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

Aminoglutethimide is an aromatase inhibitor that is successfully used for endocrine treatment of advanced breast cancer. This drug also stimulates the activity of hepatic mixed-function oxidases, increasing the metabolism of several drugs, including warfarin, digitoxin, antipyrine and theophylline. It also increases the plasma clearance rate of oestrone sulphate. As this oestrogen may be an important substrate for tumour cells, stimulation of oestrone sulphate metabolism may be a component of the mechanism of action of aminoglutethimide.
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PMID:Aminoglutethimide enzyme induction: pharmacological and endocrinological implications. 236 89

Inhibitors of the cytochrome P450 enzyme aromatase, which is involved in the biosynthesis of estrogens from androgens, are of proven utility in the treatment of hormone-dependent breast cancer. The determination of the crystal structure of one such inhibitor, 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione (2) and its 3-butyl analogue (3) is described. In the absence of three-dimensional structural information for the enzyme, conformational analysis and comparison with natural substrates has been performed in order to define possible "active" conformations. The enhanced inhibitory activity of 3 may be linked to hydrophobic interactions between the side chain and that portion of the enzyme that normally interacts with the B and C rings of a steroid substrate. Information gained from this study and previous studies by other workers has been combined in order to produce a hypothesis to explain the pattern of activity of N(1)-alkyl derivatives of 2. The successful application of this hypothesis to the prediction of the relative aromatase inhibitory activities of the two enantiomers of the N-octyl derivative (4) is described.
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PMID:Crystallographic and molecular modeling studies on 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione and its butyl analogue, inhibitors of mammalian aromatase. Comparison with natural substrates: prediction of enantioselectivity for N-alkyl derivatives. 239 6

The antiestrogen tamoxifen and the aromatase inhibitor aminoglutethimide show similar response rates when used in the endocrine management of advanced breast cancer. However, numerous clinical trials have demonstrated no increase in response rate from treatment with the drug combination of tamoxifen plus aminoglutethimide. We investigated the possibility of a pharmacokinetic interaction between these two drugs in six menopausal woman with breast cancer. All patients were investigated under three different conditions (termed phases A, B, and C). The steady state kinetics of tamoxifen were determined when administered alone (phase A) and after coadministration of aminoglutethimide for 6 weeks (phase B). In phase B, the pharmacokinetics for aminoglutethimide were determined and compared with these parameters after a tamoxifen washout of 6 weeks (phase C). The serum concentration of tamoxifen and most of its metabolites ([trans-1(4-beta-hydroxy-ethoxyphenyl)-1,2-diphenylbut-1-ene], 4-hydroxytamoxifen, 4-hydroxy-N-desmethyltamoxifen, N-desmethyltamoxifen, and N-desdimethyltamoxifen) were markedly reduced following aminoglutethimide administration, corresponding to an increase in tamoxifen clearance from 189-608 ml/min. The amount of most metabolites in serum increased relative to the amount of parent tamoxifen. These data are consistent with induction of tamoxifen metabolism during aminoglutethimide exposure. We found no effect of tamoxifen on aminoglutethimide pharmacokinetics or acetylation. We conclude that this aminoglutethimide-tamoxifen interaction should be taken into account when evaluating the clinical effect of this drug combination relative to monotherapy.
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PMID:Decreased serum concentrations of tamoxifen and its metabolites induced by aminoglutethimide. 239 54

Initially, there is a high incidence of CNS-depressant side-effects when the aromatase inhibitor, aminoglutethimide, is used in the treatment of patients with advanced breast cancer. Tolerance to these effects develops with continued dosing. This study examines the development of tolerance to various indices of CNS depression with the drug in mice. Single doses of aminoglutethimide induced a dose-dependent depression of spontaneous locomotor activity, rotarod performance, righting reflex and body temperature and a dose-related antileptazol activity. On repeated dosing with the drug, tolerance to these various activities occurred. The tolerance was found to be dose-dependent in the rotarod and righting reflex tests and time-dependent in the locomotor and body temperature tests. Although the results do not allow a determination of whether this clearly demonstrated phenomenon in the mouse is primarily functional or dispositional, the slow onset (14 days) for complete tolerance may be indicative of a functional mechanism.
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PMID:Development of tolerance to the CNS effects of aminoglutethimide in mice. 239 42

