Glucocorticoids modulate TGF-beta production

TGF- is thought to play a central role in pulmonary fibrosis inducing fibroblast differentiation and extracellular matrix synthesis. In human lung fibroblasts, it is still unclear how various TGB- isoforms affect TGF- production and whether glucocorticoids, commonly used agents to treat fibrotic lung disease, modulate these processes. To this end, human fetal lung fibroblasts (HFL-1) were cultured with various concentrations of glucocorticoids (budesonide, dexamethasone or hydrocortisone) with and without TFG-1, -2, and -3. TGF- mRNA was assessed by real time RT-PCR. Smad 2, 3, and 4 and AP-1 complex (c-fos and c-Jun) cellular localization were evaluated by immunostaining. TGF-2 and -3 stimulated TGF-1 production significantly (p < 0.01 relative to control). TGF-1 stimulated TGF-2 production (p < 0.01 relative to control). TGF-3 was undetectable. Glucocorticoids significantly inhibited TGF-1 and -2 production and reduced expression of the upregulated TGF-1 and -2 mRNA induced by exogenous TGF-1, -2 or -3 (p < 0.01 for each) but had no effect on Smads. Although c-jun-related nuclear staining was not intensified in TGF--stimulated cells, it was reduced by glucocorticoids. Thus, TGF- isoforms may stimulate production of various TGF- isoforms in the lung. Glucocorticoids then may block TGF- production by modulating mRNA levels and c-Jun.     

Synoviocytes in chronic synovitis in situ and cytokine stimulated synovial cells in vitro neo-express α1, α3 and α5 chains of β1 integrins

The expression of the 1 integrins was examined immunohistochemically in synoviocytes from normal synovial membrane and from chronic synovitis of different aetiology and intensity. Normal synoviocytes were 61-positive but lacked 1 through 5. In mild inflammation type A synoviocytes neo-expressed 1, 3, and 5 chains. In severe inflammation both type A and B synoviocytes expressed 3, 4, 5, and 6 chains. The effects of inflammatory cytokines, as single agents or in combination, on the 1 integrin expression in cultured normal synoviocytes was determined by immunocytochemistry and flow cytometry. The 1 chain, while absent in unstimulated synoviocytes, was induced by interleukin-1 (IL-1), tumour necrosis factor- (TNF-), and interferon- (INF-). This effect was enhanced by combining IL-1 and TNF-. Expression of the 3 chain was up-regulated by IL-1 and, more intensely, by IFN-. Transforming growth factor (TGF-) inhibited the up-regulating effect of IL-1 and antagonized the effect of IFN- on 3 chain expression. Expression of the 5 chain was up-regulated significantly by co-stimulation through IL-1 together with TGF- or TNF-. Thus, the 1 integrin profile of cytokine activated synoviocytes in vitro resembled that of synoviocytes in synovitis in situ. These data suggest that IL-1, TNF-, IFN-, and TGF- are likely to be among the effectors regulating 1 integrin expression in synoviocytes in vivo.     

Glucocorticoids modulate TGF-beta production by human fetal lung fibroblasts

TGF- is thought to play a central role in pulmonary fibrosis inducing fibroblast differentiation and extracellular matrix synthesis. In human lung fibroblasts, it is still unclear how various TGF- isoforms affect TGF- production and whether glucocorticoids, commonly used agents to treat fibrotic lung disease, modulate these processes. To this end, human fetal lung fibroblasts (HFLF) were cultured with various concentrations of glucocorticoids (budesonide, dexamethasone or hydrocortisone) with and without TGF-1, -2, or -3. Post-culture media were collected for ELISA assays of TGF-1, -2, and -3 . TGF- mRNA was assessed by real time RT-PCR. Smad 2, 3, and 4 and AP-1 complex (c-fos and c-Jun) cellular localization were evaluated by immunostaining. TFG-2 and -3 stimulated TGF-1 production significantly (p < 0.01 relative to control). TGF-1 stimulated TGF-2 production (p < 0.01 relative to control). TGF-3 was undetectable. Glucocorticoids significantly inhibited TGF-1 and TGF-2 production and reduced expression of the up-regulated TGF-1 and TGF-2 mRNA induced by exogenous TGF-1, -2, or -3 (p < 0.01 for each) but had no effect on Smads. Although c-jun-related nuclear staining was not intensified in TGF--stimulated cells, it was reduced by glucocorticoids. Thus, TGF- isoforms may stimulate production of various TGF- isoforms in the lung. Glucocorticoids then may block TGF- production by modulating mRNA levels and c-Jun.     

