CHEMICAL MODIFIERS OF RADIATION AND CHEMOTHERAPY

描述(改编自申请人的摘要)：本申请 建议继续实施临床和实验室一体化计划，以 开发放射和化疗的化学修饰剂。申请人 已制定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，外束照射， 开发了硝基咪唑化学修饰剂的使用，并试行使用了 持续滴注增敏剂配合近距离放射治疗。他的初步数据 提示低氧细胞增敏剂可能会改善治疗结果 并可大幅提高前列腺癌间质治疗的疗效 辐射。根据临床结果和重要的生物学概念， 他将进行临床试验，以评估SR2508的疗效 前列腺癌的放射治疗，2)化疗加放疗 在局部晚期食道癌和膀胱癌中，3) BEAM和植入放射治疗乳腺癌和脑癌，以及4)AS 一种治疗多发性骨髓瘤的化学增敏剂。当谷胱甘肽耗尽时 经纪人L-BSO上市后，他将进行临床试验 在放射治疗的同时消耗谷胱甘肽。他的实验室 将继续为联合中心提供药理学支持 放射治疗和放射肿瘤学小组试验。最基本的 实验室计划旨在开发新的临床策略 用于克服低氧细胞的治疗抗性，特别是 强调间歇性缺氧的后果。正在进行的研究 包括：1)利用分割放射治疗肿瘤模型进行研究 体内低氧；2)低氧细胞群的图像研究 Hoechst 33342和显色霉素A3体外模型系统分析 (“三明治”和受控制的气体扩散)和固有的细胞标志物 (应激蛋白模式)，以及3)体外试验的应用 药物神经毒性的机制及预防策略 改善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.