FACTORS AFFECTING BCNU/X-RAY INTERACTIONS IN VITRO

当 9L 大鼠脑肿瘤细胞被观察到增强的细胞杀伤力 立即或在最初几个小时内用 X 射线进行体外照射 用 1,3-双(2-氯乙基)-1-亚硝基脲 (BCNU) 处理后。 这个 还可以在染色体和大分子上检测到增强 水平，显然是 X 射线和 BCNU。 X 辐射增加 BCNU 诱导 DNA 的形成 链间交联，这与链间交联的增加相关 姐妹染色单体交换 (SCE) 的数量和细胞数量 杀戮。 关于这种相互作用的研究主要针对 呈指数增长的单层细胞，在大多数情况下是同质的 细胞在相同的 O2 张力和 pH 条件下进行循环，并且具有相似的 对每种抗癌药物的敏感性。 这种情况不存在于 实体瘤，比单层肿瘤更加复杂和异质 文化。 当肿瘤生长超过其血管供应时，生理梯度 的发展导致低 O2 张力和低 pH 的微环境。 这些 条件可以改变肿瘤细胞的生长状态和敏感性。 此外，在肿瘤发生过程中可能会出现耐药肿瘤亚群。 进展或在治疗期间进行选择。 我们的目的是确定 BCNU与X射线的相互作用是否受条件影响 已知存在于实体瘤中，以确定是否存在类似的相互作用 发生在对 BCNU 有一系列敏感性的脑肿瘤细胞中， 并确定交互是否可以通过选定的进行修改 外部代理。 从提议中产生的信息 研究应该有助于我们了解组合产生的细胞毒性 BCNU 辐射时间表、我们操纵细胞毒性的能力，以及 最终确定患者是否可以受益 使用这些药物的选定组合进行治疗。 具体来说，我们 建议：1）研究慢性和急性低氧张力的影响 和/或酸性 pH 值对 BCNU 和 X 射线之间发生的相互作用的影响 在单层 9L 细胞中； 2）判断是否发生交互作用 BCNU 和 X 射线之间的差异取决于 9L 细胞的生长状态； 3）研究BCNU和X射线在两种变体中的相互作用 对BCNU有不同程度敏感性的9L细胞系；以及，4) 至 确定两种试剂是否可以改变 BCNU/X 射线相互作用 已知可以改变 BCNU 和/或 X 射线的细胞毒性作用。

An enhanced cell kill is observed when 9L rat brain tumor cells are irradiated in vitro with X rays immediately or during the first few hours after treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). This enhancement can also be detected on the chromosomal and macromolecular levels, and is apparently the result of an interaction between X rays and BCNU. X irradiation increases the formation of BCNU-induced DNA interstrand crosslinks, which correlates with an increase in both the number of sister chromatid exchanges (SCEs) and in the amount of cell killing. Studies on this interaction have been conducted primarily on exponentially growing monolayer cells, which are homogeneous in that most cells are cycling, at the same O2 tension and pH, and have similar sensitivities to each anticancer agent. This situation does not exist in solid tumors, which are much more complex and heterogeneous than monolayer cultures. As tumors outgrow their vascular supply, physiological gradients develop that lead to microenvironments of low O2 tension and low pH. These conditions can alter the growth status and sensitivity of the tumor cells. In addition resistant tumor subpopulations may develop during tumor progression or be selected during treatment. Our purpose is to determine whether the interaction between BCNU and X rays is influenced by conditions known to exist in solid tumors, to determine whether a similar interaction occurs in brain tumor cells that have a spectrum of sensitivities to BCNU, and to determine whether the interaction can be modified by selected external agents. The information that will accrue from the proposed studies should help us to understand the cytotoxicity produced by combined BCNU-radiation schedules, our ability to manipulate the cytotoxicity, and ultimately in the determination of whether patients might benefit by treatment with selected combinations of these agents. Specifically, we propose: 1) to study the effects of chronic and acute low oxygen tension and/or an acidic pH on the interactions that occur between BCNU and X rays in monolayer 9L cells; 2) to determine whether the interactions that occur between BCNU and X rays are dependent on the growth status of the 9L cells; 3) to study the interaction between BCNU and X rays in two variants of the 9L cell line that have different levels of sensitivity to BCNU; and, 4) to determine whether the BCNU/X-ray interaction can be altered by two agents known to modify the cytotoxic effects of BCNU and/or X rays.