Receptor binding and biological effects of three 125I-iodinated estrogen derivatives in human breast cancer cells (MCF-7)

Abstract

Three 125I-iodinated estrogen derivatives; 16α-[ 125I]iodo-11β-methoxy-17β-estradiol ([ 125I]IME 2), E-17α-[ 125I]iodovinylestradiol ([ 125I]IVE 2) and E-17α-[ 125I]iodovinyl-11β-methoxyestradiol ([ 125I]MIME 2) were synthesized with high specific activities and their binding characteristics and biological effects were analyzed in vitro using the estrogen-receptor-positive human breast cancer cell line MCF-7. Direct and competitive bindings in a whole cell assay indicated that the three derivatives bound to the estrogen receptor (ER) with high affinity. The dissociation constants of the three compounds were higher than the one found for tritiated E 2 suggesting that the presence of the methoxy and the vinyl groups decreased the binding affinity. The decreasing affinity order is: [ 3 H] E 2 ⩾ [ 125 I] IVE 2 > [ 125 I] IVE 2 > [ 125 I] MIVE 2 . The three unlabeled derivatives as well as E 2 have been found to activate the vitellogenin promoter fused to the chloramphenicol acetyl transferase reporter gene transfected into MCF-7 cells. This assay showed that the ER is activated in the presence of the three compounds. Unlabeled IME 2 produced stimulatory effects similar to those of E 2 on MCF-7 growth in vitro. Unlabeled IVE 2 and MIVE 2 at concentrations lower than 10 −8 enhanced MCF-7 growth but a lower level that E 2 and IME 2 did. Our results clearly indicate that the three derivatives behave like estrogens and that they would be excellent candidates for imaging or monitoring ER-containing breast tumors. Because its affinity for the ER is greatest, IME 2 would be the best-suited of the three as a radiotracer.