Aminoglutethimide (Elipten-Ciba) as an Inhibitor of Adrenal Steroidogenesis: Mechanism of Action and Therapeutic Trial

Cash, Ralph; Brough, A. Joseph; Cohen, M N; Satoh, Paul S.

doi:10.1210/jcem-27-9-1239

Cited by 253 publications

(60 citation statements)

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“…The first-generation aromatase inhibitor, aminoglutethimide, was implemented in breast cancer treatment more than 20 years ago (Cash et al, 1967). While the drug is effective in hormone-sensitive breast cancer, lack of specificity (inhibition of adrenal steroid-synthesising enzymes) and side-effects (such as skin rash and lethargy) provoked the development of new aromatase inhibitors (Coombes et al, 1984;Evans et al, 1992;Johnston et al, 1994;Lipton et al, 1995; Santen et al, 1989).…”

mentioning

confidence: 99%

Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer

Geisler

King²,

Dowsett³

et al. 1996

Br J Cancer

328

149

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Sununary The effect of anastrozole ('Arimidex', ZD1033), a new, selective, non-steroidal aromatase inhibitor on in vivo aromatisation and plasma oestrogen levels was evaluated in post-menopausal women with breast cancer. Twelve patients progressing after treatment with tamoxifen were randomised to receive anastrozole 1 mg or 10 mg once daily for a 28 day period in a double-blinded crossover design. In vivo aromatisation and plasma oestrogen levels were determined before commencing treatment and at the end of each 4-week period. Breast cancer is the most common malignancy among women in the western hemisphere. Many of these patients develop metastatic disease, for which no cure is currently available. Because endocrine treatment causes fewer side-effects than chemotherapy, such therapy is first-line treatment in patients with metastatic disease and hormone receptor-positive tumours. While the anti-oestrogen tamoxifen is first choice of therapy in post-menopausal patients with metastatic breast cancer. increasing use of tamoxifen as adjuvant therapy focuses on the need for alternative endocrine treatment options on relapse in breast cancer patients.While ovarian oestrogen synthesis ceases at the menopause, oestrogens are synthesised in peripheral tissue from circulating androgens by the process called aromatisation (Grodin et al., 1973). The main pathway is conversion of androstenedione (A) into oestrone (El), with a minor contribution from conversion of testosterone into oestradiol (E2) (L0nning et al., 1990).Aromatase inhibitors are drugs that inhibit the peripheral conversion of androgens to oestrogens (Santen et al., 1982a), thereby suppressing plasma oestrogen levels in postmenopausal women. The first-generation aromatase inhibitor, aminoglutethimide, was implemented in breast cancer treatment more than 20 years ago (Cash et al., 1967). While the drug is effective in hormone-sensitive breast cancer, lack of specificity (inhibition of adrenal steroid-synthesising enzymes) and side-effects (such as skin rash and lethargy) provoked the development of new aromatase inhibitors (Coombes et al., 1984;Evans et al., 1992;Johnston et al., 1994;Lipton et al., 1995; Santen et al., 1989).Anastrozole (Arimidex; 2,2'[5-(1H-1 ,2,4-triazol-1-ylmethyl) -1,3-phenylene]bis-(2-methylpropiononitrile, Figure 1) is a new, potent and selective aromatase inhibitor belonging to the triazole class. Pilot studies in post-menopausal women have shown the drug to suppress plasma E2 by > 80% (Plourde et al., 1994), and preclinical studies as well as observations in women suggest the drug to be highly specific with no influence on adrenal steroid synthesis (Plourde et al., 1995). A major problem in evaluating the biochemical efficacy of aromatase inhibitors has been the lack of internal consistency between the percentage aromatase inhibition and degree of plasma oestrogen suppression. While aminoglutethimide as well as the second-generation aromatase inhibitor formestane and the third-generation inhibitor fadrozole (L0nning et al., 1991) ...

