The long-term objectives of the research described in this application are to clarify the relationship between the development of resistance to chemotherapeutic agents and change in radiation response, to examine the genetic control of the development of drug resistance and change in radiation response, to determine the role of the cell membrane in the expression of radiation damage by use of drug-resistant membrane mutants, and to study the damage interactions between chemotherapeutic agents and radiation in drug-resistant cell populations. If the long-term objectives are realized, the data may provide important information in the treatment of patients who have failed chemotherapeutic strategies because of the selection and/or induction of drug-resistant tumor cells. V-79, Chinese hamster lung fibroblasts and their Adriamycin-resistant mutants will be used throughout these studies. Cell survival will be assessed by the capacity of cells to form colonies on petri dish surfaces. Survival properties to chemotherapeutic agents and to radiation, or combinations of these, will be measured. One-dimensional spectrophorectic techniques will be used to identify differences in membrane glycoprotein structure between cell lines of different drug-response-states. Intracellular concentrations of drug will be determined fluorometrically for those agents which have a chromophore as part of their chemical structure. The kinetics of drug uptake and release by whole cells relative to total drug concentration and drug bound to DNA will be determined. In addition to single dose radiation responses, the repair of sublethal and potentially lethal radiation injury will also be studied. The working hypothesis of the research described in this application is that the cell membrane represents and important structure with regard to the cytotoxicity of certain chemotherapeutic agents, particularly Adriamycin, and that the interaction of Adriamycin and radiation damage occurs predominately in that structure. The experimental approach will be designed to clarify the role of the cell membrane in the expression of radiation damage.
