The influence of intramuscular 4-hydroxyandrostenedione on peripheral aromatisation in breast cancer patients

Al, Jones; MacNeill, FA; Jacobs, Stephen C.; Lønning, Per Eystein; Dowsett, Mitch; Powles, Trevor J.

doi:10.1016/0959-8049(92)90074-c

Cited by 86 publications

(32 citation statements)

References 13 publications

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“…The steroidal aromatase inhibitor, 4-hydroxyandrostenedione (formestane), is used clinically at a dose of 250 mg every 2 weeks, to avoid the high incidence of local side effects that occurs with the 500 mg dose. This compromise dose results in a suppression of aromatase activity by a mean 85%, which is therefore less than that achieved by AG (Jones et al 1992). More recently, we have been able to show that the orally active steroidal inhibitor, exemestane, at its clinically used dose of 25 mg/day suppressed activity by about 97% (Geisler et al 1998), and this compares well with the suppression achieved by the triazole inhibitor, anastrozole, at the 1 mg/day dose (Geisler et al 1996).…”

Section: Aromatase Inhibitionmentioning

confidence: 99%

“…Given that aminoglutethimide (AG) is viewed as the prototype aromatase inhibitor, this has been our reference point, with inhibition produced by the 1000 mg/day dose being approximately 90% (MacNeill et al 1992). The structural derivative of AG, rogletimide, was of greater specificity than AG, but it had only poor pharmacological efficacy, with inhibition less than 80% even at the dose of 800 mg twice daily.…”

Section: Aromatase Inhibitionmentioning

confidence: 99%

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Drug and hormone interactions of aromatase inhibitors.

Dowsett¹

1999

Endocrine-Related Cancer

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The clinical development of aromatase inhibitors has been largely confined to postmenopausal breast cancer patients and strongly guided by pharmacological data. Comparative oestrogen suppression has been helpful in circumstances in which at least one of the comparitors has caused substantially non-maximal aromatase inhibition. However, the triazole inhibitors, letrozole and anastrozole, and the steroidal inhibitor, exemestane, all cause >95% inhibition. Comparisons between these drugs therefore require more sensitive approaches such as the direct measurement of enzyme activity by isotopic means. None of these three agents has significant effects on other endocrine pathways at its clinically applied doses. Pharmacokinetic analyses of the combination of tamoxifen and letrozole have revealed that these drugs interact, resulting in letrozole concentrations approximately 35-40% lower than when Endocrine-Related Cancer (1999) 6 181-185 letrozole is used alone.

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Section: Aromatase Inhibitionmentioning

confidence: 99%

Section: Aromatase Inhibitionmentioning

confidence: 99%

Drug and hormone interactions of aromatase inhibitors.

Dowsett¹

1999

Endocrine-Related Cancer

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“…Different aromatase inhibitors like aminoglutethimide, 4-hydroxyandrostenedione (Formestane®, Ciba-Geigy) and CGS 16949 (Fadrazole®, Ciba-Geigy) inhibit aromatisation by 82-98% Jones et al, 1992;L0nning et al, 1991;Reed et al, 1990;Santen et al, 1978 ). Despite this, several investigators have reported sustained plasma oestrogens at about 30-50% of their control values in treated patients (Dowsett et al, 1989;Dowsett et al, 1990;L0nning et al, 1989b;Santen et al, 1982;Santen et al, 1989;Vermeulen et al, 1983 aromatase inhibitors may act on plasma oestrogen by mechanisms other than aromatase inhibition; aminoglutethimide has been shown to stimulate the metabolism of plasma oestrone sulphate (Oe,S) by enhancing the production of 16a-hydroxylated metabolites (16&-hydroxyoestrone and oestriol) (L0nning et al, 1987;L0nning et al, 1989a;L0nning & Skulstad, 1989).…”

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confidence: 99%

Plasma and urinary oestrogens in breast cancer patients on treatment with 4-hydroxyandrostenedione

