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

In a study of the origin of estrogens in patients with breast cancer, the concentrations of estrogens and their androgen precursors, and aromatase and 17 beta-hydroxysteroid dehydrogenase (E2DH) activities were determined in normal glandular and cancerous breast tissue. The correlation between tissue estrogens, precursor concentrations, enzyme activities and plasma levels and/or receptor status were calculated. In both normal glandular and carcinomatous breast tissue, the concentrations of androstenedione (A), dehydroepiandrosterone (DHEA), 5 androstene-3 beta, 17 beta-diol (5-Adiol), estrone (E1), estradiol (E2) and progesterone (P) were significantly higher than plasma concentrations. While testosterone (T) concentrations were similar, dehydroepiandrosterone (DHCA) and estrone sulphate (E1S) concentrations were lower in tissue than in plasma. In carcinomatous tissue androgen concentrations were lower, but estrogen concentrations were higher than in glandular breast tissue. Estradiol (E2) concentration was positively correlated with the receptor concentration with the mean E2 concentration corresponding to an estimated receptor occupancy of about 25%, probably sufficient for a submaximal biological response. Aromatase and E2DH (E2----E1) activities were observed in all breast cancer and glandular breast tissues, activities being higher in carcinoma than in glandular breast tissues; nevertheless, aromatase activity accounts probably only for a small fraction of tissue estrogen concentration. E2DH, but not aromatase activity, was significantly higher in estrogen receptor positive than in estrogen receptor negative tissues and was negatively correlated with tissue dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) concentration; the latter two steroids are non competitive inhibitors of E2DH which inactivates E2 to E1. This effect of DHEA(S) may constitute a mechanism by which these androgens stimulate cancer growth and a rationale (besides suppression of estrogen precursors) for medical or surgical adrenalectomy in hormone sensitive metastatic mammary cancer. E2DH activity might constitute an additional marker of hormone dependency of mammary cancer.
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PMID:Aromatase, 17 beta-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women. 301 31

During the last decade aminoglutethimide has been recognised as a valuable alternative in endocrine therapy for advanced breast cancer. Although some side effects do occur, most often these are initial effects which subside within a few weeks, and cessation of therapy is not usually indicated. Aminoglutethimide was originally introduced as an inhibitor of steroidogenesis in the adrenal cortex. It was soon recognised, however, that inhibition of the non-glandular aromatase, blocking the conversion of androgenic prohormones to oestrogens, was more important, resulting in decreased blood levels of oestrogens. In this review the role of aromatase inhibition as the only important aspect of the mechanism of action of aminoglutethimide is challenged. Evidence has accumulated during the last few years that aminoglutethimide is a most potent inducer of microsomal enzymes. In addition to the pharmacological implications this has (suggesting important interactions), it also points to the possibility that levels of oestrogens are decreased due to accelerated metabolism of these hormones. Based on new experimental data, and also clinical work with alternative aromatase inhibitors, it appears that the antitumour activity of aminoglutethimide may be due to both aromatase inhibition and accelerated metabolism of oestrogens. This seriously challenges the importance of aromatase inhibition alone as a strategy in endocrine therapy of breast cancer, and furthermore suggests that accelerated metabolism of key hormones is an alternative strategy to be explored.
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PMID:Mechanisms of action of aminoglutethimide as endocrine therapy of breast cancer. 304 76

Approximately one third of human breast carcinomas are hormone dependent and regress upon reduction of circulating estrogen levels. Traditional treatment strategies utilized surgical ablative methods to lower estrogen concentrations as treatment of breast cancer. Currently, investigative emphasis is focused upon development of highly specific antiestrogens and inhibitors of estrogen production. The enzyme, aromatase, as the terminal step in estrogen biosynthesis, is a logical target for blockade with potent and specific inhibitors. The earliest available aromatase antagonist, aminoglutethimide, suppresses estrogen production to the same extent as surgical ablation and is an effective treatment for breast cancer. Aminoglutethimide, however, blocks other cytochrome P-450-mediated steroid hydroxylations, requires concomitant glucocorticoid administration, and is associated with initial side effects. Several more specific inhibitors by destroying aromatase irreversibly as well as by competitive inhibition. One of these, 4-hydroxy-androstenedione, has been intensively studied in animals and is undergoing clinical trial. New data regarding these inhibitors further emphasize the key role of aromatase in estrogen production and the practical utility of blocking this enzyme.
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PMID:Aromatase in breast cancer and the role of aminoglutethimide and other aromatase inhibitors. 309 71

