NEW ANTIMICROTUBULE AGENTS FROM MARINE ORGANISMS

来自海洋生物的新型抗微管剂

• 批准号: 2839719
• 负责人: BRADLEY S DAVIDSON
• 金额: $ 18.08万
• 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 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2839719
• 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.

虽然有效治疗白血病和淋巴瘤的药物 可用，在开发方面几乎没有取得进展 新药可用于治疗临床上重要的实体瘤。 目前，癌症化疗的主要靶标是抑制 有丝分裂螺旋形成通过破坏其作用机理。 VINCA生物碱引起微管解聚，而 二萜紫杉醇及其衍生物紫杉烷稳定微管。 最近的发现充满了热情 有机化学家和癌症研究人员。 彻底彻底的犹他州立大学与 夏威夷癌症研究中心，我们发现海绵 衍生的大环内酯华酰胺和分离二硫氨基甲是有效的细胞毒素 具有紫杉醇样的抗微管稳定活性。 Laulimalide 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。 Laulimalide是 在低处IC/50的细胞增殖的有效抑制剂 纳摩尔范围。值得注意的是，与紫杉醇相比 Laulimalide抑制了SKVLB-1细胞的增殖，P- 糖蛋白过表达多药细胞系，表明 那是P-糖蛋白转运的底物差。孵化 带有Laulimalide的MDA-MD-435细胞导致有丝分裂停滞和 伴随的蛋白水解酶的激活 凋亡细胞死亡。此外，在NCI的60个单元线测定中， Laulimalide显示出对乳房活动的有趣特征 和前列腺细胞系，导致NCI请求 可以从体内评估开始的其他Laulimalide。这些 化合物代表一类新的微管稳定剂 可能在治疗上有用的活动。 该项目的长期目标是促进Laulimalide或 Laulimalide类似物作为潜在的抗癌化学治疗剂。到 实现我们建议执行以下操作的目标：1）向NCI提供 足够的Laulimalide用于体内评估 涉及回忆/再分离和化学合成的方法， 2）研究Laulimalide的结构激活关系 制备类似物，3）微管的屏幕Laulimalide类似物 稳定活性和对耐药细胞的细胞毒性 线，4）向NCI提交主动类似物以在60细胞中进行筛选 当保证时，线测定和进行体外评估，5） 有希望的Laulimalide类似物的专利覆盖范围。