NEW ANTIMICROTUBULE AGENTS FROM MARINE ORGANISMS

来自海洋生物的新型抗微管剂

基本信息

批准号：
6173871
负责人：
BRADLEY S DAVIDSON
金额：
$ 15.53万
依托单位：
UTAH STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2002-03-31
项目状态：
已结题

项目摘要

Although agents for the effective treatment of leukemias and lymphomas are available, little progress has been made toward the development of new drugs useful for the treatment of clinically important solid tumors. Currently, a major target for cancer chemotherapy is inhibition of mitotic spingle formation by disruption of their mechanism of action. The vinca alkaloids cause microtubule depolymerization, while the diterpene paclitaxel and its derivative taxotere stabilize microtubule. The recent discoveries that been met with enormous enthusiasm from organic chemists as well as cancer researchers. Thorough a collaborative program between Utah State University and the Cancer Research Center of Hawaii, we have discovered that the sponge- derived macrolides laulimalide and isolaulimalide are potent cytotoxins with paclitaxel-like anti-microtubule-stabilizing activity. Laulimalide induces the dose-dependent reorganization or cellular microtubule, the formation of abnormal mitotic spindles, and microtubule. Laulimalide is a potent inhibitor of cellular proliferation with an IC/50 in the low nanomolar range. Significantly, in contrast to paclitaxel, both laulimalide inhibited the proliferation of SKVLB-1 cells, a P- glycoprotein over-expressing multi-drug resistant cell line, suggesting that is poor substrate for transport by P-glycoprotein. Incubation of MDA-MD-435 cells with laulimalide resulted in mitotic arrest and activation of the caspase cascade of proteolytic enzymes that accompany apoptotic cell death. Furthermore, in NCI's 60 cell line assay, laulimalide demonstrated interesting profiles of activity toward breast and prostate cell lines, resulting in a request from the NCI for additional laulimalide with which to begin in vivo evaluation. These compounds represent a new class of microtubule-stabilizing agents with activities that may prove therapeutically useful. The long-term goal of this project is to advance laulimalide or a laulimalide analog as a potential anti-cancer chemotherapeutic agent. To achieve this goal we propose to do the following: 1) supply the NCI with sufficient laulimalide for in vivo evaluation using a two-pronged approach involving both recollection/reisolation and chemical synthesis, 2) investigate structure-activity-relationships for laulimalide by preparing analogs, 3) screen laulimalide analogs for microtubule- stabilizing activity and for cytotoxicity toward drug-resistant cell lines, 4) submit active analogs to the NCI for screening in the 60-cell line assay and for in vitro evaluation, when warranted, and 5) obtain patent coverage for promising laulimalide analogs.

虽然有效治疗白血病和淋巴瘤的药物已经可用，但在开发方面进展甚微可用于治疗临床上重要的实体瘤的新药。目前，癌症化疗的主要目标是抑制通过破坏其作用机制来形成有丝分裂纺锤体。长春花生物碱引起微管解聚，而二萜紫杉醇及其衍生物泰索帝稳定微管。最近的发现引起了人们的极大热情有机化学家以及癌症研究人员。犹他州立大学与夏威夷癌症研究中心，我们发现海绵- 衍生的大环内酯类月桂马内酯和异月桂马内酯是强效细胞毒素具有紫杉醇样抗微管稳定活性。劳利马利特诱导剂量依赖性重组或细胞微管，异常有丝分裂纺锤体和微管的形成。劳利马利特是一种有效的细胞增殖抑制剂，IC/50 较低纳摩尔范围。值得注意的是，与紫杉醇相比，两者 laulimalide 抑制 SKVLB-1 细胞（一种 P- 糖蛋白过度表达的多重耐药细胞系，表明这是 P-糖蛋白转运的不良底物。孵化 MDA-MD-435 细胞与月桂马内酯导致有丝分裂停滞并伴随的蛋白水解酶的半胱天冬酶级联的激活细胞凋亡。此外，在 NCI 的 60 细胞系检测中，月桂马利特表现出有趣的乳房活性特征和前列腺细胞系，导致 NCI 请求额外的月桂马内酯用于开始体内评估。这些化合物代表了一类新型微管稳定剂可能被证明具有治疗作用的活动。该项目的长期目标是推进月桂马利特或 laulimalide类似物作为潜在的抗癌化疗剂。到为实现这一目标，我们建议采取以下措施：1) 向 NCI 提供足够的月桂马内酯用于使用两管齐下的体内评估涉及回忆/重新隔离和化学合成的方法， 2) 通过以下方法研究月桂马利特的结构-活性关系制备类似物，3)筛选月桂马内酯类似物的微管- 稳定活性和对耐药细胞的细胞毒性线，4) 向 NCI 提交活性类似物以在 60 细胞中进行筛选必要时进行线性测定和体外评估，以及 5) 获得有前途的月桂马内酯类似物的专利覆盖率。