de Arruda M, Cocchiaro C A, Nelson C M, Grinnell C M, Janssen B, Haupt A, Barlozzari T
BASF Bioresearch Corporation, Worcester, Massachusetts 01605-4314, USA.
Cancer Res. 1995 Jul 15;55(14):3085-92.
LU103793 (NSC D-669356) is a new synthetic derivative of Dolastatin 15, an antiproliferative compound which was isolated from the mollusk Dolabella auricularia. Like Dolastatin 15, LU103793 is highly cytotoxic in vitro (IC50 = 0.1 nM). To investigate the mechanism of action of LU103793, we used a combination of biochemical and cellular methods. Turbidity assays with bovine brain microtubules demonstrated that LU103793 inhibits microtubule polymerization in a concentration-dependent manner (IC50 = 7 microM). Treatment with this compound also induced depolymerization of preassembled microtubules. Cell cycle analysis of tumor cell lines treated with LU103793 indicated a block in the G2-M phase. At the cellular level, it induced depolymerization of microtubules in interphase cells and development of abnormal spindles and chromosome distribution in mitotic cells. Although these effects are very similar to the cellular alterations caused by vinblastine, LU103793 does not inhibit vinblastine binding to unpolymerized tubulin in vitro. Our results suggest that LU103793 exerts its cytotoxic activity primarily through disruption of microtubule organization.
LU103793（NSC D - 669356）是多拉司他汀15的一种新型合成衍生物，多拉司他汀15是一种从软体动物耳状芋螺中分离得到的抗增殖化合物。与多拉司他汀15一样，LU103793在体外具有高度细胞毒性（IC50 = 0.1 nM）。为了研究LU103793的作用机制，我们结合了生化和细胞方法。用牛脑微管进行的浊度测定表明，LU103793以浓度依赖的方式抑制微管聚合（IC50 = 7 microM）。用该化合物处理还诱导了预组装微管的解聚。对用LU103793处理的肿瘤细胞系进行细胞周期分析表明，细胞在G2 - M期受阻。在细胞水平上，它诱导间期细胞中的微管解聚，并在有丝分裂细胞中导致异常纺锤体和染色体分布。尽管这些效应与长春碱引起的细胞改变非常相似，但LU103793在体外并不抑制长春碱与未聚合微管蛋白的结合。我们的结果表明，LU103793主要通过破坏微管组织发挥其细胞毒性活性。
