FACTORS AFFECTING BCNU/X-RAY INTERACTIONS IN VITRO

当将9 L大鼠脑肿瘤细胞接种到小鼠脑中时，观察到增强的细胞杀伤。 在体外立即或在最初几小时内用X射线照射 用1，3-双（2-氯乙基）-1-亚硝基脲（BCNU）处理后。 这 增强也可以在染色体和大分子上检测到。 水平，显然是X射线和 BCNU. X射线照射增加卡氮芥诱导的DNA形成 股间交联，这与增加， 姐妹染色单体交换（SCE）数量和细胞数量 杀人 关于这种相互作用的研究主要是在 指数生长的单层细胞，在大多数情况下是均匀的， 细胞在相同的O2张力和pH值下循环，并且具有类似的 对每种抗癌药物的敏感性。 这种情况并不存在于 实体瘤比单层肿瘤复杂得多， cultures. 当肿瘤生长超过其血管供应时，生理梯度 开发导致低O2张力和低pH值的微环境。这些 条件可以改变肿瘤细胞的生长状态和敏感性。 此外，耐药肿瘤亚群可在肿瘤生长期间形成。 在治疗过程中或选择。 我们的目的是确定 BCNU和X射线之间的相互作用是否受到条件的影响 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敏感的脑肿瘤细胞中， 并确定是否可以通过选择 外部代理人。 将从拟议的 研究应该帮助我们了解联合使用 卡努-辐射时间表，我们操纵细胞毒性的能力， 最终确定患者是否可以通过以下方式受益： 用这些药剂的选定组合治疗。 我们特别 目的：1）研究慢性低氧张力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9 L细胞中; 2）确定发生的相互作用是否 BCNU与X射线之间的作用依赖于9 L细胞的生长状态; 3)研究BCNU和X射线之间的相互作用， 9 L细胞系，其对BCNU具有不同水平的敏感性;以及，4）对 确定BCNU/X射线相互作用是否可以被两种药物改变 已知可改变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.