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Estrogen Receptor-directed Radiotoxicity with Auger Electrons: Specificity and Mean Lethal Dose¹

Ben May Institute, University of Chicago, Chicago, Illinois 60637 [E. R. D., B. S., P. C. K., A. H.], and Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Northeastern University, Boston, Massachusetts 02115 [R. N. H.]

To assess the feasibility of using estrogen receptor-directed therapy with Auger electron-emitting ligands for therapy of estrogen receptor (ER)-containing cancers, we synthesized and evaluated the radiotoxicity of several ¹²³I-labeled estrogens to specifically kill ER+ cells in culture. Auger electrons have been previously shown to be of short range, generally less than the dimensions of a cell, so that to use them therapeutically a mechanism is needed to deliver the Auger electron-emitting nuclide to the vicinity of the DNA. Since it is now well established that the estrogen receptor, when bound to estrogen, forms a high affinity association with distinct estrogen response elements in the DNA, we wished to test the hypothesis that a short exposure of cells to a ¹²³I-labeled estrogen would be specifically radiotoxic to ER+ cells, and that the decays per cell needed for cell killing would be compatible with reasonable levels of receptor occupancy. Using the halodestannylation reaction with tributyl tin precursors of several estrogens and commercially available iodine-123, we prepared the iodoestrogens, E-17-[¹²³I]-iodo-11ß-methoxyestradiol and 2-[¹²³I]iodo-1,1-bis(4-hydroxyphenyl)-2-phenylethylene, at high specific activities, in several cases at essentially the specific activity of ¹²³I itself, 240,000 Ci/mmol. When various concentrations of either of the ¹²³I-labeled estrogens were incubated for 1 h with a subline of ER+ Chinese hamster ovary cells and the washed cells plated for survival assays, a dose-dependent, unlabeled estradiol-inhibitable reduction in survival was observed. In contrast, Chinese hamster ovary cells not expressing estrogen receptor showed little sensitivity to the radiotoxicity of the ¹²³I-labeled estrogens. Calculations based on the assayed residence time of the iodoestrogens in the cells indicate that several hundred decays per cell are sufficient to kill cells.

¹ Supported by the NIH (CA49906) and Dow Chemical Company.

² To whom requests for reprints should be addressed, at The Ben May Institute, The University of Chicago, MC 6027, 5841 South Maryland Avenue, Chicago, IL 60637.

Received 5/11/92. Accepted 8/ 4/92.

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