Aminoglutethimide for the treatment of advanced postmenopausal breast cancer

Summary Eighty-one postmenopausal women with advanced breast cancer were studied for the effects of treatment with aminoglutethimide (AG) plus hydrocortisone on peripheral hormones and response to therapy. There were 40 responders (R) and 41 non-responders (NR) at 3 months from the start of treatment. Plasma oestrone concentrations were higher in non-responders at 1 and 2 months after starting AG (Means: NR 106+50, R 84+26pmoll1-, P<0.05; highest value NR 121+51, R 99+24pmoll1, P<0.05). High oestrone levels were correlated with bulky liver secondaries, but not with age, tumour-free interval, time from last menstrual period, time from relapse to start of AG or body weight. Non-responders had higher mean prolactin levels on treatment (prolactin

Section: Methodsmentioning

confidence: 99%

Aminoglutethimide induced hormone suppression and response to therapy in advanced postmenopausal breast cancer

Harris¹,

Dowsett²,

Smith³

et al. 1983

“…Peripheral aromatisation is the main source of post-menopausal oestrogens (Grodin et al, 1973). Its inhibition was first shown to be an effective clinical treatment by (Hall et al, 1969) using Aminoglutethimide (AG) and since by many others (Santen et al, 1981;Harris et al, 1982). AG is still the only widely available and used aromatase inhibitor.…”

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confidence: 99%

The influence of aminoglutethimide and its analogue rogletimide on peripheral aromatisation in breast cancer

MacNeill

Jones²,

Jacobs³

et al. 1992

Summary The influence of the prototype aromatase inhibitor Aminoglutethimide (AG) and its analogue Rogletimide (RG) on peripheral aromatisation were investigated in 13 postmenopausal women with advanced breast cancer. Seven patients received AG 1,000 mg daily plus Hydrocortisone (HC) cover and six received.RG as dose escalation of 200 mg bd, 400 mg bd and 800 mg bd. In vivo aromatase inhibition was investigated using the double bolus injection technique with [4-14C] oestrone ([4-4C]E1) and [6,7-3H] androstenedione ([6,7-3H] 4A) followed by a 96 h urine collection. The labelled urinary oestrogens were separated and purified by chromatography and HPLC. Plasma oestradiol (E2) was also measured.AG Hormonal manipulation is an effective treatment modality in 30% of post-menopausal women with advanced breast cancer (Stoll, 1981). The majority of endocrine treatments for metastatic breast cancer are aimed at oestrogen deprivation of the cancer cell, either by oestrogen receptor blockade as with tamoxifen or by inhibition of peripheral oestrogen production by the aromatase system of enzymes. Peripheral aromatisation is the main source of post-menopausal oestrogens (Grodin et al., 1973). Its inhibition was first shown to be an effective clinical treatment by (Hall et al., 1969) using Aminoglutethimide (AG) and since by many others (Santen et al., 1981;Harris et al., 1982). AG is still the only widely available and used aromatase inhibitor. However at doses greater than 500 mg a day its inhibition of cholesterol side chain cleavage in the early steps of steroidogenesis and the partial blockade of Ilp-, 18-and 21-hydroxylases in the adrenal necessitates its administration in conjunction with hydrocortisone to avoid hypoaldosteronism (Lonning & Kvinnsland, 1988). AG has other side effects ranging from self limiting rashes to serious bone marrow suppression. Neuro-toxicity can be a particular problem in the elderly, limiting its use in a group of patients ideally suited to aromatase inhibition for palliating advanced disease. These problems have encouraged the development of new, more specific second generation aromatase inhibitors (Goss et al., 1986;Harris et al., 1988;Stein et al., 1990aStein et al., , 1990bDowsett et al., 1990).Rogletimide (RG) is a non-steroidal analogue of AG which during early development showed similar in vitro aromatase potency (Foster et al., 1985). In vivo animal studies revealed a lack of toxic metabolites and CNS effects and volunteer/patient studies confirmed its ability to suppress E2 (Haynes et al., 1991). RG did not inhibit cortisol production either by interaction with cholesterol side chain cleavage or with the 21-and 11P-hydroxylases and therefore does not require cortisone replacement . Pharmacokinetic data showed that RG induced its own hepatic metabolism similar to AG Patients, materials and methods PatientsThe protocol was approved by the hospital ethical committee and all patients gave informed consent. ARSAC clearance was obtained for the use of radio-isotopes in patients. Thirt...

“…Aminoglutethimide (AG) is a clinically effective endocrine treatment for advanced postmenopausal breast cancer (Lipton et al, 1974;Smith et al, 1978;Santen et al, 1981;Harris et al, 1982), in which it has been used almost exclusively in doses of 750-1000mgday-1, in combination with hydrocortisone (HC). This therapeutic regime was derived with the aim of suppressing adrenal androgen synthesis (Lipton et al, 1974;Wells et al, 1978) which was expected to result from previously reported inhibition by AG of the conversion of cholesterol to pregnenolone by 20,22-desmolase (Cohen, 1967;Dexter et al, 1967).…”

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confidence: 99%

Effective inhibition by low dose aminoglutethimide of peripheral aromatization in postmenopausal breast cancer patients

Dowsett¹,

Santner²,

Santen³

et al. 1985

Aminoglutethimide without glucocorticoid has been shown to be a clinically effective treatment for postmenopausal breast cancer in low dosage (250 mg day-1). The mechanism of action of this approach is thought to be the inhibition of peripheral aromatase, the enzyme which converts androstenedione to oestrone. The activity of this enzyme was measured in vivo by injection with 3H-androstenedione and 14C-oestrone and found to be 0.20% +/- 0.05 in 5 patients on low dose AG therapy. In comparison with previously published data this demonstrates a 92% inhibition of peripheral aromatase activity confirming aromatase inhibition as a viable aim in the endocrine treatment of breast cancer.