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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New developments in hormone- and chemotherapy of metastasizing breast cancer comprise replacement of ovariectomy by LH-RH antagonists in premenopausal women, new antiestrogens with less residual estrogenic activity for use mainly in postmenopausal patients as well as new potent inhibitors of aromatase with fewer adverse effects also for postmenopausal women. These new drugs will possibly provide better efficacy with fewer side effects, but at higher cost. In chemotherapy the search for more potent regimes continues. Experiments are under way with high-dose chemotherapy plans in conjunction with autologous bone marrow transplantation and hemopoietic growth factors; however, the result of these latter studies are so far disappointing. It has become clear that in nonaggressive metastasizing cancer of the breast high rates of remission seem not to be the ultimate goal. At this stage of disease the natural course is very heterogeneous; therefore, chemotherapy has to be adapted to risk. The goal must be improvement of quality of life for the remaining life-span by palliation of symptomatic disease while inducing as few side effects of treatment as possible. New; more potent chemotherapeutic agents are not at sight. Research has recently produced derivatives of already known agents producing fewer adverse effects at equal efficacy. Decisive for the choice of primary chemotherapy are prognostic indicators of the disease. For most cases, tumor specific therapeutic modalities have to be optimized.
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PMID:[Current developments in systemic therapy of breast carcinoma]. 190 90

4-Hydroxyandrostenedione (4-OHA) is a specific inhibitor of aromatase activity used for the treatment of breast cancer in post-menopausal women. Treatment with 4-OHA has been shown to inhibit the peripheral conversion of androstenedione to oestrone and reduce plasma oestrogen concentrations, but the effect of treatment on breast-tissue oestrone concentrations is not known. We have therefore examined the effect of treatment with 4-OHA on oestrone concentrations in normal and malignant breast tissues and also measured plasma and tissue 4-OHA concentrations. Changes in tumour oestrone concentrations were related to DNA polymerase alpha activity, a marker of cellular proliferation. Blood and breast-tissue samples were obtained before and 36 hr after treatment with 4-OHA. The mean plasma concentration of 4-OHA was 27.9 +/- 19.3 ng/ml, compared with levels of 33.7 +/- 25.6 ng/g for breast tumour and 13.5 +/- 11.5 ng/g for normal breast tissue. There was a significant correlation between 4-OHA concentrations in plasma and normal breast tissue (r = 0.91, p less than 0.001). Treatment with 4-OHA resulted in a significant (p less than 0.02) decrease in breast-tissue oestrone concentrations. For 3/4 tumour samples, a marked decrease in the concentration of oestrone (78 +/- 4%) was associated with a similar decrease (64 +/- 16%) in DNA polymerase alpha activity. It is concluded that treatment with 4-OHA effectively reduces breast-tissue exposure to oestrogen.
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PMID:Concentrations of oestrone and 4-hydroxyandrostenedione in malignant and normal breast tissues. 191 57

The aromatase inhibitor, 'pyridoglutethimide' (PyG), has been shown previously to suppress serum oestrogen levels in postmenopausal breast cancer patients and to achieve clinical responses at a dose of 500 mg twice daily (b.d.). This report gives the results of a detailed pharmacokinetic and endocrine study of PyG in ten patients. Four doses were tested at intervals of 2 weeks in the following order: 200 mg b.d., 400 mg b.d., 800 mg b.d., 1200 mg b.d. Concentration-time profiles of serum levels of PyG were curvilinear in all patients probably reflecting a saturation of metabolic enzymes. During repeat-dosing metabolism was enhanced approximately 2-fold. Plasma levels of oestradiol were significantly suppressed by the lowest dose of PyG. Although higher doses appeared to achieve greater suppression this was not statistically significant in this small group of patients. There were no significant effects at any dose on the serum levels of cortisol, aldosterone, luteinising hormone, follicle stimulating hormone, prolactin, sex hormone binding globulin or thyroid stimulating hormone. There was a dose-related increase in 17 alpha-hydroxyprogesterone levels and a dose-related decrease in levels of dehydroepiandrosterone sulphate (DHAS). The androgens DHA, testosterone and androstenedione also were significantly suppressed with at least one of the doses of PyG. Synacthen tests did not support these changes being a result of inhibition of 17,20 lyase. It is possible that they are due to enhanced clearance of DHAS. Two patients experienced no toxicity throughout the study, whilst a total of four patients were withdrawn because of side-effects: one at 400 mg b.d., two at 800 mg b.d., and one at 1200 mg b.d. The most frequent side-effects were nausea and lethargy. One patient showed an objective response to treatment.
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PMID:Endocrine, pharmacokinetic and clinical studies of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione ('pyridoglutethimide') in postmenopausal breast cancer patients. 193 11