The effect of the adrenal steroids androst-5-ene-3 beta,17 beta-diol (delta 5-diol) and androstenedione (delta 4-dione) was studied on the growth of mammary carcinoma induced in the rat by dimethylbenz[a]anthracene (DMBA). The plasma levels of the two steroids were maintained at values within the range of those found in the circulation of post-menopausal women by constant release from osmotic pumps in ovariectomized animals. delta 5-diol and delta 4-dione, at the daily release rate of 500 micrograms, led to plasma levels of 1.26 +/- 0.19 and 1.72 +/- 0.75 ng/ml, respectively. At these physiologically relevant plasma concentrations, both delta 5-diol and delta 4-dione caused a marked stimulation of tumor growth while having minimal or no effect on uterine weight or on plasma prolactin and LH levels. Concomitant treatment with the aromatase inhibitor aminoglutethimide completely blocked the stimulatory effect of delta 4-dione released from silastic implants on tumor growth, while simultaneous administration of the antiandrogen flutamide had no significant effect. On the other hand, when aminoglutethimide was administered with delta 5-diol, the stimulatory effect of the adrenal steroid on tumor growth was not affected. Such data indicate that, under the present experimental conditions, transformation of delta 4-dione into androgens plays a minor role, the predominant effect of the adrenal steroid being stimulation of tumor growth through conversion into estrogens, while delta 5-diol exerts a direct estrogenic effect independent from aromatase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Breast Cancer Res Treat 1989 Jan
PMID:Androstenedione and androst-5-ene-3 beta,17 beta-diol stimulate DMBA-induced rat mammary tumors--role of aromatase. 249 31

Potent, specific, and nontoxic inhibitors of aromatase would be useful for experimental studies and for use in the treatment of breast cancer and other disorders. We evaluated the effects of CGS 16949A, a nonsteroidal inhibitor of aromatase activity, in 12 postmenopausal women with breast cancer by measuring plasma and/or urinary androgens and estrogens after oral administration of CGS 16949A at doses ranging from 0.6-16 mg daily; each dose was given for 2 weeks. The 0.6-mg daily dose partially lowered estrogen levels, and maximum reduction occurred at doses of 2-16 mg daily. The fall in plasma and urinary estrogens without a concomitant fall in plasma androgens confirmed the blockade of aromatase activity. The degree of estrogen reduction was greatest for urinary estrone [to 27 +/- 3% (+/- SE) of basal], followed in order by plasma estrone sulfate (30 +/- 4%), plasma estrone (32 +/- 6%), urine estradiol (45 +/- 5%), and plasma estradiol (65 +/- 5%). Use of gas liquid chromatography-mass spectrometry techniques revealed similar patterns of reduction in catechol estrogens, estriol, and total urinary estrogens, suggesting that CGS 16949A does not alter the pathways of estrogen metabolism. The degree of estrogen reduction was remarkably similar to that caused with aminoglutethimide. At doses of 4-16 mg daily, CGS 16949A inhibited the C21-hydroxylase enzyme as well, based on concomitant rises in plasma androstenedione, testosterone, and 17 alpha-hydroxyprogesterone. This effect was insufficient to lower urinary cortisol excretion during the study. However, a statistically significant blunting of plasma cortisol responses to ACTH occurred with the 16-mg daily dose. No changes in plasma dehydroepiandrosterone sulfate levels or in thyroid, hematological, liver, or renal parameters were found. No significant side-effects of the medication were encountered. CGS 16949A appears to be a specific inhibitor of aromatase at doses below 4 mg daily and to lack apparent side-effects or toxic actions at doses up to 16 mg daily. This agent shows promise as a potent aromatase inhibitor for physiological and clinical studies.
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PMID:Inhibition of aromatase with CGS 16949A in postmenopausal women. 252 Dec 24

The effect of treatment with the progestogen medroxyprogesterone acetate (MPA) on the peripheral conversion of androstenedione to oestrone and tumour aromatase activity has been examined in post-menopausal women with advanced breast cancer. In addition to being a potent progestational compound, MPA also possesses glucocorticoid properties and glucocorticoids have been shown to stimulate in vitro aromatase activity. While some evidence was obtained of an increase in aromatase activity in tumour tissue after treatment with MPA, peripheral conversion of androstenedione to oestrone was similar when measured before (2.12 +/- 0.67%) and after (1.89 +/- 0.16%) treatment. DNA polymerase alpha activity, measured as a marker of cellular proliferation, decreased from 331 +/- 145 to 156 +/- 93 pmol thymidine triphosphate (TTP)/mg protein per h (P less than 0.02) in tumour samples examined before and after treatment. It is concluded that treatment with high doses of MPA has no effect on the peripheral conversion of androstenedione to oestrone but results in a significant reduction in tumour DNA polymerase alpha activity.
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PMID:The effect of medroxyprogesterone acetate on aromatase and DNA polymerase alpha activities in breast tumours. 253 50

