Studies on the Mechanism of Estrogen Biosynthesis. VIII. The Development of Inhibitors of the Enzyme System in Human Placenta1

Schwarzel, William C.; Kruggel, W. G.; Brodie, Harry J.

doi:10.1210/endo-92-3-866

Cited by 299 publications

(76 citation statements)

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“…The enzyme system responsible for the aromatization of androstenedione to oestrone may be competitively inhibited by androst-4-ene-3,6,17-trione and androsta-l,17-dione (Schwarzel, Kruggel & Brodie, 1973 …”

Section: Materials and General Methodsmentioning

confidence: 99%

Further investigation of the antifertility effects in the rat of the antiprogestational steroid, RMI 12,936, and related compounds

Kendle¹

1978

Reproduction

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Section: Materials and General Methodsmentioning

confidence: 99%

Further investigation of the antifertility effects in the rat of the antiprogestational steroid, RMI 12,936, and related compounds

Kendle¹

1978

Reproduction

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“…By the early 1970's, I had married a fellow scientist, Harry Brodie, and joined his lab working on the biochemistry of aromatase, the key enzyme in the biosynthesis of estrogens. Harry, an organic chemist, had begun developing inhibitors of aromatase as potential contraceptive agents and reported the first of these compounds in 1973 [26].…”

Section: Translational Research With Tamoxifenmentioning

confidence: 99%

“…The first selective aromatase inhibitors were reported in 1973 and were a number of C-19 steroids [26]. These compounds were substrate analogs and exhibited properties typical of competitive inhibitors.…”

Section: 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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“…the final and rate-limiting step in the biosynthetic cascade of estrogens [6]. Selective aromatase inhibitors were reported in the early 1970s [7] and reached the clinic 10 years later [8]. Aminoglutethimide, a first generation inhibitor, has been successfully used as a non-steroidal, orally active inhibitor of steroidogenesis.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological profile of MEN 11066, a novel potent and selective aromatase inhibitor

Muratori

Lippi

Mancina

et al. 2003

The Journal of Steroid Biochemistry and Molecular Biology

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MEN 11066 is a new non-steroidal compound which potently inhibits human placenta (K i = 0.5 nM) and rat ovarian (K i = 0.2 nM) aromatase in vitro. In vivo, a single oral dose of 0.3 mg kg −1 significantly decreased uterus weight in immature rats after stimulation of uterus growth by androstenedione. MEN 11066 reduced in a dose-dependent manner plasma estradiol levels in adult female rats treated with pregnant mare serum gonadotropin (PMSG). After 2 weeks of repeated daily treatment in adult rats, a significant decrease in uterine weight was observed together with a 65% decrease in plasma estradiol, whereas plasma levels of testosterone, progesterone, aldosterone, corticosterone, cholesterol, LH and FSH were not affected. The lack of any effect by MEN 11066 on adrenal steroids was confirmed by the unchanged plasma corticosterone and aldosterone levels in immature rats and also in adult rats when the repeated treatment with MEN 11066 (15 days) was followed by the administration of a synthetic ACTH analogue. No change in 11␤-hydroxylase or 21-hydroxylase activities was produced in vitro by the addition of 10 M MEN 11066. Fifteen-day treatment with MEN 11066 did not produce changes in several rat hepatic enzymatic activities involved in the metabolism of xenobiotics. These results demonstrated that MEN 11066 is a potent inhibitor of aromatase which does not interfere with the cytochrome P450 involved in the synthesis of other steroids or in the metabolism of xenobiotics.

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Studies on the Mechanism of Estrogen Biosynthesis. VIII. The Development of Inhibitors of the Enzyme System in Human Placenta1

Cited by 299 publications

References 0 publications

Further investigation of the antifertility effects in the rat of the antiprogestational steroid, RMI 12,936, and related compounds

Further investigation of the antifertility effects in the rat of the antiprogestational steroid, RMI 12,936, and related compounds

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

Pharmacological profile of MEN 11066, a novel potent and selective aromatase inhibitor

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