Antagonism of oestrogen action in human breast and endometrial cells in vitro: potential novel antitumour agents.

PURPOSE: There is a need to find novel oestrogen receptor (ER) ligands that antagonize oestrogen action in the reproductive tissues and would therefore have therapeutic potential in oestrogen-dependent tumours. We tested novel ER ligands in both breast and endometrial cells to profile agonism/antagonism in these oestrogen target reproductive tissues. METHODS: Novel analogues of the ER antagonist ICI 182,780 were synthesized and tested for their ability to inhibit gene expression dependent on oestrogen response elements (ERE) in human breast (MCF-7) and endometrial (Ishikawa) cell lines. This activity was correlated with inhibition of oestrogen-induced cell proliferation and ER binding. RESULTS: The sulphide analogue (compound 1) and sulphone analogue (compound 2) had no intrinsic ERE-dependent agonism in either breast cancer or endometrial cells in culture. All three compounds dose-dependently inhibited ERE-mediated oestrogen agonism. Moreover, these ER ligands inhibited oestrogen-stimulated proliferation of breast cancer and endometrial cells. ICI 182,780, compound 1 and compound 2 were all able to bind both isoforms of the ER (ER alpha and ER beta). In endometrial cells, the relative binding to ER beta correlated with the ERE-dependent antioestrogenic effect of these ligands, suggesting that in this tissue this receptor is the predominant isoform that determines antioestrogenic activity. CONCLUSIONS: The ability of these analogues of ICI 182,780 to inhibit oestrogen-stimulated transcriptional activity and cell proliferation suggests that these agents, in particular the sulphone analogue, have therapeutic potential in the treatment of breast cancer without exhibiting the unwanted oestrogenic effects in the endometrium.

Fibroid calcification after uterine artery embolization: ultrasonographic appearance and pathology.

PURPOSE: To describe the ultrasonographic (US) appearance of fibroid calcification occurring after uterine artery embolization (UAE) and discuss its etiology and pathology. MATERIALS AND METHODS: Twenty-seven of a total of 38 patients were followed up clinically and with duplex US for longer than 6 months after UAE for uterine fibroids. At US, changes in uterine size, fibroid vascularity, and morphology have been recorded. Pathologic studies were performed by one of the authors on resected specimens from a different cohort of patients, at intervals ranging from 4 months to 1 year after UAE. RESULTS: Twenty patients reported complete resolution of symptoms. In 16 of these, a reduction in fibroid volume of 70%-85% was recorded and, at US, the development of a peripheral hyperechoic rim around an increasingly hypoechoic fibroid was noted. Computed tomography in two patients revealed it to be a rim of calcium. Histologic studies in a different cohort of patients who had undergone hysterectomy at variable intervals after UAE demonstrated early aggregation of polyvinyl alcohol (PVA) particles, an intermediate giant cell inflammatory reaction, and calcification in the periphery of the infarcted fibroid at 6-12 months. CONCLUSION: Calcification is the end stage of hyaline degeneration. However, its peripheral location is unlike that of natural fibroid involution and hyaline necrosis. Pathologic studies in resected human fibroids after embolization suggest that its development is the end result of aggregation of PVA particles in peripheral fibroid arteries.