Formestane = Aromatase inhibitor
Breast Cancer Res Treat. 1994;30(1):81-7.
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Second generation aromatase inhibitor--4-hydroxyandrostenedione.[/size]
Dowsett M,
Coombes RC.
Academic Dept of Biochemistry, Royal Marsden Hospital, London, UK.
4-hydroxyandrostenedione is a steroidal, suicide substrate inhibitor of aromatase, which has been widely tested in postmenopausal breast cancer patients. It is highly specific with the only notable endocrine changes other than oestrogen suppression being a dose-related suppression of sex-hormone binding globulin when the drug is given orally (a reflection of the drug's minor androgenic activity). Intramuscular administration of 250 mg every second week is the schedule of choice. This achieves peripheral aromatase inhibition of about 85% and oestradiol suppression of about 65%. The drug is usually used second-line, after tamoxifen, with an overall response rate in unselected patients of 26%. Side-effects are minimal and consist almost entirely of local reactions at the site of injection. 4-hydroxyandrostenedione is therefore a useful new treatment option as the first selective aromatase inhibitor to have wide clinical availability.
Publication Types:
PMID: 7949207 [PubMed - indexed for MEDLINE]
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Cancer Chemother Pharmacol. 1990;27(1):67-71.
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Comparison of the pharmacokinetics and pharmacodynamics of unformulated and formulated 4-hydroxyandrostenedione taken orally by healthy men.[/size]
Dowsett M,
Lloyd P.
Department of Biochemical Endocrinology, Royal Marsden Hospital, London, U.K.
A study of the aromatase inhibitor 4-hydroxy-androstenedione (4-OHA) was conducted in normal healthy men to compare the oral administration of two preparations of the drug: an unformulated, micronized powder and a formulated microcrystalline material (CGP 32349). The formulated material achieved a significantly higher mean peak concentration (88% greater than that obtained using the unformulated powder) and a higher mean AUC (not significant). The median time to peak was 1.5 h for both preparations and the elimination rate constants were similar (0.31 for micronized 4-OHA and 0.36 h-1 for formulated 4-OHA). Plasma concentrations of 4-OHA in this group were markedly lower than those previously observed in postmenopausal breast cancer patients. Significant biological activity was demonstrated with the formulated material in its suppression of plasma oestradiol levels, whereas no significant suppression was obtained using the micronized powder. An increase in androgen levels was observed that may have been due to competitive inhibition of enzymes involved in metabolic clearance of androgens and/or to decreased feedback inhibition of gonadotrophin secretion by oestradiol.
PMID: 2123133 [PubMed - indexed for MEDLINE]
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Drugs. 1993 Jan;45(1):66-84.
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Formestane. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of breast cancer and prostatic cancer.[/size]
Wiseman LR,
McTavish D.
Adis International Limited, Auckland, New Zealand.
Formestane (4-hydroxyandrostenedione) is an effective and competitive inhibitor of aromatase, the enzyme responsible for the conversion of androgens to estrone and estradiol. Significant reductions in plasma estradiol levels are observed following intramuscular administration of formestane to postmenopausal women with advanced metastatic breast cancer. Overall response rates to intramuscular formestane in these patients are approximately 25 to 30% and a further 20 to 30% of patients experience disease stabilisation during treatment. Response rates are improved in patients with hormone responsive tumours and in those who have responded to previous endocrine therapy. Soft tissue metastases generally show the best response to formestane treatment while visceral metastases (in particular liver) show a poor response. The median duration of response is usually between 7 months and 1 year. Formestane has been generally well tolerated in the relatively small clinical trials conducted to date with adverse effects reported in approximately 13% of patients following intramuscular administration. The most frequent adverse effects are local reactions at the injection site and systemic effects mainly related to the effect of the drug on the hormonal milieu. Thus, formestane is effective as a second-line endocrine treatment for advanced metastatic breast cancer in women with natural or artificially induced menopause, with apparent tolerability advantages over older agents such as aminoglutethimide; with wider study and experience it may yet challenge tamoxifen as a first-line endocrine therapy in metastatic breast cancer.
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PMID: 7680986 [PubMed - indexed for MEDLINE]
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J Enzyme Inhib. 1997 Dec;12(4):241-54.
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Inhibition and inactivation of equine aromatase by steroidal and non-steroidal compounds. A comparison with human aromatase inhibition.[/size]
Moslemi S,
Seralini GE.
Laboratoire de Biochimie et Biologie Moleculaire, EP CNRS 9, IBBA, Universite de Caen, France.
In order to approach the detailed structure-function relationships of aromatase, we studied the inhibitory and inactivatory potencies of several steroidal androstenedione analogues (1: 4-hydroxyandrostenedione, 2: 4-acetoxyandrostenedione and 3: 7 alpha-(4'-amino)phenylthio-4-androstene-3, 17-dione) and non-steroidal imidazole derivatives (4: ketoconazole, 5: miconazole and 6: fadrozole) on equine aromatase in placental microsomes, a well established mammalian model. Human placental microsomes and the purified enzyme from equine testis were also used to compare inhibition by 1 and 2. In equine microsomes, all compounds tested exhibited a competitive inhibition, with Ki values of 4.1, 26 and 1.8 nM for 1, 2 and 3, and of 2400, 1.4 and 4 nM for 4, 5, and 6, respectively. The Km for androstenedione, the substrate mainly used in these studies, was 1.8 +/- 0.13 nM. The three non-steroidal derivatives did not inactivate equine aromatase, but 1 and 2 acted as comparable inactivators to a much higher degree than 3. Compound 1 inhibited in a similar manner (89-94%) purified or equine and human microsomal aromatases, whereas 2 inhibited microsomal aromatase more efficiently in the horse than in man (92% and 33% inhibition, respectively). There was only a 40% inhibition with 2 on the purified equine enzyme, which is no more in the natural membrane environment. The comparisons between equine and human microsomal aromatases allow precise functional and structural differences to be observed with these enzymes.
