New vs old fashioned oestradiol antagonists in mammary carcinoma: 'In vitro' and 'in vivo' pharmacological approaches

The rationale underlying therapeutic strategies designed to inhibit the act ion of endogenous sex hormones in malignant breast cells is provided by the demonstration of their involvement in supporting the development and growt h of breast carcinoma. The surgical removal of steroid-secreting glands, in order to reduce the level of oestrogens reaching their target tissues, has for years been substituted by the so-called endocrinotherapeutic approach, which is based on the counteraction of the steroid hormone activity by the hormonal receptor blockade with suitable antioestrogenic compounds. Over t he past 25 years, the non-steroidal oestrogen antagonist tamoxifen has beco me the standard endocrine treatment for breast cancer. The triphenylethylen e-derivative compound competes efficiently for binding to the oestrogen rec eptor, but the complex retains some transcriptional activity. Consequently, tamoxifen exhibits, both 'in vitro and in vivo', a range of biological act ivity from full oestrogen antagonism to partial agonism. There is also evid ence suggesting that the agonist activity of this compound may ultimately s timulate breast tumour growth, thus causing some treatment failures. Moreov er, the use of tamoxifen is limited by the possible onset of drug-resistanc e in many patients. Nevertheless, widely tested tamoxifen has proved to be very helpful for the development of new compounds to be used as long-term a djuvant therapy or as preventive agents. These novel oestrogen antagonists belong to two major classes: tamoxifen analogs and new pure steroidal-like antioestrogens. The search for and development of compounds devoid of tamox ifen cross-resistance, with a safer toxicity profile as well as the lack of oestrogenic effects, provide the bases to improve the current therapeutic applications of antioestrogens. (C) 1999 Academic Press.