The long term objective of our combined chemical, pharmacokinetic, and radiobiological studies is to develop a rational method for selecting radioprotective drugs which will be useful in clinical radiotherapy with low dose/fraction of photons or cyclotron neutrons. Mechanistic and pragmatic studies will be performed with WR2721 and phosphorothioate congeners to relate drug structure and metabolism to desirable biological properties, acceptable toxicity and ability to protect selected normal tissues more than tumors against radiation. Selected protectors will be evaluated in biodistribution and metabolism studies in vivo and in vitro. Partition coefficients, ability to cross cell membranes in an RBC model system, removal of the -PO3 group protecting the active SH group and breakdown to various metabolites will be measured. HPLC, GPC, LSC and diffusible substance autoradiography techniques will be applied to 35S labeled protectors synthesized in our research group. NMR will be used to measure metabolites of 33S labeled drugs. Protector metabolism in vivo will be compared with measures of endogenous thiols. Mouse ascites tumors (a model """"""""in vivo cell suspension"""""""") will be used as a screen. In vitro colony forming ability of tumor cells irradiated +/- protector will allow quantitation of radioprotection at multiple dose levels and may allow an estimate of modification of the single hit component of radiation injury, important for cell kill at low doses. Based on these combined data, we will select protectors in addition to WR 2721 for further testing in pragmatic studies with photons and cyclotron neutrons. Radioprotection will be measured in rats using functional and/or quantitative endpoints in three tissues which may be dose limiting in radiotherapy. These are: kidney (glomerular filtration rate, effective renal plasma flow, quantitative histology); salivary gland (saliva flow, electrolyte levels, production of enzymes of ductal and acinar origin); and brain (quantitative histopathology). Protection also will be measured in transplanted mouse tumors (RIF-1, EMT-6, KHT) irradiated in vivo and assayed by colony forming ability in vitro, to indicate potential for therapeutic gain.
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