MODULATION OF THERAPEUTIC RESPONSE

“为了改善癌症治疗， 对……的修改引起了人们的极大关注 辐射损伤。这个项目的主要目标继续明确 了解独特的肿瘤生理学、解剖学、 细胞和分子过程最终定义了 肿瘤的性质使得特定剂量的电离辐射， 当使用时，会更有效。达到这一目的的一种手段是 研究电离辐射与多种物质的相互作用 化疗药物以评估肿瘤是否可以变得更多 很敏感。我们证明了对一个多样化的人类的治疗 紫杉醇诱导肿瘤细胞G2/M期阻滞 细胞周期(细胞周期的辐射敏感阶段)，导致 显著的放射增敏作用。因此，这篇文章的翻译 将临床前信息整合到一项临床试验中 紫杉醇目前用于治疗头颈部癌症 正在放射肿瘤科进行。其他 化疗药物(喜树碱衍生物、米托蒽酮、 和环硫酮等)正在调查中 确定它们作为辐射增敏剂的用途。这很好 确定缺氧是辐射的主要决定因素 敏感度。因此，我们正在使用几种小鼠肿瘤模型来 研究肿瘤缺氧情况。我们的方法是利用目前的入侵 技术，并将这些信息扩展到非侵入性方法 正在开发中的技术，比如病人的肿瘤治疗 配置文件可能会在个别基础上进行优化。为此，我们将 使用体外/体内存活技术，基于荧光的氧气 探头，硝基咪唑固定，然后免疫组织化学， F-18硝基咪唑PET扫描，血氧水平 测定(BOLD)核磁共振、电子顺磁共振、 和Overhauser核磁共振。我们获得的信息将教会我们 如何以非侵入性方式评估肿瘤中的氧气状态 效果最佳处理。同样，理解和定义 肿瘤血管和DNA表达应有助于洞察 了解新生血管如何影响肿瘤氧和 因此，对辐射的响应性以及提供 关于这些基因的信息，这些基因是为了响应 氧化应激。几种血管抑素和内皮抑素的表达 已经构建了用于直接肿瘤内注射的载体或 全身性脂质体给药。此外，体外/体内肿瘤 包含带有开关的矢量的模型，用于表达 目前正在制造内皮抑素和血管抑素，因此 血管的影响可以在以下背景下进行评估 对辐射的响应性，以及在非侵入性的背景下 功能成像。肿瘤内的基因表达作为 氧状态、再灌流、电离辐射暴露和全身 目前正在研究氧化应激以确定这些分子 在肿瘤细胞反应性和 仅通过电离辐射或与电离辐射相结合而存活 药理药剂。其目的是扩大我们对 肿瘤微环境、生理、分子生物学与 将这些知识与非侵入性学习方法相关联 让我们设计出高效有效的治疗方案 联合使用放射或与药理联合使用 特工。“

"In the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The major goal of this project continues to define and understand those aspects of unique tumor physiology, anatomy, cellular, and molecular processes that ultimately define the very nature of a tumor such that a particular dose of ionizing radiation, when used, will be more effective. One means to that end is to investigate the interaction of ionizing radiation with a variety of chemotherapy agents to assess if tumors can be made more sensitive. We demonstrated that treatment of a diverse human tumor cell lines with paclitaxel induced a block in G2/M of the cell cycle (radiosensitive phases of the cell cycle) which resulted in significant radiosensitization. As a consequence, translation of this pre-clinical information into a clinical trail combining radiation and paclitaxel in the treatment of head/neck cancer is currently underway in the Radiation Oncology Branch. Other chemotherapeutic agents (camptothecin derivatives, mitoxanthone, and epothialones, among others) are being investigated to determine their use as radiation sensitizing agents. It is well established that hypoxia is a major determinant of radiation sensitivity. Therefore, we are using several murine tumor models to study tumor hypoxia. Our approach is to use current invasive techniques and extend that information to non-invasive methods that are under development, such that patient tumor treatment profiles may optimized on an individual basis. To that end we are using in vitro/in vivo survival techniques, fluorescent based oxygen probes, nitroimidazole fixation followed by immunohistochemistry, F-18 nitroimidazole PET scanning, blood oxygen level determination (BOLD) NMR, electron paramagnetic resonance, and Overhauser NMR. The information we acquired will teach us how to assess oxygen status in a tumor in a non-invasive manner to effect optimum treatment. Likewise, understanding and defining tumor vasculature and DNA expression should provide insight to understanding how neoangiogenesis impacts on tumor oxygen and consequently responsiveness to radiation, as well as provide information regarding those genes that are expressed in response to oxidative stress. Several angiostatin and endostatin expression vectors have been constructed for direct intra-tumor injection or systemic liposome delivery. Moreover, in vitro/in vivo tumor models containing vectors with switches for expression of endostatin and angiostatin are being made presently, such that the impact of vascularity can be assessed in the context of responsiveness to radiation and also in the context of non-invasive functional imaging. Gene expression within a tumor as a function of oxygen status, reperfusion, ionizing radiation exposure and general oxidative stress is being investigated to determine those molecular events that are important in the tumor cell responsiveness and survival to insult by ionizing radiation alone or in combination with pharmacologic agents. The aim is to extend our knowledge of tumor micro-environment, physiology, and molecular biology and to correlate such knowledge with non-invasive methods of studying tumors so that we design efficient and effective treatment protocols using radiation in combination or tandem with pharmacologic agents."