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.
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