Modulation of Nav1.5 by β1- and β3-subunit co-expression in mammalian cells

Cardiac sodium channels (Na_v1.5) comprise a pore-forming -subunit and auxiliary -subunits that modulate channel function. In the heart, 1 is expressed throughout the atria and ventricles, whilst 3 is present only in the ventricles and Purkinje fibers. In view of this expression pattern, we determined the effects of 3 and 1 co-expression alone, and in combination, on Na_v1.5 stably expressed in Chinese hamster ovary cells. The current/voltage relationship was shifted –5 mV with either 1 or 3 co-expression alone and –10 mV with co-expression of both 1 and 3. In addition, 3 and 1/3 co-expression accelerated macroscopic current decay. There were significant hyperpolarizing shifts in equilibrium gating relationships with co-expression of 1 and 3 alone and in combination. Co-expression of 1/3 together resulted in a greater hyperpolarizing shift in channel availability, and an increase in the slopes of equilibrium gating relationships. Co-expression of 3 and 1/3, but not 1, slowed recovery from inactivation at –90 mV. Development of inactivation at –70 and –50 mV was accelerated by -subunit co-expression alone and in combination. -Subunit co-expression also reduced the late Na current measured at 200 ms. In conclusion, -subunits modulate Na_v1.5 gating with important differences between co-expression of 1 and 3 alone and 1/3 together.     

Statin treatment and a disease-specific pattern of β-amyloid peptides in Alzheimer’s disease

According to the amyloid cascade hypothesis, sporadic Alzheimers disease (AD) is caused by the production and aggregation of -amyloid (A), and the production of A has recently been linked to the metabolism of cholesterol. We have previously published clinical studies where the effect of statin treatment on A production has been investigated. No effect on A was found, which is in disagreement with cell and animal studies. In the present study we investigated the effect of statin treatment on a disease-specific pattern consisting of a C-terminally-truncated quintet of A peptides. Nineteen patients with AD were treated with simvastatin for 12 months and the quintet of A peptides were analysed in cerebrospinal fluid before and after treatment. Also included was a group of 15 untreated patients with AD. We found that the A peptide pattern at baseline was in agreement with earlier findings; however, we did not find any change in the A peptide pattern after statin treatment. We suggest that clinical studies with extended treatment periods are performed where higher dosages of statins are used. We also believe that the pleiotropic effects of statins should be investigated further in order to elucidate the connection between Alzheimers disease and statin treatment.     

Inhibitor of β-Hydroxy-β-Methylglutaryl Coenzyme A Reductase Decreases Energy Supply to the Myocardium in Rats

Hypocholesterolemic preparations, inhibitors of the key enzyme of cholesterol biosynthesis -hydroxy--methylglutaryl coenzyme A reductase (statins), block the synthesis of ubiquinone Q10, intermediate electron carrier in the mitochondrial respiratory chain. This should decrease energy supply to tissues. Daily peroral administration of -hydroxy--methylglutaryl coenzyme A reductase inhibitor simvastatin (24 mg/kg perorally) for 30 days had no effect on the contents of macroergic phosphates (ATP and creatine phosphate) in the liver, but decreased these parameters in the myocardium.     

Free radical lipid peroxidation inhibits enzymatic conversion of beta-carotene into vitamin A

Free radical oxidation of arachidonic acid with soybean lipoxygenase was accompanied by inhibition of retinal synthesis from -carotene catalyzed by enzyme preparation from rabbit intestinal mucosa. Lipoxygenase inhibitor salicylhydroxamic acid and antioxidants suppressing free radical reactions (ethyl gallate, -tocopherol, astaxanthine, and quercetin) promoted conversion of -carotene into retinal catalyzed by -carotene-15,15'-dioxygenase. These results indicate that lipoperoxides and/or products of their homolysis attenuate enzymatic conversion of -carotene and confirm the important role of natural antioxidants in the maintenance of stable vitamin A content in mammals.     

