REZEPTOR-VERMITTELTE ANREICHERUNG DES INTRAVENOS APPLIZIERTEN RADIOZYTOTOXISCHEN OSTROGENS 16ALPHA-[¹²³I]IOD-OSTRADIOL-17BETA IM RATTENUTERUS

Although more than 50% of adenocarcinomas of the female genital tract and breast express steroid hormone receptors in the nuclei of tumor cells, only a fraction of these receptor positive tumors respond to endocrine therapy. Heterogeneity of ER-expression in tumors, the existence of non-functioning receptor proteins, and overshooting of non-steroidal regulation mechanisms may account for this. Steroid hormone receptors accumulate their ligands specifically and selectively in the cell nucleus. Therefore, strategies for therapy proposing the use of steroid hormones as vehicles to target radionuclides to tumor cells are attractive because radionuclides with emissions of extreme short range (Auger electrons) deposit lethal doses of ionizing radiation to single cells, potentially without affecting neighboring cells. We have already demonstrated the selective, ER-mediated radiocytotoxicity of Auger- or conversion electrone-emitting radiosteroids (e.g. 16alpha-[¹²⁵I]iodo-estradiol-17beta = [¹²⁵I]E, [¹²³I]E) in vitro. The present study tested the biodistribution and elimination of intravenously administered [¹²³I]E in female rats at defined time points (1 until 24 hours after injection). High levels of radioactivity were measured in uterus, could be inhibited by DES, and peaked at approximately 2 hours after injection to an absolute and relative maximum over blood (uterus/blood 60:1). Radioactivities in other organs were low except for thyroid and liver, 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 24 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 radioactivity was influenced by unspecific binding in tissues and by accumulation of the radiopharmaceutical in organs which metabolize (liver), excrete (gut) the radioestrogen or accumulate metabolites (thyroid).