Effects of novel taxanes SB-T-1213 and IDN5109 on tubulin polymerization and mitosis
Effects of novel taxanes SB-T-1213 and IDN5109 on tubulin polymerization and mitosis
复制标题
DOI：
10.1016/s1074-5521(01)00097-7
复制
发表时间：
2002-01-01
影响因子：
--
通讯作者：
Ferlini, C
中科院分区：
文献类型：
--
作者：
Jordan, MA;Ojima, I;Ferlini, C
SB-T-1213和IDN 5109是半合成的口服紫杉烷，其对耐药细胞的活性比紫杉醇高400倍。IDN 5109正在进行临床试验。我们研究了SB-T-1213和IDN 5109的主要靶点，以及这些化合物与微管的相互作用是否与紫杉醇不同。与紫杉醇不同，在1-10 μ M时，两种新型紫杉烷在体外无延迟地引发微管聚合。它们与紫杉醇一样或更有效地促进聚合。SB-T-1213诱导具有附着的额外原丝或开放片层的不寻常微管，而IDN 5109诱导大的原丝片层。二者均能抑制HeLa细胞增殖，高浓度时阻断中期/后期过渡束微管的有丝分裂，诱导中期纺锤体异常和凋亡。它们靶向微管，但改变其聚合和结构不同于紫杉醇。这些差异可能在其增强的细胞毒性和功效中发挥作用。
SB-T-1213 and IDN5109 are semisynthetic, orally available taxanes that are up to 400-fold more active than paclitaxel against drug-resistant cells. IDN5109 is in clinical trials. We investigated the primary target for SB-T-1213 and IDN5109 and whether the compounds interact with microtubules differently than paclitaxel. Unlike paclitaxel, at 1-10 muM both novel taxanes initiate microtubule polymerization in vitro with no lag. They enhance polymerization equally or more potently than paclitaxel. SB-T-1213 induces unusual microtubules with attached extra protofilaments or open sheets, and IDN5109 induces large protofilamentous sheets. Both inhibit HeLa cell proliferation, block mitosis at the metaphase/anaphase transition bundle microtubules at high drug concentrations, an induce abnormal metaphase spindles and apoptosis. They target microtubules but alter their polymerization and structure differently than paclitaxel. These differences may play a role in their enhanced cytotoxicity and efficacy.