Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature.
Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature.
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发表时间：
1997-05
期刊：
影响因子：
11.2
通讯作者：
G. Dark;S. Hill;V. Prise;G. Tozer;G. Pettit;D. Chaplin
中科院分区：
文献类型：
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作者：
G. Dark;S. Hill;V. Prise;G. Tozer;G. Pettit;D. Chaplin
选择性诱导肿瘤内血管损伤代表了一种新兴的癌症治疗方法。组织学研究表明，几种微管蛋白结合剂可以诱导肿瘤内的血管损伤，但只能在接近最大耐受剂量的剂量下进行，这限制了它们的临床适用性。在这项研究中，我们发现考布他汀 A-4 前药在低于最大耐受剂量十分之一的剂量下可诱导肿瘤内血管关闭。体外研究表明，短暂的药物暴露会对增殖的内皮细胞产生深远的长期抗增殖/细胞毒性作用，但不会对药物暴露之前和期间处于静止状态的细胞产生影响。在全身给药后的体内实验和人类乳腺癌模型中，血管关闭被证明是在给药后 6 小时功能性血管体积减少 93%，并在接下来的 12 小时内持续存在，相应的组织学与血管损伤导致的出血性坏死一致。这些针对肿瘤血管系统的作用和广泛的治疗窗证明了这些药物的临床潜力，并需要进一步研究以阐明考布他汀 A-4 抗血管作用的机制。
Selective induction of vascular damage within tumors represents an emerging approach to cancer treatment. Histological studies have shown that several tubulin-binding agents can induce vascular damage within tumors but only at doses approximating the maximum tolerated dose, which has limited their clinical applicability. In this study, we show that the combretastatin A-4 prodrug induces vascular shutdown within tumors at doses less than one-tenth of the maximum tolerated dose. In vitro studies indicate that a short drug exposure results in profound long-term antiproliferative/cytotoxic effects against proliferating endothelial cells but not cells that are quiescent prior to and during drug exposure. Vascular shutdown, within experimental and human breast cancer models in vivo following systemic drug administration, was demonstrated with a reduction in functional vascular volume of 93% at 6 h following drug administration and persisted over the next 12 h, with corresponding histology consistent with hemorrhagic necrosis resulting from vascular damage. These actions against tumor vasculature and the broad therapeutic window demonstrate the clinical potential of these drugs and warrant further study to elucidate the mechanisms responsible for the antivascular effects of combretastatin A-4.