COMPARISON OF THE EFFECTS OF A PURE STEROIDAL ANTIESTROGEN WITH THOSEOF TAMOXIFEN IN A MODEL OF HUMAN BREAST-CANCER

Background: Tamoxifen, a nonsteroidal estrogen antagonist, is the most prescribed drug for the treatment of breast cancer. The use of tamoxi fen is limited, however, by the development of resistance to this comp ound in most patients. Although tamoxifen behaves primarily as an estr ogen antagonist, it has agonist (or growth-stimulatory) activity as we ll. ICI 182,780 is a 7 alpha-alkylsulfinyl analogue of estradiol lacki ng agonist activity. The absence of agonist activity may make this ste roidal antiestrogen superior to tamoxifen in suppressing tumor cell gr owth. Purpose: We compared the inhibitory effects of ICI 182,780, tamo xifen, and estrogen withdrawal on the growth of established tumors and on tumorigenesis in a model system that uses estrogen-dependent, huma n MCF-7 breast tumor cells growing in athymic nude mice. We also studi ed the hormonal responsiveness of tumors that became resistant to the two estrogen antagonists and the effects of these drugs on estrogen-re gulated gene expression. Methods: MCF-7 cells were injected subcutaneo usly into the flanks of castrated, female nude mice. The effects of re peated doses of tamoxifen and ICI 182,780 (500 mu g and 5 mg, respecti vely) on the growth of established tumors (8-10 mm in size) were deter mined after supplemental estrogen was removed. The effects of antiestr ogen treatments on the process of tumorigenesis, in the absence of est rogen supplementation, were determined by initiating drug administrati on on the same day as tumor cell inoculation. To evaluate the hormonal responsiveness of tumors resistant to tamoxifen and ICI 182,780, 1-mm (3) segments of the tumors were transplanted onto the flanks of new re cipient mice, which were then treated with estrogen or the antiestroge ns-alone or in combination. Tumor growth was monitored by measuring tu mor volumes twice a week. Expression of the estrogen-responsive genes, pLIV1 and pS2, in the tumors of treated animals was analyzed using bl ots of total cellular RNA and complementary DNA probes. Results: Treat ment with ICI 182,780 suppressed the growth of established tumors twic e as long as treatment with tamoxifen or estrogen withdrawal. Tumorige nesis, in the absence of supplemental estrogen, was delayed to a great er extent in ICI 182,780-treated mice than in tamoxifen-treated mice. ICI 182,780 was found to be more effective than tamoxifen in reducing the expression of estrogen-regulated genes. Most tumors eventually bec ame resistant to ICI 182,780 and grew independently of estrogen. Concl usions: ICI 182,780 is a more effective estrogen antagonist than tamox ifen in the MCF-7 tumor cell/nude mouse model system.