MECHANISM OF ACTION OF CRYTOPHYCINS

描述：此应用程序的总体目标是定义 一种新的抗微管剂念珠藻素， 细胞凋亡或程序性细胞死亡。 隐藻素是一个新的家族 微管蛋白结合剂显示出最终用于 治疗人类肿瘤疾病。 他们有独特的活动， 与长春花生物碱和紫杉醇不同， 在体外和体内模型中的肿瘤。 最近，对癌症的研究 化学治疗剂是革命性的发现， 不同的主要靶标和结合位点启动细胞凋亡。 这些研究 将研究药物作用的分子机制和信号 由念珠藻素引发的导致细胞凋亡的转导事件。 的 Cryptophycin过早激活细胞周期调节的假说 将测试导致细胞凋亡起始的蛋白质。 初步数据表明，Bcl-2的磷酸化可能是一个关键， 事件和研究者的建议，以测试的假设，Bcl-2 磷酸化和失活参与了念珠藻素诱导的 凋亡 癌症化疗药物启动 细胞凋亡可能是治疗反应的重要决定因素。 获得的关于这类新药物的作用机制的信息 将这些药物与其它微管活性药物的作用进行比较， 还可以深入了解它们的具体作用机制。 一 第二个目标是使用不同的念珠藻素类似物来确定 念珠藻素三个亚基的构效关系 分子对于特定的生物学效应。 的差异 同源物的生物反应将决定 生物学事件和启动细胞凋亡的最终能力之间的联系。

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.