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Aromatase inhibitors: basic and clinical studies
A M Brodie1, R C Coombes, M Dowsett
1Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore.
Abstract:
Application of aromatase inhibitors to the treatment of conditions in which estrogen plays, a role is discussed. Studies in vitro demonstrate that 4-hydroxyandrostenedione (4-OHA) is a potent inhibitor of aromatase. The compound reduces ovariant estrogen production and causes regression of carcinogen (DMBA)-induced mammary tumors in the rat. In the rhesus monkey, 4-OHA was also shown to inhibit peripheral aromatization. To date 58 postmenopausal breast cancer patients with advanced metastatic disease have received 500 mg im weekly while 31 patients received 250 mg 4-OHA orally per day. Estradiol levels were significantly reduced in all patients from a mean of 7.2 + 0.8 pg/ml to 2.8 + 0.3 pg/ml. Of patients receiving 4-OHA im 27% had partial or complete responses and in 10% of patients the disease was stabilized. Similar responses occurred in the patients receiving 4-OHA orally. These results suggest that 4-OHA is effective and that this compound and other aromatase inhibitors could be valuable new additions to the treatment of breast cancer.
Insights
Aromatase inhibitors like 4-hydroxyandrostenedione (4-OHA) effectively reduce estrogen levels. This shows promise for treating estrogen-dependent conditions, including advanced breast cancer in postmenopausal women.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Estrogen plays a key role in various conditions, including breast cancer.
- Aromatase inhibitors offer a potential therapeutic strategy by blocking estrogen production.
Purpose of the Study:
- To evaluate the efficacy of 4-hydroxyandrostenedione (4-OHA) as an aromatase inhibitor.
- To assess the impact of 4-OHA on estrogen levels and tumor regression in preclinical models and human patients.
Main Methods:
- In vitro studies demonstrated 4-OHA's potent aromatase inhibition.
- Preclinical studies in rats showed reduced ovarian estrogen production and mammary tumor regression.
- Clinical trials involved administering 4-OHA intramuscularly or orally to postmenopausal breast cancer patients.
Main Results:
- 4-OHA significantly reduced serum estradiol levels in all treated patients.
- Objective responses (partial or complete) were observed in 27% of patients receiving intramuscular 4-OHA.
- Disease stabilization occurred in 10% of patients, with similar outcomes in the oral 4-OHA group.
Conclusions:
- 4-hydroxyandrostenedione (4-OHA) is an effective aromatase inhibitor.
- 4-OHA demonstrates significant efficacy in reducing estrogen levels and achieving clinical responses in advanced breast cancer.
- Aromatase inhibitors like 4-OHA represent a valuable addition to breast cancer treatment options.