MECHANISMS OF CHEMOPOTENTIATION BY RADIOSENSITIZERS

辐射增敏剂米索硝唑、SR2508和RSU 1069目前 被考虑用于试图利用 它们增强各种化疗药物活性的能力 探员们。许多这样的试验将试图增加他们的能力 加强化疗药物对低氧的敏感性 细胞受到电离辐射。这些临床试验的成功将 取决于几个问题的答案。一定要把这一切 放射增敏剂在化学增强前由低氧细胞代谢 能拿到吗？化疗药物是不是应该在 某些内在能力需要加强的基础，还是应该加以选择 因为它是对抗特定肿瘤类型最有效的药物？如果 低氧是化学增强所必需的，细胞需要多长时间 在最大化学电势发生之前的低氧？速度有多快？ 在低氧细胞复氧时失去的化学增强能力？是 化学增强的时间-剂量关系由简单的或 复杂的时间剂量函数？ 而从动物肿瘤实验到临床情况的推断 总是微不足道的，然而，它比从 生理学和药动学的组织培养实验 参数有很大的不同。如果上面的问题是 在动物肿瘤系统中处理，肿瘤必须不包含可检测到的 低氧细胞。我们建议使用我们独特的9L大鼠脑瘤模型来 回答这些问题。脑内(I.C.)和皮下(S.C.)9L 肿瘤中没有可检测到的低氧细胞。然而，S.C.9L肿瘤可以 钳制以产生完全可逆的缺氧状态 把夹子取下来。夹具不会改变后续的 两种亚硝脲BCNU和CCNU的药代动力学9L肿瘤将是 用咪唑、SR2508或RSU 1069治疗，然后夹闭或 没有被夹住。随后，用亚硝脲处理BCNU、CCNU或 去掉钳子后用氯佐菌素测定细胞存活率24小时 稍后用体内到体外的测试将允许前两个问题 等待回答。夹住放射增敏剂处理过的S.C.肿瘤治疗 亚硝脲治疗前和治疗前的不同时间段 在打开放射增敏剂后的不同时间使用亚硝脲 治疗过的S.C.肿瘤应该为后三个问题提供答案 问题。显然，这是9L肿瘤模型的独特特征 使这些实验成为可能。

The radiation sensitizers misonidazole, SR2508 and RSU 1069 are presently being considered for use in clinical trials that attempt to take advantage of their ability to potentiate the activity of various chemotherapeutic agents. Many of these trials will attempt to add their ability to potentiate chemotherapeutic agents to their ability to sensitize hypoxic cells to ionizing radiation. The success of these clinical trials will depend on the answers to several questions. Must all these radiosensitizers be metabolized by hypoxic cells before chemopotentiation can be obtained? Should the chemotherapeutic agent be selected on the basis of some inherent ability to be potentiated or should it be selected because it is the most effective agent against a particular tumor type? If hypoxia is required for chemopotentiation, how long must the cells be hypoxic before the maximum chemopotentiation occurs? How rapidly is the ability to chemopotentiate lost upon reoxygenation of hypoxic cells? Is the time-dose relationship for chemopotentiation governed by a simple or complex time-dose function? While extrapolation from animal tumor experiments to the clinical situation is always tenuous, it is nevertheless preferable to extrapolation from tissue culture experiments where physiological and pharmacokinetic parameters are substantially different. If the above questions are to be addressed in an animal tumor system, the tumor must contain no detectable hypoxic cells. We propose to use our unique 9L rat brain tumor model to address these questions. Intracerebral (i.c.) and subcutaneous (s.c.) 9L tumors contain no detectable hypoxic cells. However, s.c. 9L tumors can be clamped to produce a state of hypoxia that is completely reversible upon removing the clamp. The clamp does not alter the subsequent pharmacokinetics of two nitrosoureas, BCNU and CCNU. 9L tumors will be treated with misonidazole, SR2508 or RSU 1069 and then either clamped or left unclamped. Subsequently, treating with the nitrosoureas BCNU, CCNU or chlorozotocin after removal of the clamp and measuring cell survival 24 hr later with an in vivo to in vitro assay will allow the first two questions to be answered. Clamping the radiosensitizer treated s.c. tumors for various periods of time before treating with the nitrosoureas and treating with the nitrosoureas at various times after unclamping the radiosensitizer treated s.c. tumors should provide the answers to the last three questions. Clearly, it is the unique characteristics of the 9L tumor model that make these experiments possible.