This project will investigate aminoalkylthiol radioprotective drugs and has two distinct but complementary goals: to study the mechanisms of these drugs' effects and to develop pragmatic applications for radiation therapy. Several questions are posed. How are radioprotective drugs taken up across biological membranes and distributed at the subcellular, cellular and tissue level? How are the drugs metabolized and by what mechanisms do these metabolites ameliorate radiation injury and interact with endogenous protective substances? How may the effects of these drugs be quantified in terms of direct radioprotection as well as other biological endpoints that modify expression of radiation injury? What can be learned about their application through pragmatic preclinical studies? The specific aims will address these questions in systems of increasing complexity, beginning with in vitro cell-free systems such as liposomes, DNA and enzymes in solution, and homogenates prepared from normal and malignant cells. Cultured cells from rodent sarcomas and gliomas and from normal rat and human neural tissue as well as cell isolated from liver and kidney will be used to investigate and correlate protector uptake, metabolism, and protective effect. Protective studies in vivo will emphasize temporal or spatial localization of radioprotectors to selected rodent normal tissues but not tumors. Possible differential protection of normal CNS relative to brain tumors, protection of liver by drugs targeted to that organ via specific receptor ligands, and protection of normal tissue against radiation from I-131 labeled monoclonal antibodies prior to their concentration in tumor will be tested as applications of drug targeting. To support these biological aims new molecules, including lipophilic protectors capable of crossing the blood brain barrier, thiols with less polar latentiating groups, and thiols coupled to receptor specific ligands will be synthesized and labeled with H-3 or S-35. Analytical techniques (HPLC, TLC, autoradiography) will be developed and used.
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