Endocrine, pharmacokinetic and clinical studies of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione ('pyridoglutethimide') in postmenopausal breast cancer patients

Dowsett, Mitchell; MacNeill, FA; Mehta, A.; Newton, C. J.; Haynes, Ben P.; Jones, A. S.; Jarman, Michael; Lønning, PE; Powles, T. J.; Coombes, R. Charles

doi:10.1038/bjc.1991.420

Cited by 29 publications

(3 citation statements)

References 18 publications

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“…The use of the same methodology in the same laboratory makes these results comparable in a way. The results (given in Table 3) show increasing potency concerning plasma estrogen suppression from the first to the second and third generation of aromatase inhibitors [19][20][21][22][46][47][48][49][50][51]. These results parallel the findings made with the tracer method used for the estimation of ''total body aromatase inhibition'' ( Table 2).…”

Section: Plasma Estrogen Measurementssupporting

confidence: 76%

Aromatase inhibitors: from bench to bedside and back

Geisler

2007

Breast Cancer

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The development of the novel "third generation" aromatase inhibitors (anastrozole, letrozole) and inactivators (exemestane) is one of the most successful contemporary achievements in breast cancer therapy. While clinical studies evaluated toxicity and efficacy in metastatic disease, the endocrine effects of multiple compounds were evaluated in parallel, identifying the most potent aromatase inhibitors based on estrogen deprivation in plasma and tissue samples in addition to "total body aromatase inhibition" in vivo. Thus, "translational" studies have been of vital importance identifying the unique characteristics of these drugs. While first- and second generation aromatase inhibitors inhibit estrogen synthesis in vivo by up to 90%, third generation compounds like anastrozole, exemestane and letrozole were shown to cause > or = 98% aromatase inhibition in humans. The present paper summarises and discusses the "translational research" that provided the background for the implementation of the third generation aromatase inhibitors and inactivators into large clinical trials and later on in clinical use. Finally, some of the major topics of currently ongoing translational research programs are presented. These programs focus on aromatase regulation in different tissues, mechanisms of resistance to aromatase inhibition and strategies to overcome resistance like combined therapy with aromatase inhibitors and intracellular signal transduction inhibitors.

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Section: Plasma Estrogen Measurementssupporting

confidence: 76%

Aromatase inhibitors: from bench to bedside and back

Geisler

2007

Breast Cancer

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“…A higher specific activity may be achieved with use of 125 I-labelled compounds (specific activity in the 2000 Ci/mmol range). The first sensitive 125 I-based RIA for E 2 measurement in patients treated with aromatase inhibitors was developed by Professor Mitch Dowsett at the Royal Marsden Hospital [24] and subsequently used to measure plasma E 2 suppression with different aromatase inhibitors [25][26][27][28][29][30]. Some years later, learning this assay for E 2 measurement, we used the same 125 I-E 2 standard and E 2 antibody developing a highly sensitive assay for plasma E 1 S measurement.…”

Section: Plasma Estrogen Measurements In Relation To Treatment With Amentioning

confidence: 99%

Estradiol measurement in translational studies of breast cancer

Lønning

2015

Steroids

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Plasma estrogen measurement with use of radioimmunoassays has been instrumental in the development of aromatase inhibitors for endocrine therapy of postmenopausal breast cancer. However, due to low plasma estrogen concentrations in postmenopausal women, direct radioimmunoassays lack the sensitivity required. While certain laboratories have developed highly sensitive assays for research purposes revealing plasma estrogen suppression consistent with results from tracer studies, such assays are time and labor-consuming due to need for pre-analytical chromatographic purification, sample concentration and sometimes conversion of precursors to products. While novel chromatographic methods involving mass spectrometry analysis are likely to replace such radioimmunoassays in the future, so far a limited number of laboratories have developed suitable assays with a detection limit (around 1 pM) that is required for analyzing plasma estrogen levels in patients during treatment with potent aromatase inhibitors.

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“…12,13 Roglethimide was the second glutethimide derivative, whose use was limited by its low potency and significant side effects. 14,15 The second-generation AI fadrozole was then developed and was found to be more specific than aminoglutethimide. It still has significant side effects as it suppresses aldosterone synthesis.…”

Section: Aromatase Inhibitor Developmentmentioning

confidence: 99%

The Clinical Pharmacology of Anastrozole

Bao¹,

Rudek²

2011

European Oncology &Amp; Haematology

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Anastrozole is a potent non-steroidal aromatase inhibitor that selectively inhibits aromatase. It is the first aromatase inhibitor approved by the US Food and Drug Administration as an adjuvant hormonal therapy in early-stage breast cancer. With most patients needing to take anastrozole for two to five years, it is important for physicians to understand the clinical pharmacology of anastrozole. Anastrozole has excellent oral bioavailability and is widely distributed throughout the body. It is extensively metabolised by the liver, with a half-life of 4050 hours. Anastrozole is primarily excreted through the faecal route. Steady-state concentrations are achieved after seven days of once-daily administration. The standard dosage of anastrozole is 1mg/day orally. No dose adjustments are necessary based on hepatic or renal dysfunction. No significant drugdrug interaction has been reported with anastrozole use. This article is to summarise the existing knowledge of the pharmacokinetics of anastrozole.

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Endocrine, pharmacokinetic and clinical studies of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione ('pyridoglutethimide') in postmenopausal breast cancer patients

Cited by 29 publications

References 18 publications

Aromatase inhibitors: from bench to bedside and back

Aromatase inhibitors: from bench to bedside and back

Estradiol measurement in translational studies of breast cancer

The Clinical Pharmacology of Anastrozole

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