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Aromatase and other inhibitors in breast and prostatic cancer
A M Brodie1, P K Banks, S E Inkster
1Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore.
Abstract:
Estrogens have an important role in the growth of breast and other hormone-sensitive cancers. We have shown that 4-hydroxyandrostenedione (4-OHA) selectively blocks estrogen synthesis by inhibiting aromatase activity in ovarian and peripheral tissues and reduces plasma estrogen levels in rat and non-human primate species. In postmenopausal men and women, estrogens are mainly of peripheral origin. When postmenopausal breast cancer patients were administered either by daily oral or parenteral weekly treatment with 4-OHA, plasma estrogen concentrations were significantly reduced. Complete or partial response to treatment occurred in 34% of 100 patients with advanced breast cancer, while the disease was stabilized in 12%. We recently studied the effects of 4-OHA and other aromatase inhibitors, 10-propargylestr-4-ene-3,17-dione (PED) and imidazo[1,5-alpha]3,4,5,6-tetrahydropyrin-6-yl-(4-benzonitrile) (CGS 16949A) as well as 5 alpha-reductase inhibitors, N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxyamide (4-MA) and 17 beta-hydroxy-4-aza-4-methyl-19norandrost-5-en-3-one (L651190) in prostatic tissue from 11 patients with prostatic cancer and six patients with benign prostatic hypertrophy (BPH), and from normal men at autopsy. We attempted to measure aromatase activity in tissue incubation by quantitating 3H2O released during aromatization of androstenedione or testosterone labeled at the C-1 position. The amount of 3H2O released from all samples was at least twice that of the heat inactivated tissue samples. The 3H2O release was significantly inhibited by 4-OHA and 4-MA, but not by the other aromatase inhibitors. However, when HPLC and TLC were used to isolate steroid products, no estrone or estradiol was detected in the incubates. Furthermore, no aromatase mRNA was detected following amplification by PCR. The 4-OHA was found to inhibit 5 alpha-reductase in both BPH and cancer tissue, although to a lesser extent than 4-MA. The other aromatase inhibitors were without effect. Although a mechanism involving intraprostatic aromatase is not likely, inhibitors may act to reduce peripherally-formed estrogens. In postmenopausal breast cancer, the results indicate that 4-OHA is of significant benefit.
Insights
4-hydroxyandrostenedione (4-OHA) effectively reduces plasma estrogen levels in postmenopausal women, leading to significant treatment responses in advanced breast cancer patients. This aromatase inhibitor shows promise for hormone-sensitive cancer therapy.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Estrogens play a crucial role in the proliferation of hormone-sensitive cancers, including breast cancer.
- In postmenopausal individuals, estrogens are primarily produced through peripheral aromatase activity.
- Targeting estrogen synthesis is a key strategy in managing hormone-dependent malignancies.
Purpose of the Study:
- To evaluate the efficacy of 4-hydroxyandrostenedione (4-OHA) in reducing plasma estrogen levels in postmenopausal women with advanced breast cancer.
- To investigate the effects of 4-OHA and other inhibitors on aromatase and 5 alpha-reductase activity in prostatic tissues.
- To assess the clinical response rates to 4-OHA treatment in patients with advanced breast cancer.
Main Methods:
- Administration of 4-OHA orally or parenterally to postmenopausal breast cancer patients.
- Measurement of plasma estrogen concentrations before and during 4-OHA treatment.
- In vitro studies using prostatic tissue to assess inhibition of aromatase and 5 alpha-reductase by various compounds, including 4-OHA, PED, CGS 16949A, 4-MA, and L651190.
- Quantification of 3H2O release to measure aromatase activity and use of HPLC, TLC, and PCR to detect steroid products and aromatase mRNA.
Main Results:
- 4-OHA significantly reduced plasma estrogen concentrations in postmenopausal women.
- Complete or partial response to 4-OHA treatment was observed in 34% of advanced breast cancer patients, with stabilization in 12%.
- 4-OHA and 4-MA inhibited 5 alpha-reductase activity in prostatic tissues; 4-OHA also showed some inhibition of aromatase activity, though intraprostatic aromatase was not definitively detected.
Conclusions:
- 4-hydroxyandrostenedione (4-OHA) is a beneficial treatment for postmenopausal breast cancer, effectively reducing estrogen levels and improving patient outcomes.
- While direct intraprostatic aromatase inhibition may not be the primary mechanism, 4-OHA likely reduces peripherally-formed estrogens, contributing to its therapeutic effect.
- The study highlights the clinical significance of 4-OHA in managing advanced breast cancer by targeting estrogen synthesis.