To determine the importance of local oestrogen biosynthesis within the breast, aromatase activity was measured in adipose tissue from the breast quadrants of 12 consecutive mastectomies from patients with breast cancer. Activity was detected in all samples (range 3.6-35.0 fmol oestrogen/mg protein/h) but varied considerably not only among different patients but also among the quadrants of individual breasts. The highest activity in a breast was always found in a quadrant that contained tumour, whereas quadrants with the lowest activity were never associated with the presence of tumour. These results provide evidence of a significant relation between breast adipose tissue and breast cancer. Whether such an association occurs because breast tumours are more likely to develop in areas with enhanced oestrogen biosynthesis or because they secrete into their local environment factors capable of stimulating oestrogen biosynthesis remains to be determined.
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PMID:Aromatase activity in adipose tissue from breast quadrants: a link with tumour site. 312 57

Using dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat as model, comparison was made of the effect of treatment for 20 days with the aromatase inhibitor 4-hydroxyandrostenedione (4-OH-A) (7.5 mg, twice daily) or the antiandrogen flutamide (5 mg, twice daily) on tumor growth as well as on plasma and tumor content of estrogens, androgens, and their precursors and metabolites. Tumor number and size were markedly decreased following treatment with either drug, the effect of treatment being more important on size than number, and on new tumors which developed during treatment than on tumors already present at start of treatment. Treatment with the aromatase inhibitor 4-OH-A caused a parallel decrease in plasma and tumor levels of pregnenolone (Preg), progesterone (P), and 17-OH P, while there was a marked increase in dehydroepiandrosterone (DHEA), androst-5-ene-3 beta,17 beta-diol (delta 5-diol), androstenedione (delta 4-dione), testosterone (T), androstane-3 alpha, 17 beta-diol (3 alpha-diol), and androstane-3 beta,17 beta-diol (3 beta-diol), with no significant change in dihydrotestosterone (DHT) and 17 beta-estradiol levels. The marked increase in tissue T content coupled to a decrease in P levels could well contribute to the inhibition of tumor growth induced by 4-OH-A. Flutamide, on the other hand, caused a marked fall in plasma and tissue levels of Preg, 17-OH Preg, P, and 17-OH P, with no significant change in the concentration of the other steroids, thus suggesting a possible role of the fall in tissue P levels in the inhibition of tumor growth. Since both drugs are potent inhibitors of DMBA-induced tumor growth in intact animals, better knowledge of their mechanism of action should add to our understanding of the multiple endocrine factors controlling the growth of these tumors.
Breast Cancer Res Treat 1988 Dec
PMID:Effects of the aromatase inhibitor 4-hydroxyandrostenedione and the antiandrogen flutamide on growth and steroid levels in DMBA-induced rat mammary tumors. 314 27

Differentiation is a term that indicates the degree to which a tumor resembles histologically the tissue or cell of origin. A system to quantitate the proportion of breast cancer cells participating in glandular differentiation or remaining within ducts was employed. The degree of tumor differentiation of 58 primary breast cancers was correlated with estrogen (ER) and progesterone receptors (PR) and tumor aromatase activity. There was a significant association between tumor differentiation (greater than or equal to 2% cancer cells exhibiting glandular differentiation) and the presence of ER or PR in tumors. Conversely, there was no correlation between tumor differentiation and measurable tumor aromatase activity.
Breast Cancer Res Treat 1988 Sep
PMID:Correlation of aromatase activity with histological differentiation of breast cancer--a morphometric analysis. 319 85

The prognosis from human malignant melanoma varies according to sex and to multiple histologic, biologic and cell kinetic parameters. Thus melanomas exhibit a major degree of heterogeneity in their biologic properties and further characterization of their biochemical heterogeneity should yield important information. The present study sought to demonstrate the activity of a biochemical marker of estrogen synthesis, the aromatase enzyme, in melanoma tissue and to determine its range of activity. Initially, we validated a highly sensitive radiometric assay for aromatase by comparing it with a direct product isolation method. We detected production of 417 pmol/g protein/h of estrone and 37.3 pmol/g protein/h of estradiol by direct product isolation in a human melanoma and 398 pmol estrone/g protein/h by the radiometric assay. The activity present was blocked by similar amounts of the aromatase inhibitor, aminoglutethimide, as were necessary to block placental, breast cancer, and rat brain aromatase activity. We then assayed aromatase radiometrically in 19 human melanomas and found measurable activity ranging from 9 to 398 pmol estrone/g protein/h in 15 tissues. No relationship with the patient's age or sex was demonstrated. The activity exceeded by 2-fold that previously detected in 49/61 human breast cancers. This study identified a marker enzyme in melanoma tissue which varied by 40-fold among human tumors. Correlation of aromatase activity with prognosis and response to various types of therapy is now necessary to establish the biologic relevance of this finding.
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PMID:Marked heterogeneity of aromatase activity in human malignant melanoma tissue. 322 78

