Breaks in DNA accompany estrogen-receptor-mediated cytotoxicity from 16 alpha[125I]iodo-17 beta-estradiol.

Strategies for diagnosis and therapy in which sex steroid receptor ligands serve as carriers for radionuclides are attractive because a high incidence of carcinomas of the female genital tract and the breast that are seen clinically have an abundant expression of one or more of the receptor proteins. A radiohalogenated estrogen receptor (ER) ligand, 16 alpha-[123I]iodo-17 beta-estradiol [123I]E, has met clinical criteria for receptor-mediated diagnostic imaging. Its [125]I-labeled sister nuclide derivative [125I]E decays by orbital electron capture with emission of very-low-energy (Auger) electrons, which gives this latter radiohalogen the potential to serve in pharmaceuticals for radiotherapy; as examples, [125I]deoxyuridine, when incorporated into the DNA molecule, or [125I]E, when bound to the receptor within ER-rich tumor cells, are both cytotoxic in vitro. Whereas the mechanisms and subcellular changes that accompany the cytotoxicity from [125I]deoxyuridine are well documented in the form of aberrations and breaks in the cellular DNA, the effects at the subcellular level causing the cytotoxicity of the sex steroid receptor ligand [125I]E have not been characterized and are the focus of our study. We found that in a standard colony-forming assay the addition of [125I]E to the cultures decreased the survival rate of ER-positive MCF-7 cells in a dose-dependent manner. The decreased survival rate was prevented by the addition of competing excess radioinert ER ligand (diethylstilbestrol); [125I]E did not reduce survival in ER-negative MCF-7 cells. The [125I]E-induced and ER-mediated cytotoxicity was accompanied by aberrations in the DNA components of the nuclei of the cells. These included chromatid and chromosome breaks, gaps, and tri-radial chromosome formation. Our findings add plausibility and credence to the notion that the cytotoxicity imparted by Auger-electron-emitting radioligands for sex steroid receptors is in part attributable to radiodecay that causes double-stranded breakage of DNA.