Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel nonsteroidal aromatase inhibitor, TAN-931, was isolated from the culture filtrate of a soil isolate fungus, No. 8974. The strain was identified as Penicillium funiculosum No. 8974. TAN-931 inhibited human placental and rat ovarian aromatase activity, and the IC50 value was 17.2 and 162 microM, respectively. The inhibition of human placental aromatase was uncompetitive with respect to androstenedione conversion with a Ki value of 40 microM. When TAN-931 was subcutaneously administered at doses of 25, 50 and 100 mg/kg (once/day, x4) to 20-day-old female Sprague-Dawley rats treated with gonadotropin, the plasma estradiol-17 beta level and the weight of ovaries and uterus were markedly reduced in a dose-dependent manner. The in vivo inhibitory activity of TAN-931 was more potent than that of 4-hydroxyandrostenedione. Consecutive administration of TAN-931 (100 mg/kg, sc, twice/day, x 7) to 9-week-old male Sprague-Dawley rats did not induce any adrenal hypertrophy even though administration of aminoglutethimide caused 2-fold enlargement of the adrenal under the same conditions. Specific binding of TAN-931 to the estrogen receptor from a human breast cancer cell line, MCF-7, was not detected.
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PMID:TAN-931, a novel nonsteroidal aromatase inhibitor produced by Penicillium funiculosum No. 8974. I. Taxonomy, fermentation, isolation,characterization and biological activities. 207 87

A study of the aromatase inhibitor 4-hydroxy-androstenedione (4-OHA) was conducted in normal healthy men to compare the oral administration of two preparations of the drug: an unformulated, micronized powder and a formulated microcrystalline material (CGP 32349). The formulated material achieved a significantly higher mean peak concentration (88% greater than that obtained using the unformulated powder) and a higher mean AUC (not significant). The median time to peak was 1.5 h for both preparations and the elimination rate constants were similar (0.31 for micronized 4-OHA and 0.36 h-1 for formulated 4-OHA). Plasma concentrations of 4-OHA in this group were markedly lower than those previously observed in postmenopausal breast cancer patients. Significant biological activity was demonstrated with the formulated material in its suppression of plasma oestradiol levels, whereas no significant suppression was obtained using the micronized powder. An increase in androgen levels was observed that may have been due to competitive inhibition of enzymes involved in metabolic clearance of androgens and/or to decreased feedback inhibition of gonadotrophin secretion by oestradiol.
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PMID:Comparison of the pharmacokinetics and pharmacodynamics of unformulated and formulated 4-hydroxyandrostenedione taken orally by healthy men. 212 33

Estrogen production by adipose tissue has been implicated in the etiology of such human cancers as endometrial and breast cancer. Estrogen production by adipose cells is subject to complex multifactorial regulation by a number of growth factors and cytokines, including those produced by breast cancer cells. In order to understand the mechanisms responsible for aromatase regulation, the structural gene encoding aromatase cytochrome P-450 (P-450AROM) was isolated from human genomic DNA. The gene spans at least 70 kb and is comprised of 10 exons, the first of which is untranslated. DNA sequence analysis indicates that the gene has a putative TATA (ATAAAA) sequence at -23 bp and putative CAAT binding sequences beginning at -41, -67, and -83 bp, that constitute a promoter region responsible for expression in placenta. However, this promoter does not appear to be responsible for expression in adipose, which may therefore be under the control of another, tissue-specific, promoter. Use of Polymerase Chain Reaction (PCR) technology has allowed for determination of expression of P-450AROM in samples of breast adipose. Preliminary results indicate that expression is highest in the upper lateral region, similar to the site of most frequent localization of tumors.
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PMID:The aromatase enzyme: from cloning to cancer. 213 92

Thirty-one postmenopausal women with advanced breast cancer have been treated with the nonsteroidal competitive aromatase inhibitor CGS 16949A at p.o. doses of 0.3, 1, and 2 mg twice a day. All patients were assessed for response. Five patients, all treated with 1 mg twice daily, had objective evidence of response (two complete responses and three partial responses); disease stabilized in 17 patients. Minor side effects were reported by ten patients. Two further patients treated with 2 mg twice a day experienced persistent nausea which improved after dose reduction, and one patient, treated with 0.3 mg twice daily, developed a vasculitic rash requiring discontinuation of CGS 16949A. Estradiol levels measured in 24 patients were significantly suppressed 2 wk after starting CGS 16949A treatment at all doses used. Treatment with 2 mg twice a day lowered estradiol levels to a mean of 29% of pretreatment values which was significantly lower than the corresponding figure of 57% for patients treated with 0.3 mg twice daily. Aldosterone levels were significantly lowered below pretreatment values by the 1- and 2-mg twice daily doses. No clinically apparent cases of adrenocortical insufficiency occurred, although small changes in serum electrolyte levels were noted. The results indicate that CGS 16949A is an effective aromatase inhibitor, requiring further evaluation in the treatment of advanced breast cancer. The optimal dose is likely to be 1 mg twice a day.
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PMID:Preliminary study of the treatment of advanced breast cancer in postmenopausal women with the aromatase inhibitor CGS 16949A. 213 67

