RADIATION SENSITIZATION APPLIED TO CANCER RADIOBIOLOGY

涉及硫醇消耗试剂和 亲电子放射增敏剂作用于受照射的哺乳动物细胞， 文化研究既有独立的，也有互动的。 这将是 为了确定这些试剂和敏化剂， 联合使用，可能会改善癌症的放射治疗。 已经证明，缺氧细胞存在于并限制了局部 在某些分次方案下治疗的动物肿瘤的控制。 临床证据表明，类似的情况至少在 头部、颈部和骨盆的一些肿瘤通过常规治疗 分离技术。 迄今为止， 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由细胞代谢决定。 亲电子化合物现在是可用的，其优先敏化 低氧细胞，但迄今为止的临床成功受到限制，主要是 毒性问题。 从机械的考虑， 化学竞争模型提供了解释敏化作用，手段 除了氧取代之外，也可能产生希望，即通过使用试剂 以消除或结合那些可能在以下方面起重要作用的硫醇 首先保护缺氧细胞。 的行动 巯基在细胞放射增敏中的作用尚不清楚; 有证据表明，上述模型是不完整的， 致敏作用描述不充分。 对硫醇的兴趣一直是 从临床证据来看， 5-氧代脯氨酸尿症和有趣的新的巯基消耗的可用性， 试剂，例如，丁硫酰亚胺。 在这个项目中，我们计划 表征巯基消耗试剂对NPSH的作用 和/或与放射增敏相关的蛋白质相关硫醇 缺氧细胞和DNA损伤修复过程。 我们完善的 利用超高剂量率辐照的能力， 检查硫醇作用的时间尺度， 适当 硫醇试剂和亲电子化合物的组合 将寻求提供最大优先缺氧细胞 放射增敏，毒性最小。

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.