Aromatase activity may be detected both in breast adipose tissue and breast cancer in levels similar to or greater than those in other peripheral tissues. Factors influencing such local biosynthesis have been sought. Of 247 primary breast cancers investigated, 178 showed evidence of oestrogen biosynthesis. No significant relationships were found between either the presence or levels of activity and tumour histopathology, patient characteristics (such as age and menopausal status), disease stage and prognosis (determined by disease-free interval and survival after primary treatment). Aromatase was more likely to be found in cellular cancers and those which were oestrogen receptor-positive, but these were not absolute associations, activity being detected in tumours with all degrees of cellularity and both receptor-positive and receptor-negative cancers. However, in a small group of patients with metastatic oestrogen receptor-positive tumours, response to the aromatase inhibitor, aminoglutethimide, seemed confined to tumours with aromatase activity. Oestrogen biosynthesis was detected in all specimens of breast adipose tissue examined. Activities were higher in fat from breast cancer patients compared with that from women with benign breast disease. In breasts with cancer, levels were higher in quadrants bearing tumour compared with those without evidence of malignancy. It is suggested that either enhanced aromatase in breast fat promotes the appearance of overt cancer or tumour factors induce aromatase in surrounding fat. Finally, although no significant correlations were detected in postmenopausal women between local aromatase activity and endogenous oestrogens in breast cancer, perfusion studies show that in situ oestrogen biosynthesis is primarily responsible for oestrogen levels in the majority of breast tissues. These data suggest that local aromatase activity may influence events within the breast and may be associated with the natural history and progression of certain malignancies.
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PMID:Aromatase activity in breast tissue. 195 67

To test the hypothesis of an increased activity of the enzyme aromatase in adipose tissue from affected when compared with non-affected quadrants of patients with breast cancer, the aromatase activity has been measured in tumour and fatty tissues dissected at specific sites from the breasts of 16 patients. Activity was measured after extensive purification of the product formed. Results, expressed in fmol/g of tissue, did not show a higher activity in the affected vs the non-affected quadrants. In the tumours, higher activities were found when expressed per g of tissue. Per mg of DNA, an indicator of the number of cells, tumour enzymatic activity was lower than in fatty tissues. The relations between the products of aromatase, oestrone and oestradiol in the various tissues point to the importance of additional enzymatic processes, especially of the reductive 17 beta-oestradiol dehydrogenase, in the accumulation of high quantities of oestradiol in the malignant tissue.
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PMID:Endogenous steroid hormones and local aromatase activity in the breast. 195 69

The most important mitogen for human breast cancer is oestrogen. Since oestrogens are synthesized via a protracted series of enzymic conversions from cholesterol, there are many potential targets for inhibition which could theoretically lead to suppression of oestrogen synthesis. However, inhibition of many of these targets is complicated by a resultant interference in the synthesis of other steroids, particularly glucocorticoids. This results in inhibitors of aromatase being the most rational choice for oestrogen suppression in breast cancer patients. Several aromatase inhibitors are in clinical usage. It is important that the clinical effectiveness of these is compared with that of the antioestrogen, tamoxifen.
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PMID:Inhibitors of steroidogenic enzymes for the treatment of breast cancer. 195 70

Estrogen synthesis by aromatase occurs in a number of tissues throughout the body. Strategies which reduce production of estrogen offer useful means of treating hormone-dependent breast cancer. Initially, several steroidal compounds were determined to be selective inhibitors of aromatase. The most potent of these, 4-hydroxyandrostenedione (4-OHA) inhibits aromatase competitively but also causes inactivation of the enzyme. A number of other steroidal inhibitors appear to act by this mechanism also. In contrast, the newer imidazole compounds are reversible, competitive inhibitors. In vivo studies demonstrated that 4-OHA inhibited aromatase activity in ovarian and peripheral tissues and reduced plasma estrogen levels in rat and non-human primate species. In rats with mammary tumors, reduction in ovarian estrogen production was correlated with tumor regression. 4-OHA was also found to inhibit gonadotropin levels in animals in a dose-dependent manner. The mechanism of this effect appears to be associated with the weak androgenic activity of the compound. Together with aromatase inhibition, this action may contribute to reducing the growth stimulating effects of estrogen. A series of studies have now been completed in postmenopausal breast cancer patients treated with 4-OHA either 500 mg/2 weeks or weekly, or 250 mg/2 weeks. These doses did not affect gonadotropin levels. Plasma estrogen concentrations were significantly reduced. Complete or partial tumor regression occurred in 26% of the patients and the disease was stabilized in 25% of the patients. The results suggest that 4-OHA is of benefit to postmenopausal patients who have relapsed from prior hormonal therapies. Several of the steroidal inhibitors are now entering clinical trials as well as non-steroidal compounds which are more potent and selective than aminoglutethimide. Aromatase inhibitors should provide several useful additions to the treatment of breast cancer.
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PMID:Aromatase and its inhibitors--an overview. 195 29

