BIODISTRIBUTION OF THE SELECTIVELY CYTOTOXIC RADIOHALOGENATED ESTROGEN-RECEPTOR LIGAND 16ALPHA-[I-123]IOD-ESTRADIOL-17BETA IN ADULT-RATS FOLLOWING IV APPLICATION

Although more than 50 % of adenocarcinomas of the female genital tract and breast express steroid hormone receptors in the nuclei of tumor c ells, only a fraction of these receptor positive tumors respond to end ocrine therapy. Heterogenity of ER-expression in tumors, the existence of non-functioning receptor proteins, and overshooting of non-steroid al regulation mechanisms may account for this. Steroid hormone recepto rs accumulate their ligands specifically and selectively in the cell n ucleus. Therefore, strategies for therapy proposing the use of steroid hormones as vehicles to target radionuclides to tumor cells are attra ctive because radionuclides with emissions of extreme short range (Aug er electrons) deposit lethal doses of ionizing radiation to single cel ls, potentially without affecting neighboring cells. We have already d emonstrated the selective, ER-mediated radiocytotoxicity of Auger- or conversion electrone-emitting radiosteroids (e.g. 16alpha-[I-125]iodo- estradiol-17beta = [I-125]E, [I-123]E) in vitro. The present study tes ted the biodistribution and elimination of intravenously administered [I-123]E in female rats at defined time points (1 until 24 hours after injection). High levels of radioactivity were measured in uterus, cou ld be inhibited by DES, and peaked at approximately 2 hours after inje ction to an absolute and relative maximum over blood (uterus/blood 60: 1). Radioactivities in other organs were low except for thyroid and li ver, where high values were observed (maximum 90:1 and 15:1 over blood , respectively). The i.v. injected radioactivity was rapidly excreted into gut and urine exceeding 50 % and 80 % of injected dose at 1 and 2 4 hours, respectively. These results demonstrate a quantitatively and qualitatively different retention of radioestradiol in ER-rich uterus and nontarget organs. Next to binding to ER, biodistribution of radioa ctivity was influenced by unspecific binding in tissues and by accumul ation of the radiopharmaceutical in organs which metabolize (liver), e xcrete (gut) the radioestrogen or accumulate metabolites (thyroid).