Inhibition of postmenopausal estrogen production by aromatase inhibitors is an established drug treatment modality for postmenopausal breast cancer. In this article postmenopausal estrogen disposition and the alterations caused by treatment with aromatase inhibitors are reviewed. Recent investigations have challenged the hypothesis that aromatization of androstenedione into estrone is the sole production pathway for estrogens in postmenopausal women. The finding that estrogens persist in the plasma of patients receiving aminoglutethimide treatment despite a near total inhibition of the aromatase enzyme suggests that alternative pathways for estrogen synthesis exist. While nonspecific actions of aromatase inhibitors may be disadvantageous, certain effects may also be beneficial. Recent findings that aminoglutethimide may induce estrone sulfate metabolism questions whether this "prototype" aromatase inhibitor might have a dual mechanism of action. The importance of investigating the possible influence of different aromatase inhibitors on all components of estrogen disposition is considered.
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PMID:Postmenopausal estrogen synthesis and metabolism: alterations caused by aromatase inhibitors used for the treatment of breast cancer. 213 51

Inhibitors of aromatase are useful for treatment of estrogen-dependent breast cancer and as probes for study of normal physiology. Inhibitors of this enzyme with more favorable properties are necessary since the most extensively utilized inhibitor, aminoglutethimide, lacks specificity and causes frequent side effects. The present study compared the potency and specificity of a new aromatase inhibitor, CGS-16949A, with that of aminoglutethimide in a variety of in vitro enzyme preparations. CGS-16949A blocked aromatase by 50% in human breast cancer homogenates, live breast cancer cells, human placental microsomes and porcine ovarian microsomes at concentrations of 0.008 to 0.02 microM. In contrast, concentrations of 10-25 microM of aminoglutethimide were required to inhibit aromatase similarly in these tissues. For human placental microsomes, the Ki for CGS 16949A was 0.17 nM and for aminoglutethimide, 0.54 microM. Preincubation studies indicated that CGS-16949A acts by a competitive inhibitory mechanism and not by "suicide inhibitory" properties. With respect to specificity, CGS-16949A had no effect on cholesterol side-chain cleavage activity in rat testicular mitochondria. A 54% reduction in enzyme activity was observed in adrenal mitochondria but only at concentrations five orders of magnitude higher (i.e. 100 microM) than required to inhibit aromatase. In contrast, 10 microM concentrations of aminoglutethimide blocked cholesterol side-chain cleavage activity in rat testicular and adrenal mitochondria by 67 and 91%, respectively. These data suggest that CGS-16949A has favorable properties as a specific and potent aromatase inhibitor.
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PMID:Potency and specificity of CGS-16949A as an aromatase inhibitor. 213 12

A selective inhibitor of aromatase is widely sought for the treatment of postmenopausal women with breast cancer. CGS 16949A has been shown to be a highly selective, potent inhibitor of aromatase in vitro. Its potency as an oestrogen suppressant and its selectivity were examined by treating 24 postmenopausal patients with advanced breast cancer for 4 weeks with doses of 0.3, 1.0 and 2.0 mg twice daily. The study was conducted in two parts which compared the two lower doses and the two higher doses separately in a cross-over design protocol. All doses significantly suppressed serum oestradiol and oestrone levels below pretreatment levels. Cross-over analysis indicated that the 2.0 mg twice daily dose achieved significantly greater suppression of oestradiol levels than 0.1 mg twice daily but there was no significant differences between any of the doses in the suppression of oestrone. No significant effects were noted on serum levels of LH, FSH, SHBG, prolactin, testosterone, androstenedione, 17-hydroxyprogesterone or cortisol. For the four steroids this was true both for basal samples and those collected after Synacthen stimulation. However, serum aldosterone levels were significantly suppressed by 1.0 mg twice daily CGS 16949A and further suppressed by 2.0 mg twice daily. It is concluded that CGS 16949A is a potent oestrogen suppressant in postmenopausal patients but that its effect is not totally selective.
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PMID:Potency and selectivity of the non-steroidal aromatase inhibitor CGS 16949A in postmenopausal breast cancer patients. 214 26

