investigator's propose to test the hypothesis that Bcl-2 phosphorylation and inactivation are involved in cryptophycin-induced apoptosis. The ability of cancer chemotherapeutic agents to initiate apoptosis may be an important determinant of therapeutic response. Information gained about the mechanisms of action of this new class of agents will be compared to the effects of other microtubule active drugs and insights into their specific mechanisms of action may also be gained. A second goal is to use the different cryptophycin analogs to determine structure-activity relationships of three subunits of the cryptophycin molecule with respect to specific biological effects. The differences in the biological responses of the congeners will determine the relationships between biological events and the ultimate ability to initiate apoptosis.