PMID: 9502046 [PubMed - indexed for MEDLINE]
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Br J Cancer. 1993 Aug;68(2):393-8.
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Erratum in:
- Br J Cancer 1994 Mar;69(3):626.
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Plasma and urinary oestrogens in breast cancer patients on treatment with 4-hydroxyandrostenedione.[/size]
Johannessen DC,
Adlercreutz H,
Fotsis T,
Lonning PE.
Department of Oncology, University Hospital of Bergen, Haukeland sykehus, Norway.
Plasma and urinary oestrogens were measured in nine breast cancer patients (eight postmenopausal women and one man) before and during treatment with the aromatase inhibitor 4-hydroxyandrostenedione. Urinary oestrogens were measured by using a highly specific GC-MS method. Plasma levels of oestrone, oestradiol and oestrone sulphate were suppressed by 66.6% (+/- 3.6%), 57.7% (+/- 5.1%) and 51.8% (+/- 6.4%) respectively (P < 0.005 for all). Twenty-four hour urinary excretion of total oestrogens, oestradiol, oestriol, 2-hydroxyoestrone, 16 alpha-hydroxyoestrone and the minor metabolites 16 beta- and 15 alpha-hydroxyoestrone were all suppressed by mean values ranging from 60% to 82%, (oestradiol: P < 0.025, otherwise P < 0.005). There were no significant changes in the ratios between the different plasma oestrogens. The finding of sustained plasma and urinary oestrogens at 20-40% compared to their control levels indirectly support a hypothesis of alternative oestrogen sources in postmenopausal breast cancer patients on treatment with 4-hydroxyandrostenedione.
PMID: 8135918 [PubMed - indexed for MEDLINE]
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J Steroid Biochem. 1986 Nov;25(5B):867-76.
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Aromatase inhibitors and benign prostatic hyperplasia.[/size]
Henderson D,
Habenicht UF,
Nishino Y,
Kerb U,
el Etreby MF.
A growing amount of evidence implies that estrogens may play a role together with androgens in the genesis of benign prostatic hyperplasia (BPH) in man. We review here some of this evidence together with advances made in characterizing inhibitors of estrogen biosynthesis (aromatase inhibitors). It is proposed that aromatase inhibitors may find application in non-surgical treatment of BPH.
PMID: 2433507 [PubMed - indexed for MEDLINE]
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J Steroid Biochem. 1983 Apr;18(4):391-6.
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Effects of testosterone, estradiol, aromatase inhibitor, gonadotropin and prolactin on the response of mouse testes to acute gonadotropin stimulation.[/size]
Dalterio S,
Bartke A,
Brodie A,
Mayfield D.
These studies determined the local acute responsiveness of the testis to intratesticular administration of human chorionic gonadotropin (hCG) under basal, stimulated (systemic hCG pre-treated), hypogonadotropic (steroid pre-treatment) and hyperprolactinemic conditions in male mice. In addition, testicular testosterone (T) levels were determined after intratesticular administration of the aromatase inhibitor, 4-hydroxyandrostenedione (4-OHA) or progesterone under basal or hCG-stimulated conditions. Intratesticular administration of 0.025, 0.25, 2.5 or 25 mIU hCG resulted in a dose-dependent (3- to 14-fold) increase in testicular T concentrations in hCG compared to vehicle-injected testes. Systemic (i.p.) pre-treatment with 5 IU hCG 24 h before prevented any further increases in the already elevated (10-fold basal) T levels after direct intratesticular hCG injection. Pretreatment with 250 micrograms testosterone propionate (TP) reduced basal testicular T concentrations, but resulted in increased responsiveness to intratesticular hCG administration. In contrast, estradiol benzoate (EB) pretreatment, which also reduced basal testicular T concentrations, did not affect the testicular responsiveness to hCG. Hyperprolactinemia reduced testicular responsiveness to intratesticular administration of 0.025, 0.25 or 2.5 mIU hCG, but basal levels of testicular T were elevated. One hour after intratesticular injections of an aromatase inhibitor, 4-OHA; (0.25 micrograms) testis, T levels were increased in males pre-treated with 5 IU hCG (i.p.) 24 h earlier. Higher doses of 4-OHA (2.5, 25 or 250 micrograms) resulted in significant, dose-related increases in basal testicular T levels which were attenuated by hCG-pre-treatment. Intratesticular administration of 20 micrograms progesterone increased testicular T concentrations 2.7-fold, but this effect was attenuated (1.5-fold) in hCG-pre-treated mice, suggesting that enzymatic lesions beyond progesterone may be involved in hCG-induced testicular desensitization. These results indicate that testicular responsiveness to hCG depends on the existing levels of gonadotropic stimulation. However, it is evident that estrogens and prolactin also influence the sensitivity of the testis to gonadotropin.
PMID: 6834825 [PubMed - indexed for MEDLINE]
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So Formestane *IS* a suicide aromatase inhibitor that indirectly causes testosterone release from the testes. Good for PCT I say.
That still doesn't answer my question. And please, if you KNOW the answer to something, please post it. If you BELIEVE or HAVE HEARD something about something, please don't make it out as fact. It's much easier on everyone. Thanks.
