Combining Anti Angiogenesis Strategies and Radiotherapy

描述（由申请人提供）：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 在局部治疗部位失败。新的治疗策略旨在改善 因此，肿瘤反应受到高度关注， 对于肿瘤细胞群的生长和存活至关重要， 是个很有吸引力的目标这项拨款提案的目的是调查 最佳地将抗血管生成策略与局部 放射治疗，以改善整体肿瘤反应。调查 集中于干扰两种血管生成激活剂（血管 内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF））和 内源性抑制因子（内皮抑制素）的扩增。该办法 编码反义VEGF/bFGF或内皮抑素的cDNA的递送和转移 使用腺相关病毒（AAV）或阳离子脂质体。实验 旨在首先表征和优化所提出的抗血管生成 肿瘤细胞、成纤维细胞和内皮细胞的体外研究。这些 研究将包括检查血管抑制的作用 各种细胞类型之间的旁分泌通讯策略， 确定这些策略之间是否发生直接相互作用 和放射治疗。使用的抗血管生成治疗的体内功效 然后将在异种移植物中评价与放射疗法结合 AIDS相关的卡波西肉瘤和透明细胞肾细胞癌模型。 选择这些模型是因为我们相信这些肿瘤的典型 广泛血管化的表现，加上他们缺乏 对传统治疗干预的满意反应，使他们 新的治疗策略，如抗血管生成， 接近。肿瘤反应和临界正常组织毒性均将被评估。 评估以确定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 研究将提供重要的见解， 采用抗血管生成治疗策略作为放疗的辅助。

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.