NEW ANTIMICROTUBULE AGENTS FROM MARINE ORGANISMS

来自海洋生物的新型抗微管剂

• 批准号: 6377146
• 负责人: BRADLEY S DAVIDSON
• 金额: $ 16万
• 依托单位: UTAH STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377146
• 关键词: Pacific Islands; Porifera; analog; animal extract; antimitotics; antineoplastics; apoptosis; aquatic organism; cell line; cell proliferation; chemical structure function; cytotoxicity; drug design /synthesis /production; drug discovery /isolation; drug resistance; immunofluorescence technique; lactones; microtubules; mitotic spindle apparatus; paclitaxel

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.

尽管有效治疗白血病和淋巴瘤的药物 尽管如此，在开发方面取得的进展甚微。 用于治疗临床上重要的实体瘤的新药。 目前，癌症化疗的主要靶点是抑制肿瘤细胞的增殖。 通过破坏它们的作用机制形成有丝分裂的纺锤体。 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。 最近的发现受到了来自 有机化学家和癌症研究人员。 彻底的合作计划之间的犹他州州立大学和 夏威夷癌症研究中心，我们发现海绵- 衍生的大环内酯类laulimalide和isolaulimalide是有效的细胞毒素 具有紫杉醇样的抗微管稳定活性。劳里马利得 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。劳里马利是 一种有效的细胞增殖抑制剂，在低浓度下具有IC/50 纳摩尔范围。值得注意的是，与紫杉醇相比， laulimalide抑制SKVLB-1细胞增殖，P- 糖蛋白过表达的多药耐药细胞系，提示 其是P-糖蛋白转运不良底物。孵育 具有laulimalide的MDA-MD-435细胞导致有丝分裂停滞， 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细胞系测定中， laulimalide显示出对乳腺的有趣活性特征 和前列腺细胞系，导致NCI要求 用于开始体内评价的额外的laulimalide。这些 化合物代表一类新的微管稳定剂， 可能证明有治疗作用的活性。 该项目的长期目标是推进laulimalide或 laulimalide类似物作为潜在抗癌化疗剂。到 为了实现这一目标，我们建议做以下几点：1）为NCI提供 足够的laulimalide用于体内评价， 包括回忆/再隔离和化学合成的方法， 2)通过以下方法研究laulimalide构效关系 制备类似物，3）筛选用于微管的laulimalide类似物， 稳定活性和对耐药细胞的细胞毒性 4）将活性类似物提交给NCI用于在60细胞中筛选 线测定和体外评价（必要时），以及5）获得 有前途的laulimalide类似物的专利覆盖范围。