Modulation of hematopoietic colony formation of stem cells in peripheral blood by anti-TGF-β in patients with severe immunosuppression

Summary The influence of transforming growth factor- (TGF-) on hematopoiesis has been evaluated by adding blocking antibodies against TGF- to colony forming assays (CFU-c). When optimum concentrations of recombinant growth factors, granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukin-3 (IL-3) were added to stem cells from the peripheral blood of healthy individuals and certain patients with tumors or HIV infection, the anti-TGF- capable of blocking 5 ng/ml of active TGF- had no significant influence on erythroid or myeloid colony formation. However, in certain immunosuppressed individuals, anti-TGF- resulted in a significant decrease of erythroid colony formation and slight suppression of myeloid colony formation. The significant inhibition of hematopoiesis by plasma of HIV patients could be due to the presence of active forms of TGF-. The results of the blocking experiments are consistent with the concept that TGF- in low concentrations is essential for erythropoiesis and myelopoiesis but that higher levels of TGF- primarily inhibit erythropoiesis in vitro. TGF- serves as a coordinating factor when efficient recruitment of granulocytes and monocytes is more essential than erythropoiesis and stem cell growth.Abbreviations BFU-E burst forming unit-erythroid - CFC colony forming cells - CFU-GEMM colony forming unit-granulocyte/erythroid/macrophage/megacaryocyte - CFU-GM colony forming unit-granulocyte/macrophage - EPO erythropoietin - GM-CSF granulocyte/macrophage-colony stimulating factor - HIV human immunodeficiency virus - IL-1 interleukin-1 - IL-3 interleukin-3 - IMDM Iscove's Modified Dulbecco's medium - PBS phosphate buffered saline - TGF- transforming growth factor- - TNF- tumor necrosis factor-     

Evidence for a multigenic system controlling methyl-β-carboline-3-carboxylate (β-CCM)-induced seizures

-CCM is a -carboline known to have properties opposite to those of benzodiazepines. Our approach was to analyze, in mice, the genetic mechanisms involved in -CCM-induced myoclonic seizures using recombinant congenic strains and F₁ hybrids issued from these strains. Our aim was to define the extent of the multigenic character of -CCM-induced myoclonic seizures, while also evaluating the distribution of the strength of the genes implicated in this trait. The results show that the control of reactivity to -CCM is multigenic with notable epistatic involvement.     

Bicarbonate permeability of epithelial chloride channels

To investigate the relation of arachidonate metabolism to the induction of fever by interleukin-1, indomethacin was administered in either an intracerebro-ventricular (icv) or a subcutaneous (sc) route in conscious rabbits. Fever induced by icv administration of recombinant human interleukin-1 (rhIL-1) was depressed by either icv or sc pretreatment with indomethacin. Fever induced by intravenous (iv) administration of rhIL-1 was significantly inhibited, though initial small increase in colonic temperature still remained, and was completely depressed by combination of icv and sc pretreatment with indomethacin. Intracerebroventricularly administered recombinant rabbit IL-1 (rrIL-1) induced dose-dependent increases in colonic temperature, which was depressed by sc pretreatment with indomethacin. There is little species specificity between human and rabbit IL-1, in terms of the pyrogenic potency and the inhibitory effect of sc indomethacin on fever induced by icv IL-1. Further, fever caused by icv administration of sodium arachidonate was significantly depressed by sc pretreatment with indomethacin. These results show that the inhibitory effect of indomethacin, administered either icv or sc, on IL-1-induced fever is similar to that of IL-1-induced fever reported previously [11]. This suggests that the site of arachidonate metabolism significantly involved in the mechanism of fever induction by IL-1 is easily accessible to the brain from the blood.     

Oral Administration of Gammalinolenic Acid, an Unsaturated Fatty Acid with Anti-inflammatory Properties, Modulates Interleukin-1β Production by Human Monocytes

Administration of gammalinolenic acid (GLA), an unsaturated fatty acid, reduces joint inflammation in patients with rheumatoid arthritis. Addition of GLA in vitro suppresses release of interleukin-1 (IL-1) from human monocytes stimulated with lipopolysaccharide (LPS). LPS-induced IL-1 release is followed by IL-1-induced IL-1 release, an amplification process termed autoinduction. We show here, using IL-1 stimulation to simulate autoinduction, that administration of GLA to healthy volunteers and to patients with inflammatory arthritis reduces LPS-induced IL-1 secretion mainly by reducing autoinduction of IL-1. GLA reduces LPS-induced pro-IL-1 mRNA modestly and IL-1-induced pro-IL-1 gene expression markedly. In addition to reducing amplification of IL-1, GLA increases the amount of IL-1 receptor antagonist (IL-1Ra) secreted from stimulated cells, thereby facilitating an increase in the secreted IL-1Ra/IL-1 ratio. IL-1 is important to host defense, but the amplification mechanism may be excessive in genetically predisposed individuals. Thus, reduction of IL-1 autoinduction may be protective in some patients with endotoxic shock and with diseases characterized by chronic inflammation.     

