TISSUE-SELECTIVE ACTION OF TAMOXIFEN METHIODIDE, RALOXIFENE AND TAMOXIFEN ON CREATINE-KINASE-B ACTIVITY IN IN-VITRO AND IN-VIVO

We have compared the cell and tissue selective estrogenic and antiestr ogenic activities of tamoxifen, raloxifene, ICI 164,384 and a permanen tly ionized derivative of tamoxifen - tamoxifen methiodide (TMI). This non-steroidal antiestrogen has limited ability to cross the blood bra in barrier and is therefore less likely to cause the central nervous s ystem disturbances caused by tamoxifen. We have used the stimulation o f the specific activity of the ''estrogen induced protein'', creatine kinase BE, as a response marker in bone, cartilage, uterine and adipos e cells and in rat skeletal tissues, uterus and mesometrial adipose ti ssue. In vitro, TMI, tamoxifen and raloxifene mimicked the agonistic a ction of 17 beta-estradiol in ROS 17/2.8 rat osteogenic osteosarcoma, female calvaria, and SaOS(2) human osteoblast cells. In Ishikawa endom etrial cancer cells, tamoxifen showed reduced agonistic effects and ra loxifene showed no stimulation. However, as antagonists, tamoxifen and raloxifene were equally effective in Ishikawa or SaOS(2) cells. In im mature rats, all four of the antiestrogens inhibited estrogen action i n diaphysis, epiphysis, uterus and mesometrial adipose tissue; when ad ministered alone, tamoxifen stimulated creatine kinase (CK) specific a ctivity in all these tissues. Raloxifene and TMI, however, stimulated only the skeletal tissues and had no stimulatory effect in the uterus or mesometrial fat, and the pure antiestrogen ICI 164,384 showed no st imulatory effect in any of the tissues. The simultaneous injection of estrogen, plus an antiestrogen which acted as an agonist, resulted in lower CK activity than after injection of either agent alone. These di fferential effects, in vivo and in vitro, may point the way to a wider therapeutic choice of an appropriate antiestrogen which, although ant agonizing E(2) action in mammary cancer, can still protect against ost eoporosis and cardiovascular disease and not stimulate the uterus with its attendant undesirable changes, or interfere with the beneficial a ction of E(2) in the brain. Copyright (C) 1996 Elsevier Science Ltd.