Enhancing Radiation Therapy: Vascular Targeting Agents

尽管放射治疗是癌症治疗的支柱，但相当数量的放射治疗患者 带有治疗意图的治疗最终仍然失败。改善癌症治疗的传统方法已成为人们关注的焦点 主要是实现更高的肿瘤细胞杀伤率。然而，在过去的十年里，另一种治疗方法已经 出现了。该策略旨在通过靶向肿瘤血管来损害肿瘤的营养支持系统 网络。这种“血管靶向”方法是基于这样一种认识，即不断扩大的 血管系统是肿瘤发生、发展和转移的基本条件。血管破裂 药物(VDA)被设计成在肿瘤中引起快速和选择性的血管关闭。由此产生的 缺血可迅速而广泛地杀死肿瘤细胞。一个主要的焦点一直是可逆地结合的药物 与微管蛋白结合，防止微管聚集。使用这种VDA的治疗已被证明会导致 在多种肿瘤模型中广泛的肿瘤坏死以及与传统的 抗癌治疗，包括放射治疗。后者被归因于这些代理人有能力 选择性地破坏肿瘤的中心区域，人们普遍认为这些区域包含对 细胞毒疗法。主要的VDA现在已经进入临床试验，但关于他们的成功有新的问题 已经出现了申请。这项研究计划要解决的问题之一是，这些步骤是否 被认为改善VDA治疗相关高血压实际上可能损害抗肿瘤作用 这些药剂的功效。其次，我们将检查是否了解病理生理信息 使用更接近于临床可获得的剂量获得的剂量将允许优化剂量安排和 药物传递，导致卓越的抗肿瘤效果。这项研究提案的最后一个方面将探讨 利用定量VDA治疗诱导循环内皮细胞动员的潜力 祖细胞可作为VDA活性的潜在生物标志物。将使用当前的铅微管蛋白进行研究 BINDING VDA CA4P及其前景看好的第二代类似物Oxi4503也已进入患者试验阶段。 我们相信，拟议的临床前调查将对提出的问题产生关键的见解，并 为未来肿瘤学的临床VDA计划提供有价值的指导/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.