Wang Huaijun, Marchal Guy, Ni Yicheng
Huaijun Wang, Guy Marchal, Yicheng Ni, Department of Radiology, University Hospitals, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.
World J Radiol. 2011 Jan 28;3(1):1-16. doi: 10.4329/wjr.v3.i1.1.
Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis; a process known as tumor angiogenesis. Angiogenesis is largely involved in tumor survival, progression and spread, which are known to be significantly attributed to treatment failures. Over the past decades, efforts have been made to understand the difference between normal and tumor vessels. It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes, which provides opportunities for developing novel anticancer strategies. Targeting tumor vasculature is not only a unique therapeutic intervention to starve neoplastic cells, but also enhances the efficacy of conventional cancer treatments. Vascular disrupting agents (VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors, cause catastrophic vascular shutdown within short time, and induce secondary tumor necrosis. VDAs are cytostatic; they can only inhibit tumor growth, but not eradicate the tumor. This novel drug mechanism has urged us to develop multiparametric imaging biomarkers to monitor early hemodynamic alterations, cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected. In this article, we review the characteristics of tumor vessels, tubulin-destabilizing mechanisms of VDAs, and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials. We also compare the different tumor models adopted in the preclinical studies on VDAs. Multiparametric imaging biomarkers, mainly diffusion-weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging, are evaluated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs.
实体恶性肿瘤为实现其侵袭性生长和转移，必须建立自身的血液供应，这一过程称为肿瘤血管生成。血管生成在很大程度上参与肿瘤的存活、进展和扩散，而这些已知是导致治疗失败的重要原因。在过去几十年里，人们一直在努力了解正常血管与肿瘤血管之间的差异。已证实肿瘤血管系统在结构上不成熟，具有紊乱和渗漏的表型，这为开发新的抗癌策略提供了机会。靶向肿瘤血管系统不仅是一种独特的治疗干预手段，可使肿瘤细胞缺乏营养，还能提高传统癌症治疗的疗效。血管破坏剂（VDA）已被开发出来，用于破坏活跃生长肿瘤中已有的新生血管，在短时间内导致灾难性的血管关闭，并诱导继发性肿瘤坏死。VDA具有细胞抑制作用；它们只能抑制肿瘤生长，而不能根除肿瘤。这种新的药物作用机制促使我们开发多参数成像生物标志物，以在检测到肿瘤尺寸变化之前监测早期血液动力学改变、细胞功能障碍和代谢损伤。在本文中，我们综述了肿瘤血管的特征、VDA的微管去稳定机制以及在临床前研究和临床试验中大多被研究的VDA的体内效应。我们还比较了在VDA临床前研究中采用的不同肿瘤模型。对主要来自磁共振成像的扩散加权成像和动态对比增强成像等多参数成像生物标志物作为监测VDA治疗效果的形态学和功能成像生物标志物的潜力进行了评估。