Johannessen

Adlercreutz²,

Fotsis³

et al. 1993

Br J Cancer

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Summary Plasma and urinary oestrogens were measured in nine breast cancer patients (eight postmenopausal women and one man) before and during treatment with the aromatase inhibitor 4-hydroxyandrostenedione. Urinary oestrogens were measured by using a highly specific GC-MS method. Plasma levels of oestrone, oestradiol and oestrone sulphate were suppressed by 66.6% (± 3.6%), 57.7% (± 5.1%) and 51.8% (± 6.4%) respectively (P<0.005 for all). Twenty-four hour urinary excretion of total oestrogens, oestradiol, oestriol, 2-hydroxyoestrone, 16&x-hydroxyoestrone and the minor metabolites 16p -and 15a-hydroxyoestrone were all suppressed by mean values ranging from 60% to 82%, (oestradiol: P<0.025, otherwise P<0.005). There were no significant changes in the ratios between the different plasma oestrogens. The finding of sustained plasma and urinary oestrogens at 20-40% compared to their control levels indirectly support a hypothesis of alternative oestrogen sources in postmenopausal breast cancer patients on treatment with 4-hydroxyandrostenedione.The aim of contemporary endocrine treatment of advanced breast cancer is to reduce oestrogen stimulation to the tumour cell. This could be achieved either by blocking oestrogen action at the receptor level with antioestrogens or by reducing the oestrogen supply to the tumour cell.The major pathway of oestrogen production in postmenopausal women is peripheral conversion (aromatisation) of circulating androstenedione (A) into oestrone (Oel) (Grodin et al., 1973). Aromatase inhibition is a successful approach to achieve plasma oestrogen suppression and tumour shrinkage in postmenopausal women suffering from breast cancer. The 'classic' aromatase inhibitor, aminoglutethimide (Orimetene®), has been in clinical use for more than two decades (L0nning & Kvinnsland, 1988). The toxic side effects caused by this drug has prompted the development of new and more selective aromatase inhibitors (L0nning et al., 1990).4-Hydroxyandrostenedione (Formestanee, Ciba-Geigy) is a second generation aromatase inhibitor (Brodie et al., 1977), first reported to cause tumour shrinkage in breast cancer patients in 1984 (Coombes et al., 1984). In contrast to aminoglutethimide, 4-hydroxyandrostenedione seems to act specifically on the aromatase enzyme (Brodie et al., 1981;Dowsett et al., 1989). The drug causes few side-effects, and results from phase I and II trials including more than 500 patients have revealed an overall response rate of 26% among unselected patients (L0nning, 1992).The biochemical action of aromatase inhibitors in vivo is still incompletely understood. Different aromatase inhibitors like aminoglutethimide, 4-hydroxyandrostenedione (Formestane®, Ciba-Geigy) and CGS 16949 (Fadrazole®, Ciba-Geigy) inhibit aromatisation by 82-98% Jones et al., 1992;L0nning et al., 1991;Reed et al., 1990;Santen et al., 1978 ). Despite this, several investigators have reported sustained plasma oestrogens at about 30-50% of their control values in treated patients (Dowsett et al., 1989;Dowsett et al., 1990;L0n...

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“…†Data for both drugs obtained from the same study ) ) (Dowsett et al, 1990. Lønning et al, 1991) (Geisler et al, 1996) (Johannessen et al, 1996) (Geisler et al, 2002) (Geisler et al, 2002) Figure 2 Indirect comparison of oestradiol suppression and aromatase inhibition by first-and second-vs third-generation aromatase inhibitors (Dowsett et al, 1990;Lnning et al, 1991;Jones et al, 1992;MacNeill et al, 1992;Geisler et al, 1996;Johannessen et al, 1997;Geisler et al, 2002). *P ¼ 0.0022 for anastrozole vs letrozole.…”

Section: Clinical Efficacymentioning

confidence: 99%

“…suppressed oestradiol levels by 75% , while formestane (250 mg o.d.) and fadrozole (1 mg twice daily) suppressed oestradiol by approximately 59% (Dowsett et al, 1990;Lnning et al, 1991;Jones et al, 1992). Anastrozole (1 mg o.d.)…”

Section: Whole-body Oestrogen Suppression and Aromatase Inhibitionmentioning

confidence: 99%

Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between potency and clinical efficacy?

Sainsbury

2004

Br J Cancer

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Two-thirds of breast tumours are oestrogen-receptor positive and 60 -70% of these tumours respond to interventions that reduce the effects of oestrogen. Until recently, tamoxifen was the drug of choice for the treatment of hormone-responsive early and advanced breast cancer. However, tamoxifen is associated with increased incidences of endometrial cancer and thromboembolic disease, and many tumours eventually become resistant to treatment with tamoxifen. Thus, there is a need for alternative therapies with different mechanisms of action. In postmenopausal women, aromatase inhibitors (AIs) suppress oestrogen levels by inhibiting oestrogen synthesis via the aromatase enzyme pathway. The third-generation AIs (anastrozole, letrozole and exemestane) are more potent than the earlier AIs (aminoglutethimide, formestane and fadrozole) with respect to both aromatase inhibition and oestrogen suppression. While the earlier AIs were unable to show any benefit over megestrol acetate or tamoxifen as second-and first-line therapy, respectively, in postmenopausal women with advanced breast cancer, third-generation AIs have shown significant benefits in both settings. Comparison of aromatase inhibition and oestrogen suppression between the third-generation AIs anastrozole and letrozole showed a small but significantly greater difference in the degree of suppression of oestrone and oestrone sulphate (but not oestradiol), with letrozole. In an open-label trial, there were no significant differences between letrozole and anastrozole for the clinical end points of time to progression (primary end point), time to treatment failure, overall survival, clinical benefit, duration of clinical benefit, time to response, duration of response or objective response rate in patients with confirmed hormone receptorpositive tumours. Together these data suggest that once a certain threshold of aromatase inhibition is reached, small differences in oestrogen suppression between the third-generation AIs do not lead to clinically significant differences in overall efficacy.

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The influence of intramuscular 4-hydroxyandrostenedione on peripheral aromatisation in breast cancer patients

Cited by 86 publications

References 13 publications

Drug and hormone interactions of aromatase inhibitors.

Drug and hormone interactions of aromatase inhibitors.

Plasma and urinary oestrogens in breast cancer patients on treatment with 4-hydroxyandrostenedione

Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between potency and clinical efficacy?

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