RADIATION SENSITIZATION APPLIED TO CANCER RADIOBIOLOGY

辐射敏化应用于癌症放射生物学

• 批准号: 3164997
• 负责人: EDWARD R EPP
• 金额: $ 25.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1975
• 资助国家: 美国
• 起止时间: 1975-06-01 至 1989-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3164997
• 关键词: cell population study; cytotoxicity; hypoxia; imidazole; ionizing radiation; neoplasm /cancer radiation therapy; oxygen consumption; oxygen tension; physical chemical interaction; pulse radiolysis; radiation recovery; radiation sensitivity; radiopharmacology; radiosensitizer; relative biological effectiveness; thiols; tissue /cell culture

The effects and mechanisms which involve thiol-depleting reagents and electron-affinic radiosensitizers acting on irradiated mammalian cells in culture will be studied both independently and interactively. This will be done with the view to determining how such reagents and sensitizers, manipulated in combination, might improve the radiation therapy of cancer. It has been demonstrated that hypoxic cells exist in and limit the local control of animal tumors treated under some fractionated regimens. Clinical evidence suggests that a similar situation obtains for at least some tumors of the head, neck and pelvis treated by conventional fractionated techniques. Much of the attention to date in dealing with hypoxic cells has been focussed on seeking substitutes for oxygen in view of its limited tumor penetrability set by cell metabolism. Electron-affinic compounds are now available which preferentially sensitize hypoxic cells but clinical success to date has been restrained, chiefly by toxicity problems. From mechanistic considerations of the oft-quoted chemical competition model offered to explain sensitizing action, means other than oxygen substitution may yield promise, namely, by using reagents to eliminate or bind those thiols which may play an important role in affording protection to the hypoxic cells in the first place. The actions and roles of thiols in cell radiosensitization are not well understood; evidence is available indicating that the above model is an incomplete and inadequate description of sensitizing action. Interest in thiols has been heightened recently both from clinical evidence on patients suffering from 5-oxoprolinuria and by the availability of interesting new thiol-depleting reagents, e.g., buthionine sulfoximine. In this project we plan to characterize those actions of thiol-depleting reagents acting on NPSH and/or protein-associated thiols which are relevant to radiosensitization of hypoxic cells and to DNA damage repair processes. Our well-established capabilities with ultra-high dose rate irradiation will be exploited to examine the time scale of thiol action where important and where appropriate. Combinations of thiol reagents and electron-affinic compounds will be sought which offer maximum preferential hypoxic cell radiosensitization with minimum toxicity.

去硫醇试剂和去硫醇试剂的作用和机制 电子亲和型放射增敏剂作用于受照射的哺乳动物细胞 文化将被独立和互动地研究。这将是 这样做的目的是为了确定这种试剂和敏化剂如何， 联合操作，可能会改善癌症的放射治疗。 已有研究表明，低氧细胞存在于并局限于局部。 一些分割方案治疗的动物肿瘤的控制。 临床证据表明，类似的情况至少在 常规手法治疗头颈部及盆腔肿瘤 分级技术。到目前为止，在处理 低氧细胞一直专注于寻找氧气的替代品。 其有限的肿瘤穿透性是由细胞代谢决定的。 现在有了电子亲和化合物，它们优先敏化 低氧细胞，但到目前为止，临床成功一直受到限制，主要是由于 毒性问题。从机械的角度考虑经常被引用的 提供化学竞争模型来解释敏化作用、手段 而不是氧替代可能产生希望，即通过使用试剂 清除或结合那些可能在…中起重要作用的硫醇 首先为缺氧细胞提供保护。行动 硫醇在细胞放射增敏中的作用还不是很清楚； 有证据表明，上述模型是不完整的， 对致敏作用的描述不充分。对硫醇的兴趣一直是 最近，从临床证据来看，这两种疾病都患有 5-氧代脯氨酸尿症和有趣的新的硫醇耗竭的可用性 试剂，例如丁硫氨酸亚磺胺。在这个项目中，我们计划 硫醇耗竭试剂对NPSH作用的特征 和/或与放射增敏相关的蛋白质相关硫醇 对缺氧细胞和DNA损伤修复过程的影响。我们久负盛名 超高剂量率辐射能力将被开发出来 检查硫醇作用的时间尺度，哪里重要，哪里 恰如其分。硫醇试剂和电子亲和化合物的组合 将寻找提供最大优先低氧细胞的 放射增敏，毒性最小。