Non-toxic melanoma therapy by a novel tubulin-binding agent.
Non-toxic melanoma therapy by a novel tubulin-binding agent.
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DOI：
10.1002/ijc.24765
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发表时间：
2010-01-01
影响因子：
6.4
通讯作者：
Joshi, Harish C.
中科院分区：
文献类型：
--
作者：
Aneja, Ritu;Asress, Seneshaw;Dhiman, Neerupma;Awasthi, Anshumali;Rida, Padmashree C. G.;Arora, Sudarshan K.;Zhou, Jun;Glass, Jonathan D.;Joshi, Harish C.
(S)-3-((R)-9-溴-4-甲氧基-6-甲基-5,6,7,8-四氢-[1,3]dioxolo[4,5-g]isoquino-lin-5-yl)-6,7-二甲氧基异苯并呋喃-1(3H)-one （EM011）是一种具有显著抗癌活性的微管蛋白结合剂。在这里，我们表明EM011在不改变微管蛋白总聚合物质量的浓度下调节微管动力学。特别是，EM011降低了生长阶段和缩短阶段之间的过渡频率，并增加了微管处于空闲“暂停”状态的持续时间。使用B16LS9小鼠黑色素瘤细胞，我们发现EM011通过形成多个aster纺锤体在G2/M期短暂地阻止细胞周期进程。在没有细胞分裂的情况下发生异常的有丝分裂退出，导致异常多核细胞在凋亡之前积累。我们的药代动力学研究符合150mg /kg以下的线性剂量-反应关系。但在300 mg/kg时出现非线性。在同基因小鼠皮下黑色素瘤模型中，与300 mg/kg的EM011相比，150 mg/kg的EM011抗肿瘤效果更好。与目前可用的化疗药物不同，EM011对正常组织无毒，最重要的是，它不会引起任何免疫抑制和神经毒性。因此，我们的数据保证了EM011用于黑色素瘤治疗的临床评估。
(S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquino-lin-5-yl)-6,7-dimethoxyisobenzofuran-1(3H)-one (EM011) is a tubulin-binding agent with significant anticancer activity. Here we show that EM011 modulates microtubule dynamics at concentrations that do not alter the total polymer mass of tubulin. In particular, EM011 decreases the transition frequencies between growth and shortening phases and increases the duration microtubules spend in an idle ‘pause’ state. Using B16LS9 murine melanoma cells, we show that EM011 briefly arrests cell-cycle progression at the G2/M phase by formation of multiple aster spindles. An aberrant mitotic exit without cytokinesis then occurs, leading to the accumulation of abnormal multinucleated cells prior to apoptosis. Our pharmacokinetic studies conformed to a linear dose-response relationship upto 150 mg/kg. However, non-linearity was observed at 300 mg/kg. In a syngeneic murine model of subcutaneous melanoma, better antitumor responses were seen at 150 mg/kg compared to 300 mg/kg of EM011. Unlike currently available chemotherapeutics, EM011 is non-toxic to normal tissues and most importantly, does not cause any immunosuppression and neurotoxicity. Our data thus warrant a clinical evaluation of EM011 for melanoma therapy.
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影响因子：
3
作者：
Aneja, Ritu;Dhiman, Neerupma;Joshi, Harish C.
通讯作者：
Joshi, Harish C.
影响因子：
11.2
作者：
Wang, MS;Fang, GF;Glass, JD
通讯作者：
Glass, JD
影响因子：
11.2
作者：
Wang, MS;Davis, AA;Glass, JD
通讯作者：
Glass, JD
影响因子：
3.8
作者：
Silva, Angelica;Wang, Qingbo;Glass, Jonathan D.
通讯作者：
Glass, Jonathan D.
影响因子：
2.2
作者：
Serrone, L;Horsey, P
通讯作者：
Horsey, P