[Antagonism of tamoxifen and antidepressants among women with breast cancer]. / Tamoxifeno y antidepresivos: ¿Antagonistas en la prevención del cáncer de mama?

Tamoxifen is used as an adjuvant therapy to reduce breast cancer recurrence among women with estrogen receptor positive tumors. Antidepressants are also commonly used in such women, to treat depression or to manage hot flushes, a frequent tamoxifen secondary effect. Some antidepressants could potentially inhibit cytochrome P450 2D6, required to activate tamoxifen, interfering with its action. Although there is not a clear cut directive on the subject, it is nowadays recommended to treat women with antidepressants with the lower cytochrome P450 2D6 inhibition potential to avoid a possible antagonism that may reduce tamoxifen s prevention of breast cancer recurrence at least in some patients with CYP2D6 genetic variation. The recommended antidepressants are desvenlafaxine, milnacipran, venlafaxin, escitalopram and citalopram.

Tamoxifeno y antidepresivos: ¿Antagonistas en la prevención del cáncer de mama? / Antagonism of tamoxifen and antidepressants among women with breast cancer

Tamoxifen is used as an adjuvant therapy to reduce breast cáncer recurrence among women with estrogenreceptor positive tumors. Antidepressants are also com-monly used in such women, to treat depression or to manage hotflush.es, afrequent tamoxifen secondary effect. Some antidepressants couldpotentially inhibit cytochrome P450 2D6, required to actívate tamoxifen, interfering with its action. Although there is not a clear cut directive on the subject, it is nowadays recommended to treat women with antidepressants with the lower cytochrome P450 2D6 inhibition potential to avoid apossible antagonism that may reduce tamoxifen s prevention of breast cáncer recurrence at least in some patients with CYP2D6 genetic variation. The recommended antidepressants are desvenlafaxine, milnacipran, venlafaxin, escitalopram and citalopram.

Characterization of membrane estrogen binding proteins from rabbit uterus.

Estrogens exert fast non-genomic actions in their target tissues which may involve the participation of receptors located at the cell membrane. Studies were performed to identify and characterize membrane-associated 17beta-estradiol binding proteins in rabbit uterus. Specific and saturable [3H]17beta-estradiol binding sites of high affinity (Kd = 0.36 nM) were detected in uterine microsomes at higher concentration than in cytosol (370 +/- 98 vs. 270 +/- 87 fmol/mg protein, respectively). Various other steroid hormones, the stereoisomer 17alpha-estradiol and the antiestrogen tamoxifen were significantly less effective than 17beta-estradiol to compete with the radioactive ligand for binding to the membranes. The microsome binding sites were trypsin-sensitive and could be extracted to a great extent (80-90%) with 0.4/0.6 M KCl. Assays of the marker enzyme glucose-6-P dehydrogenase excluded membrane contamination with cytosolic soluble components. Immunoblot analysis of particulate and soluble fractions using monoclonal antibodies against the transactivation, heat shock protein recognition, and steroid binding domains of the nuclear estrogen receptor (ER; 67 kDa), revealed lower concentrations of the ER in membranes and the presence of five additional immunoreactive proteins of 57, 50, 32, 28, and 11 kDa which were absent in cytosol. Moreover, the antibody against the steroid binding domain was as effective as an inhibitor for cytosolic and membrane specific radioligand binding. Extraction of microsomes with the nondenaturing detergent CHAPS allowed a 2-fold enrichment of ER-like binding proteins as shown by antibody labeling and [3H]17beta-estradiol binding analysis. The results of this work are consistent with the existence of novel 17beta-estradiol membrane binding proteins structurally related to the intracellular ER. Future studies should investigate whether any of these proteins are involved in the primary events (e.g. receptor function) mediating nongenomic estrogen effects.

Evaluation of a displacement assay with tamoxifen as prognostic indicator in breast-cancer patients with estrogen-receptor-positive tumors.

A displacement assay with tamoxifen, based on the relative binding affinity of tamoxifen and estradiol for the estrogen receptor (ER), was proposed in 1990 as prognostic indicator for breast-cancer patients. Validation of its predictive results in relation to the outcome of 73 patients with ER+ tumors is analyzed. ER, progesterone receptor (PgR) determinations and other conventional prognostic factors in relation to the displacement assay, were considered. Displacement assay results allowed ER+ tumors to be grouped as displaceable (D) or weakly displaceable (WD), with the implication that D tumors should respond better to tamoxifen (Tam) administration. Survival and disease-free interval curves showed highly significant differences between patients with ER+ D and ER+ WD tumors. For survival, including all tumor stages, 73.9% of patients were alive at 9 years after surgery in the group with D tumors and 37.0% in the group with WD tumors (p < 0.005); relative contribution of the different stages is analyzed. Addition of axillary-node number increased the prognostic significance of displacement categories for survival and disease-free interval. PgR determination as another ER functional expression failed to show significant differences for survival and disease-free interval between ER+ PgR+ and ER+ PgR- tumors. Thus, results from the displacement assay and from PgR determinations reflect 2 independent ER functional expressions. Displacement assay data appear as reliable prognostic indicators of breast-cancer outcome, and contribute to more appropriate treatment decisions in this pathology.

Indomethacin inhibits the effects of oestrogen in the anterior pituitary gland of the rat.

Two inhibitors of prostaglandin synthesis, indomethacin and aspirin, blocked the increase of oestrogen-binding sites in the nuclear subcellular fraction, an increase which occurs after the administration of oestradiol. Consequently the biological effects of oestrogens in the anterior pituitary gland of the rat (prolactin synthesis, concentration of progesterone-binding sites and cell proliferation) are diminished. The anterior pituitary gland synthesized prostaglandin F2 alpha (PGF2 alpha), PGE2 and PGD2 from arachidonic acid. This synthesis was blocked when indomethacin was added to the culture media. Oestrogen increased the concentration of PGE2: an increase that was partially prevented by indomethacin. Prostaglandins may have an important role on the effects of oestrogen in the anterior pituitary gland of the rat.