NEW ANTIMICROTUBULE AGENTS FROM MARINE ORGANISMS

尽管有效治疗白血病和淋巴瘤的药物 都是可用的，但在开发 用于治疗临床上重要的实体肿瘤的新药。 目前，癌症化疗的一个主要靶点是抑制 通过破坏它们的作用机制形成有丝分裂纺锤体。 长春花碱可引起微管解聚，而 二萜紫杉醇及其衍生物稳定微管。 最近的发现引起了来自 有机化学家和癌症研究人员。 通过犹他州州立大学和 夏威夷癌症研究中心，我们发现海绵- 大环内酯类化合物劳利马利和异马豆内酯是一种有效的细胞毒素 具有紫杉醇样的抗微管稳定活性。洛利马利 诱导剂量依赖的重组或细胞微管， 异常有丝分裂纺锤体和微管的形成。洛利马利是 一种有效的细胞增殖抑制因子，其IC/50处于低水平 纳摩尔范围。值得注意的是，与紫杉醇相比，两者 劳利马利可抑制SKVLB-1细胞的增殖。 糖蛋白高表达多药耐药细胞系，提示 这对于P-糖蛋白的转运来说是很差的底物。孵化 含劳利马利的MDA-MD-435细胞有丝分裂停滞 伴随着caspase级联的蛋白水解酶的激活 细胞凋亡性死亡此外，在NCI的60细胞系实验中， 劳利马利特表现出有趣的乳房活动特征 和前列腺细胞系，导致NCI要求 开始体内评价时使用的附加劳利马利。这些 化合物代表了一类新的微管稳定剂，具有 可能被证明对治疗有用的活动。 该项目的长期目标是推进劳利马利或一种 劳利马利类似物作为潜在的抗癌化疗药物。至 为实现这一目标，我们建议做以下工作：1)为NCI提供 体内评价使用双管齐下的足够的劳利马利 既涉及回收/再分离又涉及化学合成的方法， 2)研究劳利马利的构效关系 制备类似物，3)筛选用于微管的洛伊马利类似物- 对耐药细胞的稳定活性和细胞毒作用 行，4)向NCI提交活性类似物，以便在60-cell中进行筛选 LINE化验和体外评估，如有必要，以及5)获得 前景看好的劳利马利类似物的专利覆盖率。

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.