The overall objective of the proposed research is to develop new strategies in radiation oncology using the Auger effect of iodine-125 and the alpha emissions of astatine-211. We will also synthesize and evaluate the cytotoxicity of radiolabeled steroids and peptide hormones. We will expand our understanding of receptor-mediated cytotoxicity using iodinated steroid hormones and their analogues. We will apply the strategies developed for breast cancer to other steroid receptor containing tumors (viz., endometrium and prostate). Both approaches offer the potential of specifically localizing lethal amounts of ionizing radiation within target tumors while sparing the surrounding normal tissue. We will synthesize position specific, carrier-free 125-I-labeled estrogens and progestins with high receptor affinity, prolonged nuclear retention time and low non-specific binding. The goals can be accomplished using flourine substituted estrogen, 11b-methoxy substitutions and mesylate/chloromethyl derivatives. We will synthesize several progesterones including fluorinated derivatives, iodo- megesterol, an agent with enhanced PgR affinity, and iodomibolerone which binds to both progesterone and androgen receptors. We will synthesize 211-At-labeled steroids and peptide hormones (viz., prolactin and oxytocin) which, on the basis of 125-I studies, show high receptor affinity for breast cancer cells. We will also determine the cytotoxicity of these compounds in breast cancer cell lines. We will study the in vivo distribution and therapeutic activity of 125-I and 211-At labeled steroid and peptide ligands in experimental tumor models - MCF-7 cells in athymic mice, DMBA mammary tumors, LNCaP prostatic carcinoma and MTW9 mammary adenocarcinoma. This proposal aims to answer general quantitative questions about the potential use of Auger and alpha emitters for radiation therapy. The research has significance at two levels - in the field of oncology, the emphasis is on the possibility of using the radiotoxicity of Auger and alpha emitters for cancer treatment; in the field of cellular and molecular radiation biology, the emphasis is on the mechanism of action of alpha particles and the Auger effect.