Enhancing Radiation Therapy: Vascular Targeting Agents

尽管放射治疗是癌症管理的主要手段，但大量放射治疗患者仍需要接受放射治疗。 治疗的意图最终还是失败了。改善癌症治疗的传统方法集中在 主要是实现增加的肿瘤细胞杀伤。然而，在过去的十年中，另一种治疗方法 涌现该策略旨在通过靶向肿瘤血管来破坏肿瘤的营养支持系统 网络这样的“血管靶向”方法基于这样的认识，即， 脉管系统是肿瘤发生、发展和转移的基本要求。血管破坏 药物（VDA）被设计用于在肿瘤中引起快速和选择性的血管关闭。所得 局部缺血产生快速和广泛的肿瘤细胞杀伤。一个主要的焦点一直是可逆结合剂， 与微管蛋白结合并阻止微管组装。已证明使用此类VDA治疗可导致 在多种肿瘤模型中广泛的肿瘤坏死，以及与常规药物的协同相互作用 抗癌治疗，包括放射治疗。后者被归因于这些代理人的能力， 选择性地破坏肿瘤的中心区域，这些区域被广泛认为含有抵抗肿瘤的细胞群。 细胞毒疗法主要VDA现已进入临床试验，但有关其成功的新问题 应用已经出现。在这项研究计划中要解决的问题之一是， 被认为改善VDA治疗相关的高血压实际上可能损害抗肿瘤作用。 这些药剂的功效。其次，我们将研究是否病理生理信息的知识， 使用更接近临床可获得的剂量获得的剂量将允许优化剂量安排， 药物递送，导致上级抗肿瘤功效。本研究建议的最后一个方面将探讨 利用VDA治疗诱导的循环内皮细胞动员的定量的潜力 祖细胞作为VDA活性的潜在生物标志物。研究将用目前的微管蛋白先导物进行 结合VDA CA 4P和其有前途的第二代类似物OXi 4503，OXi 4503也已进入患者试验。 我们相信，所提出的临床前研究将对所提出的问题产生重要的见解， 为未来的肿瘤临床VDA计划提供有价值的指南/建议。

Although radiation therapy is a mainstay of cancer management, significant numbers of radiotherapy patients treated with curative intent still ultimately fail. Traditional methods of improving cancer therapy have focused primarily on achieving increased tumor cell kill. However, over the last decade another treatment approach has emerged. This strategy aims to impair the tumor's nutritional support system by target the tumor blood vessel network. Such "Vascular Targeting" approaches are based on the recognition that a continuously expanding vasculature is an essential requirement for tumor initiation, progression and metastasis. Vascular Disrupting Agents (VDAs) are designed to cause a rapid and selective vascular shutdown in tumors. The resulting ischemia produces rapid and extensive tumor cell kill. A main focus has been on agents that reversibly bind with tubulin and prevent microtubule assembly. Treatment with such VDAs has been shown to lead to extensive tumor necrosis in a wide variety of tumor models and to synergistic interactions with conventional anticancer treatments including radiotherapy. The latter has been attributed to the ability of these agents to selectively destroy central regions of tumors, areas widely believed to contain cell populations resistant to cytotoxic therapies. Lead VDAs have now entered clinical trials but new questions regarding their successful application have arisen. One of the issues to be addressed in this research program is whether the steps considered to ameliorate VDA-treatment associated hypertension might actually compromise the antitumor efficacy of these agents. Secondly we will examine whether knowledge of pathophysiologic information obtained using doses closer to those attainable in the clinic will allow the optimization of dose scheduling and drug delivery, leading to superior antitumor efficacy. The final aspect of this research proposal will explore the potential of utilizing the quantification of VDA treatment induced mobilization of circulating endothelial progenitor cells as potential biomarkers of VDA activity. Studies will be carried out with the current lead tubulin binding VDA CA4P and its promising second generation analog OXi4503 which has also entered patient trials. We believe that the proposed preclinical investigations will yield critical insights to the questions posed and provide valuable guidelines/suggestions for future clinical VDA initiatives in oncology.