Development of a novel tumor-targeted vascular disrupting agent activated by membrane-type matrix metalloproteinases.
Development of a novel tumor-targeted vascular disrupting agent activated by membrane-type matrix metalloproteinases.
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DOI：
10.1158/0008-5472.can-10-1440
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发表时间：
2010-09-01
期刊：
影响因子：
11.2
通讯作者：
Gill JH
中科院分区：
文献类型：
--
作者：
Atkinson JM;Falconer RA;Edwards DR;Pennington CJ;Siller CS;Shnyder SD;Bibby MC;Patterson LH;Loadman PM;Gill JH
血管阻断剂（VDA）提供了一种使实体瘤缺乏营养和氧气并伴随肿瘤缩小的策略。几种VDA已进入早期临床试验，但其治疗价值似乎受到全身毒性的影响。在这份报告中，我们描述了一种新的VDA，ICT 2588的设计和表征，这是无毒的，直到激活特异性在肿瘤中的膜型1基质金属蛋白酶（MT 1-MMP）。表达MT 1-MMP的HT 1080癌细胞对ICT 2588选择性化疗敏感，而不表达MT 1-MMP的MCF 7细胞无反应。相对于MCF 7匀浆、小鼠血浆和肝匀浆，在HT 1080的肿瘤匀浆中观察到ICT 2588优先水解为其活性代谢产物（ICT 2552）。ICT 2588的激活被MMP抑制剂Ilomastat抑制。在HT 1080荷瘤小鼠中，ICT 2588给药导致活性代谢物形成、肿瘤血管减少和肿瘤出血性坏死。ICT 2588的抗肿瘤活性上级于其活性代谢物，表现出降低的毒性、改善的治疗指数、增强的药效学作用和更大的功效。ICT 2588与多柔比星的共同给药导致显著的抗肿瘤反应（22.6天生长延迟），其上级作为单一药剂的ICT 2588或多柔比星的给药，包括完全肿瘤消退。我们的研究结果支持ICT 2588的临床开发，该药物基于肿瘤微环境中MT-MMP的活化实现选择性VDA靶向。
Vascular disrupting agents (VDA) offer a strategy to starve solid tumors of nutrients and oxygen concomitant with tumor shrinkage. Several VDAs have progressed into early clinical trials but their therapeutic value seems to be compromised by systemic toxicity. In this report, we describe the design and characterization of a novel VDA, ICT2588, that is non-toxic until activated specifically in the tumor by membrane-type-1 matrix metalloproteinase (MT1-MMP). HT1080 cancer cells expressing MT1-MMP were selectively chemosensitive to ICT2588, whereas MCF7 cells that did not express MT1-MMP were non-responsive. Preferential hydrolysis of ICT2588 to its active metabolite (ICT2552) was observed in tumor homogenates of HT1080 relative to MCF7 homogenates, mouse plasma and liver homogenate. ICT2588 activation was inhibited by the MMP inhibitor Ilomastat. In HT1080 tumor-bearing mice, ICT2588 administration resulted in formation of the active metabolite, diminution of tumor vasculature and hemorrhagic necrosis of the tumor. The antitumor activity of ICT2588 was superior to its active metabolite, exhibiting reduced toxicity, improved therapeutic index, enhanced pharmacodynamic effect and greater efficacy. Co-administration of ICT2588 with doxorubicin resulted in a significant antitumor response (22.6 day growth delay), which was superior to administration of ICT2588 or doxorubicin as a single agent, including complete tumor regressions. Our findings support the clinical development of ICT2588 which achieves selective VDA targeting based on MT-MMP activation in the tumor microenvironment.
影响因子：
8.8
作者：
Quinn, P K;Bibby, M C;Cox, J A;Crawford, S M
通讯作者：
Crawford, S M