Topic
Formestane
About: Formestane is a research topic. Over the lifetime, 174 publications have been published within this topic receiving 7017 citations. The topic is also known as: CGP-32349 & 4-hydroxy-Δ4-androstenedione.
Papers published on a yearly basis
Papers
TL;DR: The saga of these studies of aromatase and the ultimate utilization of inhibitors as highly effective treatments of breast cancer and for use in reproductive disorders serves as the basis for this first Endocrine Reviews history manuscript.
Abstract: Aromatase is the enzyme that catalyzes the conversion of androgens to estrogens. Initial studies of its enzymatic activity and function took place in an environment focused on estrogen as a component of the birth control pill. At an early stage, investigators recognized that inhibition of this enzyme could have major practical applications for treatment of hormone-dependent breast cancer, alterations of ovarian and endometrial function, and treatment of benign disorders such as gynecomastia. Two general approaches ultimately led to the development of potent and selective aromatase inhibitors. One targeted the enzyme using analogs of natural steroidal substrates to work out the relationships between structure and function. The other approach initially sought to block adrenal function as a treatment for breast cancer but led to the serendipitous finding that a nonsteroidal P450 steroidogenesis inhibitor, aminoglutethimide, served as a potent but nonselective aromatase inhibitor. Proof of the therapeutic concept of aromatase inhibition involved a variety of studies with aminoglutethimide and the selective steroidal inhibitor, formestane. The requirement for even more potent and selective inhibitors led to intensive molecular studies to identify the structure of aromatase, to development of high-sensitivity estrogen assays, and to "mega" clinical trials of the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, which are now in clinical use in breast cancer. During these studies, unexpected findings led investigators to appreciate the important role of estrogens in males as well as in females and in multiple organs, particularly the bone and brain. These studies identified the important regulatory properties of aromatase acting in an autocrine, paracrine, intracrine, neurocrine, and juxtacrine fashion and the organ-specific enhancers and promoters controlling its transcription. The saga of these studies of aromatase and the ultimate utilization of inhibitors as highly effective treatments of breast cancer and for use in reproductive disorders serves as the basis for this first Endocrine Reviews history manuscript.
439 citations
TL;DR: 4-OH-A treatment of rats having estrogen-dependent breast tumors induced by 7,12-dimethylbenz(a)anthracene caused 80% of the tumors to regress significantly in 4 weeks of treatment; 42% of these regressed completely.
Abstract: 4-Hydroxy-f-androstene-3,17-dione (4-OH-A) when tested at various concentrations was found to inhibit markedly the conversion of 4-andorstene-3,17-dione to estrogens inhuman placental and rat ovarian microsomes. To obtain evidence that estrogen biosynthesis could also be reduced in vivo with 4-OH-A, rats were treated sc at a dose level of 50 mg/kg body weight. After 3 h the ovarian veins were cannulated and blood collected. Estradiol concentrations in the plasma were reduced by 80% compared to control values during the proestrous surge and on Day 4 of pregnancy. 4-OH-A was also found to be effective in controlling estrogen-dependent reproductive and neoplastic processes. In rats treated from Day 2-7 of pregnancy, implantation of fertilized ova was completely prevented in some rats, while in others either implantation was delayed or the development of implants was retarded. 4-OH-A treatment of rats having estrogen-dependent breast tumors induced by 7,12-dimethylbenz(a)anthracene caused 80% of the tumors to regress significantly in 4 weeks of treatment; 42% of these regressed completely.
382 citations
TL;DR: In vitro studies demonstrated that aminoglutethimide (AG), a drug previously used as an adrenal steroidogenesis inhibitor, is also a potent aromatase blocker, and in vivo effects of AG on the rate of aromatization of δ4-A to E1 by direct radioisotopic kinetic methods were examined.
Abstract: Extraglandular aromatization of androstenedione (δ4-A) to estrone (E1) provides the primary source of estrogen production in spontaneously postmenopausal or surgically castrate women. Estrogens produced by this enzymatic reaction in peripheral tissues can be biologically important, particularly in women with metastatic breast carcinoma. In such patients, an aromatase inhibitor would have potential usefulness clinically. In vitro studies demonstrated that aminoglutethimide (AG), a drug previously used as an adrenal steroidogenesis inhibitor, is also a potent aromatase blocker. A similar in vivo effect of AG was suggested by clinical observations of suppressed plasma E1 without concomitant reductions in δ4-A concentrations in postmenopausal women given this drug. Based upon these considerations, we examined the in vivo effects of AG on the rate of aromatization of δ4-A to E1 by direct radioisotopic kinetic methods. AG inhibited the fractional conversion of δ4-A to E1 in blood from 1.65 ± 0.28% (se) before t...
360 citations
Journal Article•
TL;DR: 4-Hydroxyandrostenedione (4-OHA) is a potent inhibitor of estrogen production by aromatase and causes suppression of plasma estradiol levels and disease regression in postmenopausal breast cancer patients.
Abstract: 4-Hydroxyandrostenedione (4-OHA) is a potent inhibitor of estrogen production by aromatase and causes suppression of plasma estradiol levels and disease regression in postmenopausal breast cancer patients. Groups of patients were given p.o. or parenteral 4-OHA, and plasma estradiol and 4-OHA levels were measured to enable the delineation of the minimal effective dose and optimal therapeutic regimen. A single injection of 500 mg i.m. suppressed estradiol levels to a mean 36.3 ± 3.3% (SE) (n = 14) of base line after 4 to 7 days and maintained this suppression in six of seven patients for >14 days. The half-life of 4-OHA was approximately 8 days, and when the level had fallen to less than 3 ng/ml, estradiol levels began to rise. Similar suppression was achieved by a single i.m. injection of 125 mg of 4-OHA and by 500 mg of 4-OHA p.o daily after 1 wk, but escape from suppression was more rapid.
243 citations
Journal Article•
TL;DR: 4-Hydroxyandrostenedione (4-OHA), a potent new aromatase inhibitor, was given to 58 patients with advanced postmenopausal breast cancer and does not produce notable systemic side effects.
Abstract: 4-Hydroxyandrostenedione (4-OHA), a potent new aromatase inhibitor, was given i.m. (500–1000 mg) to 58 patients with advanced postmenopausal breast cancer. Of 52 assessable patients 14 responded (27%), in 10 (19%) the disease stabilized, and in 28 (54%) the disease progressed. Sterile abscesses occurred at the injection site in 6 patients and painful lumps were found in a further 3 patients. Two patients developed allergictype reactions and 4 developed lethargy, suspected to be treatment induced. Plasma estradiol levels were suppressed from a mean of 7.2 ± 0.8 (SE) pg/ml before treatment to 2.6 ± 0.2, 2.7 ± 0.2, and 2.8 ± 0.3 pg/ml after 1, 2, and >4 months, respectively, of treatment and remained suppressed in patients whose disease relapsed. No significant fall in estrone levels was seen. Similarly, dehydroepiandrosterone sulfate, sex hormone binding globulin, and gonadotrophin levels were unaltered after 6 months of treatment. Plasma 4-OHA levels were measured in a radioimmunoassay for androstenedione after chromatographic separation of 4-OHA from androstenedione. Drug concentrations ranged from 0.7 to 23.2 (7.8 ± 1.1) ng/ml after 2 months on treatment. 4-OHA is an effective drug in the management of postmenopausal patients with breast cancer and does not produce notable systemic side effects.
234 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2020 | 5 |
| 2019 | 6 |
| 2018 | 1 |
| 2017 | 2 |
| 2016 | 1 |
| 2015 | 2 |