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Kinetic, hormonal and clinical studies with aminoglutethimide in breast cancer
Abstract:
Approximately one-third of patients with metastatic breast carcinoma respond to surgical ablative therapy but the morbidity associated with these procedures has limited their use to highly selected patients. Consequently, a chemical method of adrenal suppression was developed using a potent inhibitor of adrenal steroid synthesis, aminoglutethimide, in combination with a synthetic glucocorticoid, dexamethasone. While this regimen effectively blocked adrenal function, it was complicated by a drug interaction in which aminoglutethimide accelerated the metabolism and reduced the bioavailability of dexamethasone. To overcome this problem, a new regime using aminoglutethimide and hydrocortisone, a glucocorticoid less susceptible to altered metabolism, was developed. Kinetic studies confirmed that aminoglutethimide does not interact with hydrocortisone to alter its rate of metabolism. Hormone measurements established that 1000 mg of aminoglutethimide and 40 mg of hydrocortisone daily suppressed DHA-sulfate, androstenedione, estrone, estradiol and aldosterone to a greater extent than the prior protocol using aminoglutethimide and 2-3 mg of dexamethasone. Patients experienced objective tumor regression with equal frequency while receiving the aminoglutethimide-hydrocortisone regimen or aminoglutethimide and dexamethasone and the overall rate of response in 50 evaluable patients was 38%. Side effects occurred frequently in the first few weeks of treatment but disappeared nearly uniformly thereafter. The present aminoglutethimide-hydrocortisone regimen is simple, non-toxic, effective in inhibiting estradiol synthesis and capable of inducing tumor regression as frequently as previously reported with adrenalectomy.
Insights
A new regimen using aminoglutethimide and hydrocortisone effectively suppresses adrenal steroids in metastatic breast cancer patients. This approach offers a safe and effective alternative to surgical adrenalectomy, achieving similar tumor regression rates.
Area of Science:
- Endocrinology
- Medical Oncology
- Pharmacology
Background:
- Surgical adrenalectomy for metastatic breast carcinoma has limited use due to high morbidity.
- Aminoglutethimide with dexamethasone was an effective chemical adrenal suppression method.
- Drug interactions between aminoglutethimide and dexamethasone reduced dexamethasone bioavailability.
Purpose of the Study:
- To develop and evaluate a new regimen for chemical adrenal suppression using aminoglutethimide and hydrocortisone.
- To overcome the drug interaction observed with aminoglutethimide and dexamethasone.
- To assess the efficacy and safety of the aminoglutethimide-hydrocortisone regimen in metastatic breast cancer patients.
Main Methods:
- Administered aminoglutethimide (1000 mg daily) with hydrocortisone (40 mg daily).
- Conducted kinetic studies to assess drug metabolism and interaction.
- Measured hormone levels (DHA-sulfate, androstenedione, estrone, estradiol, aldosterone) before and during treatment.
- Evaluated objective tumor regression in 50 patients.
Main Results:
- The aminoglutethimide-hydrocortisone regimen effectively suppressed adrenal steroid synthesis, including estradiol.
- Kinetic studies confirmed no significant drug interaction between aminoglutethimide and hydrocortisone.
- Tumor regression occurred in 38% of evaluable patients, comparable to the previous regimen.
- Side effects were frequent initially but resolved over time.
Conclusions:
- The aminoglutethimide-hydrocortisone regimen is a simple, non-toxic, and effective method for inhibiting estradiol synthesis.
- This new regimen provides an effective alternative to surgical adrenalectomy for metastatic breast carcinoma.
- The study demonstrates comparable tumor regression rates with improved tolerability compared to previous methods.