Inhibition of Adrenal Corticosteroid Synthesis by Aminoglutethimide: Studies of the Mechanism of Action<sup>1</sup>

Dexter, R. N.; Fishman, Lawrence M.; Ney, Robert L.; Liddle, Grant W.

doi:10.1210/jcem-27-4-473

Cited by 277 publications

(74 citation statements)

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“…Treatment of cultures with aminoglutethimide, an inhibitor of the conversion of cholesterol to pregnenolone (24), reduced the ACTH and monobutyryl cyclic AMP (cAMP)-stimulated level of steroid production to the nonstimulated level seen in the absence of aminoglutethimide (Table I). Under these conditions, ACTH and monobutyryl cAMP continued to reduce [3H]thymidine incorporation into DNA to the same extent as in the non-aminoglutethimide-treated cultures.…”

Section: Resultsmentioning

confidence: 99%

Hormonal Control of Adrenocortical Cell Proliferation

Hornsby¹,

Gill²

1977

J. Clin. Invest.

122

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A B S T R A C T A primary bovine adrenocortical cell culture system responsive to physiological concentrations of ACTH has been established. When added to cultures, ACTH inhibited DNA synthesis and cell division over the same concentration range required for stimulation of fluorogenic steroid production (0.01-10 nM). With chronic exposure to ACTH, cells became desensitized to the growth inhibitory effects of ACTH. Though cell growth was initially completely inhibited by ACTH, cells ultimately began to grow in its continued presence. The lag time to initiation of cell growth, the rate of growth, and the final density achieved depended on the ACTH concentration. Desensitization to ACTH1_39 was not induced by monobutyryl cyclic AMP nor by ACTH11-24. Specificity of desensitization was apparent because cells which had become desensitized to ACTH1_39 remained fully responsive to monobutyryl cyclic AMP, prostaglandin E1, and cholera toxin. Though the effects of ACTH on cell growth were readily reversible upon hormone removal, the desensitized response to readdition of ACTH persisted for at least 8 h.

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Section: Resultsmentioning

confidence: 99%

Hormonal Control of Adrenocortical Cell Proliferation

Hornsby¹,

Gill²

1977

J. Clin. Invest.

122

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“…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). HC was added to the regime to prevent a rise in adrenocorticotrophic hormone, which would result from suppression of cortisol synthesis, and which might overcome the enzyme block (Wells et al, 1978).…”

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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

Br J Cancer

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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.

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“…The response of some patients to cortisone alone (Miller & Hinman, 1954) or to bilateral adrenalectomy (Mahoney & Harrison, 1972;Hendry, 1974) suggests that in some cases the tumour may retain sensitivity to residual adrenal androgens. Aminoglutethimide is an inhibitor of several enzymes involved in adrenal steroid synthesis (Dexter et al, 1967) and in prostaglandin metabolism (Harris et al, 1983c). The combination of aminoglutethimide and hydrocortisone had previously been reported both to reduce circulating levels of adrenal androgen and, in small numbers of patients, to induce responses in hormone-relapsed advanced prostatic cancer (Robinson et al, 1974;Sanford et al, 1976).…”

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Response to aminoglutethimide and cortisone acetate in advanced prostatic cancer

Ponder¹,

Shearer²,

Pocock³

et al. 1984

Br J Cancer

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Summary Forty patients with metastatic adenocarcinoma of the prostate were evaluated for response to treatment with aminoglutethimide plus cortisone acetate. All had relapsed from or failed to respond to primary endocrine treatment with orchidectomy or stilboestrol. Nineteen patients (48%) showed subjective response, in most cases relief of bone pain. Side effects limited treatment in only 3 patients. We conclude that aminoglutethimide plus cortisone acetate is a useful addition to the treatment available for this difficult group of patients. The mechanism by which this treatment has a beneficial effect remains unclear.

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Inhibition of Adrenal Corticosteroid Synthesis by Aminoglutethimide: Studies of the Mechanism of Action¹

Abstract: The first of the three volumes of this encyclopaedic dictionary of dermatology was reviewed in this Journal in April 1971. The second volume covers eczema, including occupational dermatoses, seborrhoea.

Cited by 277 publications

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Hormonal Control of Adrenocortical Cell Proliferation

Hormonal Control of Adrenocortical Cell Proliferation

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

Response to aminoglutethimide and cortisone acetate in advanced prostatic cancer

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Inhibition of Adrenal Corticosteroid Synthesis by Aminoglutethimide: Studies of the Mechanism of Action1

Abstract: The first of the three volumes of this encyclopaedic dictionary of dermatology was reviewed in this Journal in April 1971. The second volume covers eczema, including occupational dermatoses, seborrhoea.

Cited by 277 publications

References 0 publications

Hormonal Control of Adrenocortical Cell Proliferation

Hormonal Control of Adrenocortical Cell Proliferation

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

Response to aminoglutethimide and cortisone acetate in advanced prostatic cancer

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Inhibition of Adrenal Corticosteroid Synthesis by Aminoglutethimide: Studies of the Mechanism of Action¹