In order to characterize the main enzymatic systems involved in androgen and estrogen formation as well as metabolism in ZR-75-1 human breast cancer cells, incubation of intact cells was performed for 12 or 24 h at 37 degrees C with tritiated estradiol (E2), estrone (E1), androst-5-ene-3 beta, 17 beta-diol (5-ene-diol), dehydroepiandrosterone (DHEA), testosterone (T), androstenedione (4-ene-dione), dihydrotestosterone (DHT) or androsterone (ADT). The extra- and intracellular steroids were extracted, separated into free steroids, sulfates and non-polar derivatives (FAE) and identified by HPLC coupled to a Berthold radioactivity monitor. Following incubation with E2, 5-ene-diol or T, E1, DHEA and 4-ene-dione were the main products, respectively, thus indicating high levels of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD). When 4-ene-dione was used, on the other hand, a high level of transformation into 5 alpha-androstane-3,17-dione (A-dione), Epi-ADT and ADT was found, thus indicating the presence of high levels of 5 alpha-reductase as well as 3 alpha- and 3 beta-hydroxysteroid dehydrogenase. Moreover, some T was formed, due to oxidation by 17 beta-HSD. No estrogen was detected with the androgen precursors T or 4-ene-dione, thus indicating the absence of significant aromatase activity. Moreover, significant amounts of sulfates and non-polar derivatives were found with all the above-mentioned substrates. The present study shows that ZR-75-1 human breast cancer cells possess most of the enzymatic systems involved in androgen and estrogen formation and metabolism, thus offering an excellent model for studies of the control of sex steroid formation and action in breast cancer tissue.
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PMID:Multiple steroid metabolic pathways in ZR-75-1 human breast cancer cells. 200 38

R 76713 (6-[(4-chlorophenyl)(1-H-1,2,4-trizol-1-yl)methyl]1-H benzotriazole) is a highly potent and selective inhibitor of the aromatase enzyme both in vitro and in vivo. The ability of R 76713 to inhibit peripheral aromatization of androstenedione (A) to estrone (E1) in vivo was studied in male cynomolgus monkeys (Macaca fascicularis). Peripheral aromatization was measured using a primed constant infusion of [3H] A and [14C]E1 for 3.5 h. Blood samples, collected during the final hour of infusion, were analyzed for plasma radioactivity as infused and product steroids. MCRs, conversion ratios (CR), and percent conversion of A to E1 were calculated. R 76713 (0.03-10 microgram/kg) or vehicle (10% hydroxypropyl-beta-cyclodextrin) were administered iv 90 min before beginning the infusion of radiolabeled steroids. In vehicle-treated monkeys, the aromatization of A (mean +/- SEM, 1.35 +/- 0.11%) was similar to that previously reported for cynomolgus and rhesus monkeys, baboons, and humans. Aromatization of A, measured 4-5 h after injection of R 76713, was dose-dependently decreased from the control value by 87 +/- 3%, 85 +/- 2%, 61 +/- 5%, and 33 +/- 8% (all P less than 0.05) at doses of 10.0, 3.0, 0.3, and 0.03 micrograms/kg, respectively, with an ID50 of 0.13 microgram/kg, iv (95% confidence interval, 0.06-0.21). When measured 15-16 h after iv administration of 3.0 micrograms/kg R 76713, aromatization (0.55 +/- 0.13%) was significantly inhibited by 53 +/- 11% compared to that in control monkeys (1.16 +/- 0.18%). The CRs between androgens, the CRs between estrogens, and the MCRs of A and E1 were not significantly altered by R 76713 compared to those after vehicle treatment. R 76713 potently decreased peripheral conversion of androgen to estrogen in vivo in male cynomolgus monkeys and may be a useful therapeutic agent in treating estrogen-dependent diseases, including post-menopausal breast cancer.
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PMID:Inhibition of peripheral aromatization in the male cynomolgus monkey by a novel nonsteroidal aromatase inhibitor (R 76713). 200

The synthesis of 3-(cyclohexymethyl)-1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2, 4-dione (1h), with its optical enantiomers, and a series of novel achiral 1-(4-aminophenyl)-3-azabicyclo[3.1.1]haptane-2,4-diones (2a-i,k) is described. These compounds were tested in vitro for inhibition of human placental aromatase, a cytochrome-P450-dependent enzyme responsible for the conversion of androgens to estrogens. All of them displayed enzyme-inhibiting activity, and 3-cyclohexyl derivative 2g and 3-cyclohexylmethyl derivative 1h both proved more potent (greater than 140-fold) than the clinically effective agent aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione, AG]. As with AG and its derivatives, the 1R-(+)-enantiomer of 1h was responsible for the enzyme inhibitory activity. These novel compounds are of interest as potential drugs for endocrine therapy of hormone-dependent tumors, e.g. breast cancer.
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PMID:Synthesis and aromatase inhibitory activity of novel 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane- and -[3.1.1]heptane-2,4- diones. 201 6


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