Plasma level, plasma clearance, production rate and interconversions of oestrone and oestrone sulphate were measured in six breast cancer patients receiving aminoglutethimide therapy. Three additional patients had the production rate of oestrone sulphate investigated. Plasma oestrone and oestrone sulphate levels were reduced by a mean of 46% (P less than 0.05) and 71% (P less than 0.005) respectively. These alterations were due to a combined action of aminoglutethimide inhibiting oestrogen production but also increasing oestrogen metabolism. While oestrone and oestrone sulphate production rate was reduced by a mean of 31% (P less than 0.05) and 41% (P less than 0.005) respectively, the plasma clearance rate of oestrone was found to be increased by a mean of 30% (P less than 0.05), and the plasma clearance rate of oestrone sulphate was increased by a mean of 112% during aminoglutethimide treatment. The fraction of oestrone sulphate converted into plasma oestrone was reduced by 52% (P less than 0.05), the transfer of circulating oestrone into sulphate was non-significantly reduced by a mean of 16%. The findings in this investigation show that aminoglutethimide treatment influences oestrogen disposition by mechanisms unrelated to aromatase inhibition. The possibility that such effects might be partly responsible for the mechanism of action of aminoglutethimide in advanced breast cancer should be considered.
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PMID:Alterations in the production rate and the metabolism of oestrone and oestrone sulphate in breast cancer patients treated with aminoglutethimide. 255 85

This study was undertaken to investigate whether miconazole (MCZ), an antifungal agent, inhibits aromatase activity in human breast cancer tissue preparations (n = 6). Aromatase activity in breast cancer tissue was significantly suppressed by an addition of MCZ (1 microM). The aromatase inhibition rate of MCZ was in the range 15-58%. The change of androgen and estrogen levels was also examined in peripheral blood after administering MCZ (200 mg) intravenously to four patients both with breast cancer and two with systemic fungal infection. Serum androstenedione and testosterone levels fluctuated only little. However, serum estrone and estradiol levels tended to decrease after administration of MCZ. These results suggest that MCZ may be useful in the treatment of breast cancer.
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PMID:In vivo and in vitro effects of the antifungal agent miconazole on estrogen biosynthesis in human breast cancer. 259 41

Breast cancer is a highly heterogeneous disorder with regard to biologic and clinical characteristics. Identification of patients with different biologic subtypes is important both prognostically and therapeutically. The recent introduction of estrogen and progesterone receptor measurement has considerably increased our ability to identify patients with hormone-dependent tumors who are likely to respond to endocrine therapy and enjoy a longer survival. Assessment of the tumor growth fraction by autoradiographic or flow cytometric methods and measurement of EGF receptors in tumor specimens are likely to produce additional independent information on the clinical outcome of patients with breast cancer. The endocrine therapy of breast cancer has been greatly facilitated with the introduction of newer forms of therapy such as antiestrogens and aromatase inhibitors. These forms of treatments are well established, not only in patients with metastatic disease but also in selected subgroups of women with operable breast cancer following surgery. In view of its low toxicity and ease of administration, modern endocrine therapy has obviated the need for major ablative procedures such as surgical adrenalectomy and hypophysectomy. Unfortunately, duration of response and survival have not been prolonged by these newer endocrine treatments when compared with traditional hormonal therapy. Thus, new treatment strategies need to be developed, since current therapy does not cure any patient with advanced disease and at best only a small fraction of women with early breast cancer. Hormonally induced manipulation of tumor cell kinetics may provide a tool to enhance the efficacy of cytotoxic chemotherapy, in both metastatic as well as locally advanced disease. This potential approach needs to be further evaluated in prospective randomized clinical trials. Prostate cancer is the male counterpart of hormone-dependent neoplasia. Conventional therapy of this malignancy consists of surgical or medical castration. However, despite a high initial response rate, disease progression invariably occurs with poor response to secondary forms of therapy. Potential new treatment strategies currently being tested in the attempt to improve clinical outcome include simultaneous early blockade of both adrenal and testicular androgens as well as hormonally induced tumor cell growth synchronization and recruitment prior to administration of cytotoxic chemotherapy.
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PMID:Endocrine therapy of breast and prostate cancer. 266 86


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