Combining Anti Angiogenesis Strategies and Radiotherapy

描述(申请人提供)：放射治疗是最重要的 癌症的非手术治疗。即便如此，仍有大量患者 在当地治疗现场失败。旨在改善的新治疗策略 因此，肿瘤反应受到高度关注，而肿瘤血管系统 对肿瘤细胞群体的生长和生存至关重要， 提供了一个有吸引力的目标。这项拨款提案的目的是调查 抗血管生成治疗与局部治疗的最佳结合方法 放射治疗，以提高肿瘤的整体反应。调查 专注于干扰两种血管生成激活剂(血管 血管内皮细胞生长因子、碱性成纤维细胞生长因子)和 内源性抑制因子(内皮抑素)的扩增。方法将是 反义血管内皮生长因子/碱性成纤维细胞生长因子或内皮抑素基因的表达和转移 使用腺相关病毒(AAV)或阳离子脂质体。实验是 旨在首先表征和优化所提出的抗血管生成药物 肿瘤细胞、成纤维细胞和血管内皮细胞的体外研究进展。这些 研究将包括检查血管抑制的影响。 不同类型细胞间旁分泌通讯的策略 确定这些策略之间是否发生直接交互作用 和放射治疗。抗血管生成治疗的体内疗效 联合放射治疗将在异种移植中进行评估 艾滋病相关卡波西肉瘤和肾透明细胞癌模型的建立。 之所以选择这些模型，是因为我们认为这些肿瘤的典型 广泛血管化的表现，加上他们缺乏 对传统治疗干预措施的满意反应，使他们 抗血管生成等新治疗策略的极佳候选者 接近了。肿瘤反应和严重的正常组织毒性都将是 进行评估以确定在以下情况下是否可以实现治疗益处 血管抑制治疗和放射治疗相结合。我们相信这些都是 研究将提供对治疗效用的基本见解。 采用抗血管生成治疗策略作为放射治疗的辅助手段。

DESCRIPTION (provided by applicant):Radiotherapy is the most important non-surgical treatment for cancer. Even so, large numbers of patients still fail at the local treatment site. New treatment strategies aimed at improving tumor response are therefore of high interest and the tumor vasculature, which is critical for the growth and survival of the neoplastic cell population, offers an attractive target. The goal of this grant proposal is to investigate approaches for optimally combining antiangiogenic strategies with localized radiation therapy in order to improve overall tumor response. Investigations are focused on interfering with two activators of angiogenesis (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF)) and amplification of an endogenous suppressor (endostatin). The approach will be the delivery and transfer of cDNA coding for antisense VEGF/bFGF or endostatin using adeno-associated virus (AAV) or cationic liposomes. Experiments are designed to first characterize and optimize the proposed antiangiogenic approaches in tumor cells, fibroblasts and endothelial cells in vitro. These studies will include the examination of the effect of angiosuppression strategies on the paracrine communication between the various cell types and the determination of whether direct interactions occur between such strategies and radiation treatment. The in vivo efficacy of antiangiogenic treatments used in conjunction with radiation therapy will then be evaluated in xenograft models of AIDS associated Kaposi's Sarcoma and clear cell renal cell carcinoma. These models were chosen because we believe that these neoplasms' typical manifestation of extensive vascularization, coupled with their lack of satisfactory responses to traditional therapeutic interventions, make them excellent candidates for new therapeutic strategies such as antiangiogenic approaches. Both tumor response and critical normal tissue toxicities will be assessed to determine whether a therapeutic benefit can be achieved when angiosuppressive treatments and radiation are combined. We believe that these studies will provide essential insights into the therapeutic utility of employing antiangiogenic treatment strategies as adjuvants to radiotherapy.