CHEMICAL MODIFIERS OF RADIATION AND CHEMOTHERAPY

此应用程序是为了继续支持临床和 实验室计划，以开发和优化化学品的使用 放疗或化疗的修饰剂。 修改器，而 不需要治疗价值本身，将改变 肿瘤或正常组织对治疗的反应， 上级肿瘤控制和减少正常组织损伤。 在 联合中心放射治疗，我们已经组装了一个 一组研究人员可以开发这些方法， 基本概念，通过药物开发和初步的 I期和II期试验，大规模疗效试验。 这群 包括具有不同专业领域的基础科学家， 来自癌症治疗各个方面的临床医生。 的主要重点 临床试验将是使用 低氧细胞放射增敏剂，特别是药物SR 2508。 最近的数据表明，肿瘤具有急性和 慢性缺氧细胞，缺氧细胞很可能是 具有临床意义，亲电子敏化剂 具有治疗功效。 因此， 缺氧细胞与SR 2508缺氧细胞细胞毒性剂和 全氟化碳是必要的。 递送SR的新方法 2508，通过连续输注和瘤内注射， 将评价药物相关的胶原基质。 我们将 研究肿瘤的氧合和生化状态 在体内分次放疗期间， 各种化学改性剂在临床上的效用。 我们有 建立了研究SR神经病变的体外系统 2508为了改善其剂量限制性毒性， 从而进一步增加该试剂的效用。 基于 一个随机的II期试验的阳性结果- 我们将继续使用米索咪唑 硝基咪唑作为化学增敏剂。 巯基修饰可以 增加低氧细胞放射增敏剂的功效，并改变 肿瘤和正常人的化学敏感性和放射敏感性 组织中 我们将进行实验室研究和临床试验，如果 被认为是适当的，与代理人，要么或增加 谷胱甘肽和其它硫醇。 相关的临床和 本申请中提出的实验室研究提供了一种 联合中心其他项目的重要基础，以及 为国家临床试验提供指导和支持， 致敏剂。

This application is for the continued support of the clinical and laboratory program to develop, and optimize the use of chemical modifiers of radiation or chemotherapy. The modifiers, while not necessary of therapeutic value by themselves, will alter the response of tumors or normal tissues to treatment resulting in superior tumor control and reduction in normal tissue injury. At the Joint Center for Radiation Therapy we have assembled a group of investigators who can develop these approaches from the basic concept, through drug development and the initial Phase I and II trails, to large scale efficacy trails. This group includes basic scientists with different areas of expertise, and clinicans from all aspects of cancer care. The major emphasis of the clinical trails will be the continuation of the use of the hypoxic cell radiosensitizers, particularly the drug SR 2508. Recent data suggest that tumors have both acutely and chronically hypoxic cells, that hypoxic cells may well be clinically significant, and that the electron affinic sensitizers have therapeutic efficacy. Therefore, the approach to the hypoxic cell with SR 2508 hypoxic cell cytoxic agents and perfluorocarbons is warranted. Novel methods of delivery of SR 2508, by continuous infusion and by intratumoral injection with a drug-associated collagen matrix will be evaluated. We will investigate the oxygenation and biochemical status of tumors during fractionated radiotherapy in vivo in order to optimize the utility of the various chemical modifiers in the clinic. We have established an in vitro system to study the neuropathy of SR 2508 in an attempt to ameliorate its the dose-limiting toxicity, thereby further increasing the utility of this agent. Based on the positive results of a randomized phase II trail of mephalan - Misonidazole we will continue to pursue the use of nitroimidazoles as chemosenitizers. Thiol modifications can increase the efficacy of hypoxic cell radiosensitizers, and alter chemosensitivity and radiosensitivy of tumors and normal tissues. We will conduct laboratory studies, and clinical trails, if deemed appropriate, with agents that either or augment glutathione and other thiols. The interrelated clinical and laboratory research proposed in this application, provides an important base for other programs of the Joint Center, as well as providing direction and support for national clinical trails with sensitizers.