Department of Vascular Biology, Tohoku University, Aoba-ku, Sendai, Japan.
Cancer Metastasis Rev. 2012 Jun;31(1-2):109-22. doi: 10.1007/s10555-011-9333-9.
Combretastatin can prevent the supply of nutrients to cancer cells by selectively interrupting tumor blood flow (TBF). Therefore, combretastatin may serve as a new anticancer drug that utilizes starvation tactics to attack solid tumors. Among combretastatin compounds, combretastatin A-4 and a combretastatin A-4 derivative (Cderiv) are now in phase III clinical trials. These two combretastatin compounds have similar chemical structures and provide marked TBF interruption. However, their mechanisms of action are reportedly quite different and remain controversial. Precise mechanisms of action of these agents must be elucidated so as to develop safe clinical treatments and wider clinical applications. By using various kinds of rodent tumors, we showed that Cderiv produced potent interruption of TBF in all primary tumors and metastatic foci, without exception, and had beneficial therapeutic effects including significantly improved survival. Cderiv caused host arterioles to constrict. However, a tumor vascular bed scarcely reacted to a direct topical application of Cderiv. In addition, the fact that Cderiv did not have cytotoxic drug-like accumulated toxicity usually caused by repeated administration means that inhibition of tubulin polymerization by Cderiv may not occur to a great degree in vivo. Therefore, at least for Cderiv, our studies demonstrated that TBF interruption was mainly caused indirectly, via enhancement of vascular resistance of host arterioles, rather than being caused by a direct effect of Cderiv on tumor vessels. In this review, I describe cancer therapy that utilizes such TBF interruption, which leads to Cderiv-induced necrosis, and discuss details of its microcirculation mechanism.
Combretastatin 可以通过选择性地中断肿瘤血流（TBF）来阻止癌细胞的营养供应。因此，Combretastatin 可能成为一种利用饥饿策略攻击实体瘤的新型抗癌药物。
在 Combretastatin 化合物中，Combretastatin A-4 和 Combretastatin A-4 衍生物（Cderiv）目前正在进行 III 期临床试验。这两种 Combretastatin 化合物具有相似的化学结构，可提供明显的 TBF 中断。然而，它们的作用机制据报道有很大的不同，仍存在争议。
这些药物的精确作用机制必须阐明，以便开发安全的临床治疗方法和更广泛的临床应用。
通过使用各种啮齿动物肿瘤，我们表明 Cderiv 确实会在所有原发性肿瘤和转移灶中产生强烈的 TBF 中断，无一例外，并具有有益的治疗效果，包括显著提高生存率。Cderiv 导致宿主小动脉收缩。然而，肿瘤血管床几乎没有对 Cderiv 的直接局部应用做出反应。此外，Cderiv 没有累积通常由重复给药引起的细胞毒性药物样毒性这一事实意味着 Cderiv 抑制微管蛋白聚合的程度在体内可能不大。
因此，至少对于 Cderiv，我们的研究表明，TBF 中断主要是通过增强宿主小动脉的血管阻力间接引起的，而不是由 Cderiv 对肿瘤血管的直接作用引起的。
在这篇综述中，我描述了利用这种 TBF 中断导致 Cderiv 诱导坏死的癌症治疗方法，并讨论了其微循环机制的细节。
