Cellular and Subcellular Studies of the Radiation Effects of Auger Electron-Emitting Estrogens

Abstract

We studied the effect of ¹²³I-labeled estrogen (¹²³I-E) in estrogen receptor (ER)-rich cells in culture and in cell free model systems in vitro to elucidate the nature of the radiotoxicity for ER + cells of estrogens containing nuclides which emit Auger electrons. In cells the ¹²³I-E caused a dose-dependent, unlabeled estrogen-inhibitable induction of chromosome aberrations. A dose of about 1000 decays per cell, which is approximately the mean lethal dose for these cells, resulted in an average of 1 chromosome break per cell. This supports the hypothesis that the lethal lesion induced by ¹²³I-E is a chromosome break. Incubation of ¹²³I-E/ER complex, but not ¹²³I-E alone, with 27-mer duplex estrogen response element (ERE) DNA produced a dose-dependent cleavage of the ERE. However, we were unable to detect any fragmentation of either the 66 kDa full length ER in cell extracts or a purified 31 kDa hormone binding domain when incubated with excess ¹²³I-E. Thus it appears that ¹²³I-E effects its radiotoxicity by binding to ER, associating with ERE DNA and, by directing high LET radiation to DNA, inducing lethal chromosome breaks.