Our objectives are severalfold: A. To produce specific single-locus mutations from stable strains of mammalian cells growing in various environments of radiation and in combination with various carcinogenic and chemotherapeutic agents. B. To quantitate the relative and absolute probabilities of mutagenesis for the various agents mentioned above and combinations of same simulating approximately their use in clinical cancer therapy in order to assess the possibility of synergistic action. Very low dose rates of ionizing radiations are also to be used in order to possibly evaluate environmental dose rate effects. C. To quantitate the growth rate of selected mutants of mammalian cells maintained continuously under various concentrations of chemotherapeutic and mutagenic agents. Combinations of these various agents including ionizing radiation and representing typical clinical conditions encountered in cancer therapy are also to be studied for synergistic and/or cytotoxic effects. The effects of very small doses and dose rates of both drugs and ionizing radiations are also to be determined. D. To further identify, describe and assess the biochemical, biophysical and cytological differences between our established lines of radioresistant mutants and their common parental source. The attainment of these primary objectives will extend our understanding of those factors affecting radiation resistace and sensitization, mutagenesis and tumor growth under various conditions in current and proposed practice for cancer therapy. Lastly, the quantitation of both growth and rates of mutagenesis at very low dose rates can have import not only for highly fractionated therapy involving heat, drugs and radiation but also for the assessment of environmental contaminations.
