RADIOSENSITIZATION AND CHEMOSENSITIZATION OF AERATED AND HYPOXIC MAMMALIAN CELLS

该项目的主要目标是确定各种方法， 导致有氧和有氧条件下细胞杀伤的辐射增强， 缺氧条件下，并更好地了解机制， 放射增敏 我们以前的工作中发现细胞内 谷胱甘肽（GSH）作为重要的管理细胞毒性的某些 化疗药物和乏氧细胞放射增敏。我们最近 表明两种新硝基咪唑类化合物对低氧辐射增敏作用， GSH耗竭显著增强。 与外科医生合作， 分支，我们已经测量了一些肺肿瘤活检的GSH水平 与正常肺GSH相比。我们的研究结果表明，1）精确 肿瘤细胞的GSH测量由于肿瘤细胞的浸润而变得复杂。 白细胞（在某些肿瘤中浸润超过总肿瘤的40 正常肺组织GSH值与正常肺组织GSH值无显著差异 3）多个肺鳞癌样本 活检中肿瘤细胞的GSH含量高出3-5倍 这些研究支持使用 GSH合成的抑制剂，可能增强辐射和 化疗的细胞毒性和临床试验已经开始 在其他机构测试这种可能性。 目前，我们正在 与一系列可能用于提高细胞中GSH的GSH酯， 组织的想法恢复细胞/组织正常的GSH水平 在耗尽和药物治疗后。 此外，我们还证明了 非致命性高温与持续低温同时实施 剂量刺激导致显著的放射增敏作用。这将是 进一步研究包括GSH耗竭。 最后，我们证明了 人类B系淋巴前体细胞对辐射敏感。

The major objectives of this project are to identify approaches that will result in radiation enhancement of cell killing both in aerobic and hypoxic conditions and to better understand mechanisms of radiosensitization. Much of our previous work identified intracellular glutathione (GSH) as important in governing the cytotoxicity of certain chemotherapy drugs and hypoxic cell radiation sensitizes. We have recently shown that hypoxic radiation sensitization by two new nitroimidazoles is markedly enhanced with GSH depletion. In collaboration with the Surgery Branch, we have measured GSH levels from a number of lung tumor biopsies and compared than to normal lung GSH. Our findings show that 1) precise GSH measurement of tumor cells are complicated by infiltration of leukocytes (infiltration in some tumors exceeded 40% of the total tumor mass) in lung tumors; 2) normal lung GSH values were remarkably constant among the 27 samples evaluated; 3) Several squamous lung cancer samples had populations of tumor cells in the biopsy with 3-5 fold higher GSH levels than found in normal lung, Such Studies support the idea of using an inhibitor of GSH synthesis to possibly enhance both radiation and chemotherapy cytotoxicity and indeed clinical trials have been initiated at other institutions to test this possibility. Presently we are working with a series of GSH esters that might be used to elevate GSH in cells and tissues with the idea of restoring cells/tissues to normal GSH levels after depletion and drug treatment. Additionally, we have demonstrated that non-lethal hyperthermia administered concurrently with continuous low dose irritation results in dramatic radiosensitization.This will be further explored including GSH depletion. Lastly, we have demonstrated that human B-lineage lymphoid precursor cells radiosensitive.