CHEMICAL MODIFIERS OF RADIATION AND CHEMOTHERAPY

描述（改编自申请人的摘要）：本申请 建议继续实施综合临床和实验室计划， 开发放射和化学疗法的化学修饰剂。 申请人 制定了2-硝基咪唑安全使用的临床指南 低氧细胞放射增敏剂SR 2508，体外照射， 开发了硝基咪唑化学修饰剂的使用，并试用了 用近距离放射治疗连续输注敏化剂。 他的初步数据 表明低氧细胞敏化剂可以改善 前列腺癌，并可能大大提高疗效间质 辐照 基于临床结果和重要的生物学概念， 他将进行临床试验，以评估SR 2508的疗效 前列腺癌的放疗，2）化疗和放疗 在食管和膀胱的局部晚期癌症中，3）外部 在乳腺癌和脑癌中的束和植入辐射，以及4）作为 多发性骨髓瘤的化疗增敏剂。 当消耗谷胱甘肽的 代理人，L-BSO，变得可用，他将进行临床试验， 在放射治疗的同时减少谷胱甘肽。 他的实验室 将继续为联合中心提供药理学支持， 放射治疗和放射治疗肿瘤组试验。 基本 实验室项目旨在开发新的临床策略 用于克服缺氧细胞的治疗抗性，特别是 强调间歇性缺氧的后果。 正在进行的研究 包括：1）使用分次放疗肿瘤模型来研究 体内缺氧; 2）使用图像研究缺氧细胞群 Hoechst 33342和色霉素A3体外模型系统分析 （“三明治”和调节气体扩散），和内在细胞标志物 （应激蛋白模式），和3）应用体外测定来研究 药物神经毒性的机制和预防或治疗策略 改善与SR 2508相关的神经病变。

DESCRIPTION (adapted from the applicant's abstract): This application proposes continuation of an integrated clinical and laboratory program to develop chemical modifiers of radiation and chemotherapy. The applicant has established clinical guideline for the safe use of the 2-nitroimidazole hypoxic cell radiosensitizer, SR 2508, with external beam irradiation, developed the use of nitromidazole chemomodifiers, and piloted the use of continuous infusion of sensitizer with brachytherapy. His preliminary data indicate that hypoxic cell sensitizers may improve treatment outcome for prostate cancer and may substantially enhance the efficacy of interstitial irradiation. Based on clinical results and important biological concepts, he will conduct clinical trials to assess the efficacy of SR2508 1) With radiotherapy in cancer of the prostate, 2) With chemotherapy and radiation in locally advanced cancers of the esophagus and bladder, 3) With external beam and implanted radiation in cancers of the breast and brain, and 4) as a chemosensitizer in multiple myeloma. When the glutathione-depleting agent, L-BSO, becomes available, he will conduct a clinical trial to deplete glutathione in conjunction with radiation therapy. His laboratory will continue to provide pharmacologic support for the Joint Center for Radiation Therapy and the Radiotherapy Oncology Group trials. The basic laboratory program is directed toward developing novel clinical strategies for overcoming treatment resistance of hypoxic cells, with particular emphasis on the consequences of intermittent hypoxia. Ongoing studies include: 1) the use of a fractionated radiotherapy tumor model to study hypoxia in vivo; 2) investigation of hypoxic cell populations using image analysis with Hoechst 33342 and chromomycin A3, in vitro model systems ("sandwich" and regulated gas diffusion), and intrinsic cellular markers (stress protein patterns), and 3) application of an in vitro assay to study mechanisms of drug-induced neurotoxicity and strategies for preventing or ameliorating the neuropathy associated with SR 2508.