Potential pro-drugs for aminoglutethimide (1) an agent used for the treatment of hormone-dependent breast cancer have been synthesized, namely the azo-(2), azoxy-(3) and hydrazo-(4) derivatives. These compounds have been tested for inhibitory action towards the two main target enzymes for 1, aromatase and the cholesterol side-chain cleavage enzyme complex, P-450scc. None inhibited aromatase but 3 and 4 inhibited P-450scc, the respective IC50 values being about twice and one-half that for 1. Compounds 1 and 3 were also tested as inhibitors of the 17 alpha-hydroxylase-C17,20 lyase complex in comparison with ketoconazole which acts against prostatic cancer by this mechanism. The azoxy-derivative 3 was a weak inhibitor but 1 was inactive.
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PMID:Selective inhibition of cholesterol side-chain cleavage by potential pro-drug forms of aminoglutethimide. 326

Whilst endocrine therapy has a long-established role in the management of patients with advanced breast cancer, current therapies produce remission in, at best, only between 30 and 40% of cases. The most efficient use of hormonal measures therefore requires the accurate identification of individuals with hormone-responsive tumours. Oestrogen receptor measurements are useful but not fully discriminatory and additional predictive factors are required. Markers, such as specific hormonally induced proteins and mRNA, and antagonistic systems, such as epidermal growth factor receptors and cyclic AMP binding proteins are currently being evaluated. In terms of therapy, surgical manoeuvres such as adrenalectomy and hypophysectomy have already been replaced by the medical administration of anti-oestrogens, progestogens and drug regimes such as aminoglutethimide-hydrocortisone. Although castration by surgery or radiation remains the first-line treatment in premenopausal women with advanced disease, the advent of depot preparations of LHRH agonists offers the opportunity of performing medical ovariectomies which have the added advantage of being reversible. As a result of laboratory studies, more potent anti-oestrogens and more specific "suicide" aromatase inhibitors are entering into clinical practice. These can be expected to increase efficacy of treatment whilst reducing its side-effects. Research using cell-lines of human breast cancer also suggests that anti-progestins and agents capable of antagonizing steroid-induced growth factors will inhibit tumour growth. Such novel therapies potentially could make a major impact in the endocrine management of breast cancer. Lastly, although the primary management of early breast cancer predominantly involves non-hormonal modalities, clinical trials are now providing evidence of survival benefit from adjuvant endocrine therapy. The knowledge accrued from the use of newer endocrine agents in advanced cancer could therefore ultimately be relevant to the treatment of earlier stages of the disease.
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PMID:Fundamental research leading to improved endocrine therapy for breast cancer. 332 May 38

Application of aromatase inhibitors to the treatment of conditions in which estrogen plays, a role is discussed. Studies in vitro demonstrate that 4-hydroxyandrostenedione (4-OHA) is a potent inhibitor of aromatase. The compound reduces ovariant estrogen production and causes regression of carcinogen (DMBA)-induced mammary tumors in the rat. In the rhesus monkey, 4-OHA was also shown to inhibit peripheral aromatization. To date 58 postmenopausal breast cancer patients with advanced metastatic disease have received 500 mg im weekly while 31 patients received 250 mg 4-OHA orally per day. Estradiol levels were significantly reduced in all patients from a mean of 7.2 + 0.8 pg/ml to 2.8 + 0.3 pg/ml. Of patients receiving 4-OHA im 27% had partial or complete responses and in 10% of patients the disease was stabilized. Similar responses occurred in the patients receiving 4-OHA orally. These results suggest that 4-OHA is effective and that this compound and other aromatase inhibitors could be valuable new additions to the treatment of breast cancer.
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PMID:Aromatase inhibitors: basic and clinical studies. 332 May 68


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