The basic objective of this research project is to gain further information about the mechanism of radiation carcinogenesis induced by x-rays or UV light in in vitro assay systems. We will investigate interactions between radiation and chemical agents in the induction of malignant transformation in vitro. The specific chemical agents we are studying have known interactive effects on carcinogenesis in vivo, and have been observed to enhanced or suppress the induction of malignant cells in vitro by radiation. Many of the studies will be focussed on the mechanism(s) for the observed suppressive effects of protease inhibitors on malignant transformation induced by radiation. Studies on the mechanisms involved in the induction of radiation transformation and its modification by chemical agents in an in vitro system, in which cellular proliferation and other environmental conditions can be precisely controlled, should yield much information about the mechanisms involved in radiation induced cancer. Specifically, during the present grant period we will attempt to determine whether the following phenomena are involved in radiation transformation in vitro and its modification by chemical agents: oncogenes (involving studies on myc and ras), amplification of specific DNA sequences, proteoltyic activity (Boc-val-pro-arg-MCA hydrolyzing activity), free radical intermediates and growth factor processing. We plan to utilize several different in vitro transformation system in our studies including rat embryo fibroblasts. NIH 3T3 cells and human diploid (1522) cells, but most of our transformation studies will continue to be performed in C3H10T1/2 cells. In addition to our studies designed to determined the mechanisms involved in radiation transformation and its modification by chemicals, our studies also have a practical aim. Many of our studies will be performed with compounds which show promise as human cancer chemopreventive agents, with the aim of evaluating them for use as nontoxic dietary supplements to prevent the development of cancer in human populations.
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