Factors influencing serum neopterin and β2-microglobulin levels in a healthy diverse population

Sera and questionnaire data from a population-based random sample of healthy adults was used to evaluate factors influencing neopterin and 2-microglobulin (2m) values. Both neopterin and 2m levels increased with age and were higher among white than blacks (mean values for whites and blacks: neopterin, 5.06 vs 4.49 nmol/L; 2m, 1.36 vs 1.28 mg/L). Gender differences were noted for 2m but not neopterin values (2m males vs females: 1.37 vs 1.29 mg/L). Neopterin values were lower among current smokers than among nonsmokers (4.32 vs 5.16 nmol/L) and were higher among users of antihistamines (5.46 among users vs 4.65 nmol/L among nonusers). Neopterin and 2m were correlated in this healthy adult population (adjustedr=0.53,P=0.001), yet no other interrelationships with numerous biologic markers except between 2m and serum-soluble interleukin-2 receptor levels (adjustedr=.41,P=0.05) were observed. These findings provide important baseline information to consider before planning or evaluating studies utilizing neopterin or 2m levels.     

Function associated transforming growth factor-β gene polymorphism in chronic beryllium disease

Chronic beryllium disease (CBD) is a rare occupational, granulomatous lung disease clinically resembling sarcoidosis. The immune response to beryllium is thought to depend on genetic susceptibility. Although a glutamic acid in position 69 of the human leukocyte antigen-DP chain (HLA-DPB1-Glu69) is associated with the development of CBD, it cannot fully explain susceptibility. It is likely that additionally other genes are involved in regulating the immune and inflammatory response in the pathogenesis of this disease. Functional gene polymorphisms (PMs) of the tumor necrosis factor (TNF)A and transforming growth factor (TGF) ₁ genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-₁ (codon 25) PM in 59 patients with CBD and 164 matched healthy controls, from two groups of European/Israeli and United States origin. Additionally, patients were genotyped for HLA class II gene variants and the TNFA (–308) PM. The most significant results were found for the TGF-₁ (codon 25) PM with a shift towards the low producing non-GG genotypes in the subgroup of European and Israeli patients with CBD (62.50% vs. 13.82% in healthy controls; P<0.001). This phenomenon was not observed in the group from the United States. Moreover, TGF-₁ (codon 25) PM genotype frequencies from United States CBD patients differed significantly from those of European and Israeli patients. In contrast, increased frequencies for the high producing TNFA2 allele were found only in the patients from the United States (28.20% vs. 8.96% in healthy controls; P<0.005) but not in the group of Europe and Israel. In conclusion, the increase in TGF-₁ (codon 25) PM genotype frequency associated with a low TGF- release suggests that immunoregulatory cytokines such as TGF- are involved in the pathogenesis of CBD. Moreover, based on the interaction of gene PMs associated with the control of the immune response, such as TNF- and TGF-₁, with a specific immune response gene such as HLA-DPB1-Glu69 or other HLA-class II PMs driving the immune response to Be, the present data suggest that a combination of different genetic backgrounds determine susceptibility for the same immunopathological reaction and disease.     

