PREDICTORS OF VINCA ALKALOID PHARMACOKINETICS

描述：（申请人摘要）这项拟议的研究将增加 我们对抗肿瘤疗效的生物化学基础的理解， 长春花生物碱的剂量限制毒性。 最终目标是 提供了一个基本原理的化疗药物的设计， 更有效，毒性更低。 石蒜生物碱已经成为 在过去的三十年里，许多化疗方案;然而，只有 目前在美国和欧洲可获得四种长春花生物碱。 的 药物受体是微管蛋白，微管纺锤体纤维的主要成分 在细胞分裂中必不可少。 微管破坏微管动力学至关重要 并诱导非微管螺旋聚合物的形成。 化学结构非常相似的药物，如长春新碱和 长春碱，具有非常不同的毒性特征和独特性，以及 重叠的抗肿瘤功效。 这些药物差异的原因 没有这些知识，合理的药物设计 受到阻碍。 对药物-受体能量学的认识 相互作用对于解释药代动力学和 药效学数据。 到目前为止，还无法获得可靠的 长春花生物碱结合亲和力的估计（药物诱导的微管蛋白 螺旋电位）进行结构-功能比较。 改进 近年来的新技术使分析超浓缩成为一种有用的方法， 用于容易地收集多个数据集的方法， 定量结合研究。 申请人已完成热力学 八种长春花生物碱的沉降速率分析 这是她 假设细胞药物摄取与微管蛋白的量一起 螺旋形成与细胞药物滞留和细胞毒性相关。 申请人建议确定如何增强的化学修饰 或抑制螺旋形成影响长春花生物碱在体外和体内的作用 细胞 本研究的具体目的是系统地分析 八种长春花生物碱化学修饰对1）细胞的影响 增殖，2）细胞的药物摄取和保留，3）体外 微管组装和4）个体微管动力学。 这些数据 将与先前确定的总体药物结合进行比较 亲和力（诱导微管蛋白螺旋的潜力）。 这项工作将衍生 预测药物药代动力学的体外标准， 了解药物的细胞毒性作用。

DESCRIPTION: (Applicant's Abstract) This proposed research will increase our understanding of the biochemical basis for the antitumor efficacy and the dose-limiting toxicities of vinca alkaloids. The ultimate goal is to provide a rationale for the design of chemotherapeutic agents that are both more effective and less toxic. Vinca alkaloids have become the mainstay of numerous chemotherapy protocols over the past thirty years; however, only four vinca alkaloids are currently available in the U.S. and Europe. The drug receptor is tubulin, the major component of microtubule spindle fibers essential in cell division. Vincas disrupt microtubule dynamics essential for mitosis and induce the formation of nonmicrotubule spiral polymers. Drugs with very similar chemical structures, such as vincristine and vinblastine, have very different toxicity profiles and unique, as well as overlapping antitumor efficacies. The reasons for these drug differences have eluded researchers and without this knowledge rational drug design has been hampered. An understanding of the energetics of drug-receptor interactions is essential for interpreting pharmacokinetic and pharmacodynamic data. Until now it has not been possible to obtain reliable estimates of vinca alkaloid binding affinities (drug-induced tubulin spiraling potential) for structure-function comparisons. Improved technology in recent years has made analytical ultracentrifugation a useful method for readily collecting the multiple data sets necessary for quantitative binding studies. The applicant has completed a thermodynamic analysis of eight vinca alkaloids using sedimentation velocity. It is her hypothesis that cellular drug uptake together with the magnitude of tubulin spiral formation correlate with drug retention by cells and cytotoxicity. The applicant proposes to identify how chemical modifications that enhance or inhibit spiral formation influence vinca alkaloid effects in vitro and in cells. The specific aims of this research are to systemically assay the effect of chemical modifications of eight vinca alkaloids on 1) cell proliferation, 2) drug uptake and retention by cells, 3) in vitro microtubule assembly and 4) individual microtubule dynamics. These data will be compared with the previously determined overall drug binding affinities (potential for inducing tubulin spirals). This work will derive in vitro criteria to predict drug pharmacokinetics and will contribute to understanding drug cytotoxic effects.