BNP7787-Mediated Modulation of Paclitaxel- and Cisplatin-Induced Aberrant Microtubule Protein Polymerization In vitro
BNP7787-Mediated Modulation of Paclitaxel- and Cisplatin-Induced Aberrant Microtubule Protein Polymerization In vitro
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DOI：
10.1158/1535-7163.mct-10-0300
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发表时间：
2010-08
影响因子：
5.7
通讯作者：
A. Parker;P. Petluru;Meizhen Wu;Min Zhao;H. Kochat;Frederick H Hausheer
中科院分区：
文献类型：
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作者：
A. Parker;P. Petluru;Meizhen Wu;Min Zhao;H. Kochat;Frederick H Hausheer
紫杉烷和铂类药物是治疗癌症的重要药物，无论是作为单一药物还是与其他化疗药物联合使用，都显示出对多种肿瘤的活性，包括卵巢癌、乳腺癌和肺癌。然而，紫杉醇(多西紫杉醇和紫杉醇的所有制剂/衍生物)和铂(顺铂、卡铂和奥沙利铂)类药物的一个严重和普遍的副作用是剂量限制性化疗引起的周围神经病(CIPN)。CIPN可能导致治疗延误、剂量改变，在严重情况下，还可能导致停止化疗。因此，需要对CIPN进行有效的治疗。DEMSNA(BNP7787；Tavocept TM；2，2‘-二硫代双乙烷磺酸二钠)是一种正在进行研究的药物，正在进行国际临床开发，作为一种与紫杉烷和铂联合化疗一线联合治疗无法手术的晚期肺腺癌患者的治疗方法。目前正在开发BNP7787，目的是提高接受紫杉烷和/或顺铂化疗的癌症患者的存活率。更多的数据表明，BNP7787还可以预防化疗所致的常见和严重毒性，包括化疗所致的贫血、恶心、呕吐、肾毒性和神经病变，而不干扰化疗药物(S)的抗肿瘤活性。这里的研究表明，BNP7787可以防止微管蛋白(MTP)的异常聚合，这是由于MTP暴露于紫杉醇或顺铂而引起的。BNP7787以剂量依赖的方式调节紫杉醇诱导的MTP超聚合，BNP7787的体内代谢产物Mesna对时间依赖的顺铂诱导的MTP失活具有保护作用。我们认为BNP7787和MTP之间的相互作用可能在BNP7787介导的CIPN保护作用中发挥作用。摩尔癌症治疗；9(9)；2558-67。©2010 AACR。
Taxane and platinum drugs are important agents in the treatment of cancer and have shown activity against a variety of tumors, including ovarian, breast, and lung cancer, either as single agents or in combination with other chemotherapy drugs. However, a serious and prevalent side effect of taxane (docetaxel and all formulations/derivatives of paclitaxel) and platinum (cisplatin, carboplatin, and oxaliplatin) agents is dose-limiting chemotherapy-induced peripheral neuropathy (CIPN). CIPN can result in treatment delays, dose modifications, and, in severe cases, discontinuation of chemotherapy. Consequently, effective treatments for CIPN are needed. Dimesna (BNP7787; Tavocept TM; disodium 2,2′-dithio-bis-ethanesulfonate) is an investigational drug that is undergoing international clinical development as a treatment that is coadministered with first-line taxane and platinum combination chemotherapy in patients with inoperable advanced primary adenocarcinoma of the lung. BNP7787 is currently being developed with the objective of increasing the survival of cancer patients receiving taxane- and/or cisplatin-based chemotherapy. Additional data indicate that BNP7787 may also protect against common and serious chemotherapy-induced toxicities, including chemotherapy-induced anemia, nausea, emesis, nephrotoxicity, and neuropathy, without interfering with antitumor activity of the chemotherapeutic agent(s). Studies herein show that BNP7787 prevents aberrant microtubule protein (MTP) polymerization that is caused by exposure of MTP to paclitaxel or cisplatin. BNP7787 modulates paclitaxel-induced hyperpolymerization of MTP in a dose-dependent manner, and mesna, an in vivo metabolite of BNP7787, protects against time-dependent cisplatin-induced inactivation of MTP. We propose that interactions between BNP7787 and MTP may play a role in BNP7787-mediated protection against CIPN. Mol Cancer Ther; 9(9); 2558–67. ©2010 AACR.