Beta-glucuronidase release from leukocytes in children

Summary The release of -glucuronidase from polymorphonuclear leukocytes (PMNs) is important in the killing of bacteria and in producing tissue damage in acute inflammation. To investigate the effects of various diseases or drugs on degranulation, we studied the kinetics of -glucuronidase release from PMNs exposed to opsonized zymosan. PMNs of children with bacterial infections demonstrated increased degranulation. Within 5, 15, and 30 min the PMNs released 19±3%, 23±3%, and 26±3% of total -glucuronidase compared to 12±2%, 15±2%, and 16±2% of total -glucuronidase of control PMNs. Viral infections induced a significant delay of -glucuronidase release from PMNs. Maintenance therapy of acute lymphoblastic leukemia with 6-mercaptopurine and methotrexate, as well as administration of vincristine, diminished the degranulation. After 5, 15, and 30 min the PMNs released 8±1%, 10±1%, and 11±1%, as well as 6±3%, 8±2%, and 9±2% of total -glucuronidase. This study demonstrated that bacterial infections stimulate -glucuronidase release by PMNs. In contrast, cytostatic drugs inhibit lysosomal enzyme release, increasing the susceptibility to bacterial infections. The total enzyme activities were unchanged.Abbreviations c-AMP cyclic Adenosinemonophosphate - c-GMP cyclic Guanosinemonophosphate - PMNs polymorphonuclear Leukocytes Supported by DFG Ri 275/6-1Dedicated to Prof. Dr. E. Gladtke on the occasion of his 60^th birthday     

Potassium tolerance and bronchial reactivity in asthmatic and nonasthmatic atopic subjects

Abnormal autonomic nervous system responsiveness may contribute to the pathogenesis of allergic diseases. Therefore, we measured the -adrenergic systemic (metabolic) responsiveness by means of acute potassium load in 10 normal healthy subjects and in 19 patients with allergic asthma and/or rhinitis. Ten allergic patients showed a greater potassium increment, as in normal subjects, when potassium was infused in the presence of propranolol. There was no difference between asthmatic and rhinitic patients. We then examined the relation between the response to potassium tolerance and the nonspecific, nonpharmacological bronchial reactivity in response to inhalation of ultrasonically nebulized distilled water. Some allergic patients showed bronchial hyper-reactivity, while others did not show a difference compared with the controls; there was no significant difference between asthmatics and rhinitics, and there was no relation between nonspecific bronchial reactivity and potassium load tolerance. These findings suggest that systemic -adrenergic hyporesponsiveness may be present only in some allergic patients. There is no demonstrable relation among atopic state, nonspecific, nonpharmacological bronchial reactivity, and systemic -adrenergic hyporesponsiveness.     

Parallel minisequencing followed by multiplex matrix-assisted laser desorption/ionization mass spectrometry assay for β-thalassemia mutations

-thalassemia is a common monogenic disease caused by mutations in the human -globin gene (HBB), many of which are differentially represented in human subpopulations stratified by ethnicity. This study describes an efficient and highly accurate method to screen for the eight most-common disease-causing mutations, covering more than 98% of HBB alleles in the Taiwanese population, using parallel minisequencing and multiplex assay by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The MALDI-TOF MS was optimized for sensitivity and resolution by mass tuning the PinPoint assay for eight HBB SNPs. Because of the close proximity and clustering of mutations in HBB, primer extension reactions were conducted in parallel. Efficient sequential desalting using POROS and cationic exchange chromatography allowed for an unambiguous multiplex genotyping by MALDI-TOF MS. The embellishing SNP assay allowed for highly accurate identification of the eight most-common -thalassemia mutations in homozygous normal control, carrier, and eight heterozygous carrier mixtures, as well as the diagnosis of a high-risk family. The results demonstrated a flexible strategy for rapid identification of clustering SNPs in HBB with a high degree of accuracy and specificity. It can be adapted easily for high-throughput diagnosis of various hereditary diseases or to establish family heritage databases for clinical applications.     

Glucocorticoids and TGF-β1 Synergize in Augmenting Fibroblast Mediated Contraction of Collagen Gels

TGF- plays a central role in the initiation and progression of pulmonary fibrosis. Glucocorticoids are frequently used to treat fibrotic diseases, but beneficial effects are often modest. Both TGF- and glucocorticoids have been reported to increase fibroblast contraction of native collagen gels, a model of fibrotic tissue remodeling. Therefore, we sought to determine how glucocorticoids interact with TGF- in this system. In this study, human fetal lung fibroblasts (HFL-1) were pretreated with or without TGF- for 72 h before they were cast into type I collagen gels. Various concentrations of glucocorticoids (budesonide or hydrocortisone) were added at the time of casting. Gel size was then monitored at different times after gel release. The surrounding media were collected for the assay of prostaglandin E₂ (PGE₂) and the cell lysates were analyzed for cyclooxygenase (COX) expression by immunoblot. Glucocorticoids alone significantly enhanced fibroblast-mediated contraction of collagen gels (P < 0.01) and dose-dependently inhibited PGE₂ release by HFL-1 fibroblasts. TGF- significantly augmented gel contraction but also induced a 30% increase in PGE₂ release and increased the expression of COX-1. Glucocorticoids inhibited TGF-1 induced-PGE₂ release, and enhanced TGF- augmented gel contraction without significantly affecting TGF- augmented COX-1 expression. Indomethacin, a COX inhibitor, increased TGF- augmented gel contraction but had no further effect when added together with glucocorticoids. Thus, glucocorticoids can synergize with TGF- in augmenting fibroblast mediated collagen gel contraction through the inhibition of PGE₂ production. Such interactions between glucocorticoids and TGF- may account, in part, for the lack of response of fibrotic diseases to glucocorticoids.     

