DeSombre E R, Shafii B, Hanson R N, Kuivanen P C, Hughes A
Ben May Institute, University of Chicago, Illinois 60637.
Cancer Res. 1992 Oct 15;52(20):5752-8.
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 alpha(-)[123I]-iodo-11 beta-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.
为评估使用含俄歇电子发射配体的雌激素受体导向疗法治疗含雌激素受体（ER）癌症的可行性，我们合成并评估了几种123I标记雌激素对培养物中ER+细胞的放射毒性。此前已表明，俄歇电子射程较短，通常小于细胞尺寸，因此要将其用于治疗，需要一种机制将发射俄歇电子的核素递送至DNA附近。由于现已明确，雌激素受体与雌激素结合后，会与DNA中不同的雌激素反应元件形成高亲和力结合，我们希望验证以下假设：细胞短暂暴露于123I标记的雌激素会对ER+细胞产生特异性放射毒性，且细胞杀伤所需的每个细胞衰变次数与合理的受体占有率水平相符。通过与几种雌激素的三丁基锡前体及市售碘-123进行卤代锡烷化反应，我们以高比活度制备了碘雌激素，即E-17α(-)[123I]-碘-11β-甲氧基雌二醇和2(-)[123I]碘-1,1-双（4-羟苯基）-2-苯乙烯，在某些情况下，其比活度基本达到123I本身的比活度，即240,000 Ci/mmol。当将不同浓度的任一123I标记雌激素与ER+中国仓鼠卵巢细胞亚系孵育1小时，然后洗涤细胞并进行存活测定时，观察到存活呈剂量依赖性、可被未标记雌二醇抑制的降低。相比之下，不表达雌激素受体的中国仓鼠卵巢细胞对123I标记雌激素的放射毒性几乎不敏感。根据测定的碘雌激素在细胞中的停留时间进行的计算表明，每个细胞几百次衰变足以杀死细胞。
