Our long term objectives are to use biochemical principles to create metabolic states which increase the vulnerablity of human cancer cells to radiation. Our immediate concern is to determine the underlyng chemical and biochemical mechanisms involved in responses to radiation. We are interested in understanding the role of glutathione, protein and membrane thiols as well as NADPH in both the aerobic and hypoxic radiation response. We have three major specific aims: (1) To determine the importance of NADPH(generated via the pentonse cycle) in radical repair under hypoxic conditions, and hydrogen donor to glutathione or protein radicals, and as cofactor in reduction of oxidized glutathione. (2). To separate relative contritutions of electron transfer between hydrogen donors such as NADPH, GSH, protein thiols as well as the importance of enzymes in various aspects of hypoxic and aerobic radiation damage and repair. (3). To continue our studies on the importance of alterations in electron transfer as related to radiation damage under hypoxic conditions and inhibition of oxygen utilization under aerobic conditions. Our research will involve use of cells derived from human lung tumors, in particular the A549, small(SCLC) and large(LC) carcinoma lines. We have chosen these human cell lines over the classical rodent lines becasue there is evidence that they are considerably different in biochemical make-up and the difference may influence initial radiation damage and subsequent repair. Human lung tumors cultured in vitro resemble in vivo tumors with respect to radiation response. There is also evidence that in vitro conversions of SCLC cell(radiosensitive) lines to LC(radioresistant) is related to SCLC patient relapse and failure to respond to additional therapy. Our emphasis on these lines is also concerned with the fact that lung cancer is a major medical problem in the United States. Biochemical, chemicals and/or drugs will be employed to estblish a particular cellular state prior to irradiation. We plan to study long and plateu phase cells under hypoxic or aerobic conditions.
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