The effect of intravenously administered salbutamol on serum potassium in asthmatic and nonasthmatic atopic subjects

The role of adrenergic mechanism in the pathogenesis of allergic disease is controversial. Recent experimental and clinical reports have suggested that -adrenergic blockade impairs and stimulation enhances extrarenal potassium uptake in humans. This led us to study the effect of the intravenous administration of salbutamol, a specific -2-adrenergic agonist, on serum potassium in 9 healthy subjects and in 23 patients with allergic asthma and/or rhinitis. Serum potassium fell significantly and reached a peak decline at the end of venous infusion in all the normal subjects. Seventeen atopic subjects showed a lower or absent serum K⁺ decrement: there was no difference between asthmatic and rhinitic patients. There was no relation among the salbutamol-induced serum potassium decrement, serum glucose increment, blood pressure and heart-rate changes, and nonspecific bronchial reactivity. These findings suggest that -2-adrenergic hyporesponsiveness is present only in some allergic patients.     

Low E-cadherin and β-catenin expression correlates with increased spontaneous and artificial lung metastases of murine carcinomas

This study examined the relationship between the expression of E-cadherin or -catenin in murine adenocarcinomas and their hematogenous metastatic propensity, assessed by both spontaneous and artificial lung metastasis. Seven different carcinomas, syngeneic to C3Hf/Kam mice were used: 4 mammary carcinomas (MCa-4, MCa-29, MCa-35, and MCa-K), ovarian carcinoma OCa-I, hepatocarcinoma HCa-I, and adenosquamous carcinoma ACa-SG. These tumors vary widely in their ability to spontaneously metastasize to the lung (from 0 to 100% metastatic incidence), and their cells greatly differ in their ability to form artificial lung nodules when injected i.v. Primary tumors in the leg were assessed for E-cadherin and -catenin expression by western botting. The expression of both proteins showed wide variation among the tumors; however, the expression of E–cadherin correlated well with that of -catenin. There was significant inverse correlation between the expression of E-cadherin, as well as -catenin, and the incidence of both spontaneous and artificial lung metastases from these tumors. Spontaneous metastases of highly metastatic HCa-I and moderately metastatic MCa-35 were significantly lower in E-cadherin and -catenin expression than their corresponding primary tumors were. Thus, the propensity of murine carcinomas for hematogenous spread is highly related to E-cadherin and -catenin levels in primary tumors. The inverse correlation between the expression of these molecules and spontaneous and artificial metastases implies that tumor cells with low E-cadherin and -catenin content have increased ability to enter the vascular circulation at the primary tumor site and to colonize distant tissues.     

Expression of estrogen receptors-α and -β in primary breast neoplasms and tumors exposed to neoadjuvant hormonal therapy

We studied the content and expression of mRNA for estrogen receptors receptors- and - in breast tumors before and after 3-month neoadjuvant hormone therapy with antiestrogen tamoxifen and/or aromatase inhibitors. Expression of estrogen receptors- and - was most often detected in ER⁺PR⁺ tumors and most significantly decreased in these neoplasms after exemestane therapy. Immunocytochemical and radioligand assays showed that tamoxifen and anastrozole have little effect on the number of estrogen receptors- The number of progesterone receptors in tumors decreased by the end of anastrozole therapy. Estrogen receptors- were immunocytochemically revealed in 50% primary breast tumors. Anastrozole slightly decreased, while tamoxifen increased the incidence of these receptors. Interruption of signaling through estrogen receptors and suppression of estrogen biosynthesis had different effects on the receptor status of neoplasms and distribution of estrogen receptors- and -.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 11, pp. 559–562, November, 2004