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mentioning

confidence: 99%

Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer

Geisler

King²,

Dowsett³

et al. 1996

Br J Cancer

328

149

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“…AG alone had no effect on SHBG binding capacity but the combination of AG and danazol caused a marked reduction after 1-2 months (P<O·OOl) to 26% of pre-treatment level. The apparent further fall in the mean level after [3][4] months to 17% of pre-treatment was not statistically significant.…”

Section: Percentage Of Free Oestradiolmentioning

confidence: 64%

Biochemical Basis for the Antagonism between Aminoglutethimide and Danazol in the Endocrine Treatment of Breast Cancer

et al. 1986

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Only 13% of postmenopausal advanced breast cancer patients responded to endocrine treatment with aminoglutethimide plus danazol whilst 33% responded to aminoglutethimide alone, despite a similar suppression of serum oestradiol levels in the two groups. The patients on aminoglutethimide and danazol showed a marked suppression of sex hormone binding-globulin binding capacity and a consequent rise in percent-free oestradiol. This led to the concentration of free oestradiol being less well suppressed than that of total oestradiol and in some patients free oestradiol concentrations were higher on treatment than before. Patients on aminoglutethimide alone showed no change in the binding of oestradiol and the percentage suppression of the free oestradiol concentration was similar to that of total oestradiol. The opposing effects of danazol and aminoglutethimide on the concentration of the free, biologically active fraction of oestradiol in the circulation may explain the poor therapeutic efficacy of this combination in breast cancer patients.

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“…Compounds that carry a nitrogen heteroatom have been the most studied and their binding with cytochrome P-450 enzymes give rise to a Type II difference spectrum with Soret maximum at 421-430 nM and minimum at 390-410 nM [62,63]. Intrinsically, nonsteroidal inhibitors are likely to be less enzyme specific than steroidal substrate analogs and can inhibit other cytochrome P450-mediated hydroxylations as was the case for aminoglutethimide [30,64]. The newer non-steroidal inhibitors, anastrozole and letrozole, are triazole derivatives are potent, reversible inhibitors with high specificity.…”

Section: Non-steroidal Aromatase Inhibitorsmentioning

confidence: 99%

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

Jordan¹,

Brodie²

2007

Steroids

259

183

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The enthusiasm with which the clinical community has embraced the use of antiestrogenic therapy to treat breast cancer is based upon the proven record of success that first the nonsteroidal antiestrogen tamoxifen and then the aromatase inhibitor have demonstrated in clinical trial. The reasons for the enthusiasm are obvious. Antihormonal therapy, particularly aromatase inhibition to create a "no estrogen state" in the postmenopausal breast cancer patient is effective, saves women's lives, is contributing successfully to reducing the national mortality from breast cancer, is relatively cheap and has fewer side effects and easy administration (oral) than any other anticancer strategy. However, the successful application of a therapeutic strategy to block the known growth stimulation property of estrogen in breast cancer was not greeted with such enthusiasm 40 years ago.Estrogen is essential for life. Without the critical role of estrogenic steroids, reproduction would not be possible. Based on emerging knowledge from laboratory studies, the value of modulating the steroid environment during the menstrual cycle was advanced to clinical testing during the 1950's as a means of oral contraception. The results of these studies were to change society forever.The Worcester Foundation for Experimental Biology is the place where Gregory Pincus established the scientific principles necessary to propose clinical testing of the oral contraceptive and M.C. Chang subsequently established the first protocols to perform in vitro fertilization. Simply stated, the Worcester Foundation was, at that time, the world center for steroid endocrinology and reproductive biology. Over the years, hundreds of scientists have trained at the Foundation and subsequently spread their knowledge throughout the world [1]. However, fashions in research change and new opportunities emerge.In 1971, President Nixon made a national commitment to seek a cure for cancer by signing the National Cancer Act. Mahlon Hoagland, the President of the Worcester Foundation, responded to the initiative by appointing Professor Elwood V. Jensen, Director of the Ben May Cancer Research Laboratory at the University of Chicago, to be a member of the Foundation's Scientific Advisory Board. Jensen had discovered the estrogen receptor (ER) as the putative mechanism of estrogen action in its target tissues [2]. The known link between estrogen and breast cancer suggested that "antiestrogenic strategies" might have potential as therapeutic Correspondence to: V. Craig Jordan, v.craig.jordan@fccc.edu. Present Address: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be d...

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Aminoglutethimide (Elipten-Ciba) as an Inhibitor of Adrenal Steroidogenesis: Mechanism of Action and Therapeutic Trial

Cited by 253 publications

References 0 publications

Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer

Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer

Biochemical Basis for the Antagonism between Aminoglutethimide and Danazol in the Endocrine Treatment of Breast Cancer

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

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