The aromatase inhibitor, 4-hydroxyandrostenedione (4OHA) is an effective treatment for advanced post-menopausal breast cancer. The clinical and endocrine effects of 4OHA treatment were studied in five pre- and perimenopausal women with metastatic breast cancer. Serum oestradiol levels were not significantly reduced as a result of treatment with 500 mg of 4OHA by weekly i.m. injections and no patient had a tumour response. Four patients were subsequently treated with the luteinising hormone releasing hormone (LHRH) analogue, gosereline, and three had objective responses. The endocrine effects of combined treatment with goserelin (Zoladex), and 4OHA were studied in a further five premenopausal women. Serum oestradiol levels after treatment with goserelin alone were typical of post-menopausal women. Addition of 4OHA led to a further suppression of oestradiol to within the range observed in post-menopausal patients treated with further suppression of oestradiol to within the range observed in post-menopausal patients treated with 4OHA. Six patients whose tumours had regressed as a result of goserelin treatment and who subsequently relapsed were then given combined treatment. Four of the six experienced a second remission. We conclude that while 4OHA alone is unlikely to be a satisfactory treatment for premenopausal patients with advanced breast cancer, 4OHA in conjunction with goserelin leads to profound suppression of oestradiol. The combination of LHRH analogue and aromatase inhibitor may prove to be a superior treatment to LHRH analogue alone in these patients.
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PMID:The clinical and endocrine effects of 4-hydroxyandrostenedione alone and in combination with goserelin in premenopausal women with advanced breast cancer. 214 64

The supposed mechanism of action of aminoglutethimide (AG), medical adrenalectomy, has been challenged. AG is now considered to act as an inhibitor of the aromatization of mainly adrenal androgens to estrogens in peripheral tissues and/or breast cancer itself. To further establish the AG dose required to sufficiently reduce estrogen levels in plasma and the possible role of hydrocortisone (HC) in combination with AG or by itself, postmenopausal advanced breast cancer patients received AG low (125 mg bid) or medium (250 mg bid) dose alone or combined with HC (20 mg bid) or HC alone (20 mg bid). Preliminary hormonal data show a similar reduction of serum estrone and estrone sulphate by at least some 50% at 8 wk in all treatment groups. At 6 months these effects persist except for patients treated with HC alone. In the latter a normalization of estrone levels is observed with effective suppression of adrenal androgen precursors, suggesting increased aromatase activity with prolonged glucocorticoid treatment.
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PMID:Second line endocrine treatment of postmenopausal advanced breast cancer. Preliminary endocrine results of a 5-arm randomized phase II trial of medium vs low dose aminoglutethimide, with or without hydrocortisone vs hydrocortisone alone (EORTC 10861). 214 1

In postmenopausal women with breast cancer, aromatase, which is the enzyme converting androstenedione to estrone and testosterone to estradiol, is the rate-limiting step in estrogen biosynthesis. The currently available aromatase inhibitor, aminoglutethimide, effectively blocks estrogen production and products tumor regression in patients previously treated with tamoxifen. This drug, however, produces frequent side effects and blocks steroidogenic steps other than the aromatase enzyme. Thus, newer aromatase inhibitors with greater potency and specificity are under intense study. More than 20 such compounds have recently been developed. In several clinical trials, 4-hydroxyandrostenedione, given parenterally, has been highly active and specific for aromatase inhibition in patients with breast cancer. In two large recent studies, one-third of heavily pretreated woman experienced objective tumor regression with this therapy. CGS 16949A, a newer agent, is also in Phase III clinical trials. This compound is an imidazole derivative with nearly 1000-fold greater potency than aminoglutethimide. An initial Phase I study compared the potency of 0.6-16 mg daily in 12 postmenopausal women and found maximal suppression of urinary and plasma estrogens with 2 mg daily. The degree of inhibition was similar to that induced by aminoglutethimide or by surgical adrenalectomy. No CNS, hematologic or biochemical toxicity was observed. A larger Phase II study in 54 patients confirmed this high degree of potency of CGS since a plateau effect was observed at the 1.8, 2 and 4 mg daily doses. The endocrine effects were not absolutely specific as a blunting of ACTH-stimulated but not basal aldosterone levels were observed. This and other emerging aromatase inhibitors offer promise as pharmacologic methods to inhibit estrogen production specifically and without side effects.
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PMID:Recent progress in development of aromatase inhibitors. 214 3


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