Formestane

Abstract

Formestane (4-hydroxyandrostenedione) is an aromatase inhibitor which significantly reduces plasma levels of estrogen and has shown antitumour activity in postmenopausal women with breast cancer. Objective response rates in heavily pretreated patients with advanced breast cancer generally range between 20 and 30% during treatment with intramuscular formestone 250 or 500mg once every 2 weeks, and a further 20 to 30% of patients experience disease stabilisation. The median duration of response is between 8 and 14 months. Highest response rates are observed in soft tissue metastases, in patients with estrogen-responsive tumours and in those showing a response to previous endocrine therapy. Furthermore, there is some evidence to suggest that higher response rates are achieved with formestane 500 versus 250mg once every 2 weeks. In comparative studies, the clinical efficacy of intramuscular formestane 250mg did not differ significantly from that of oral megestrol when administered as second-line endocrine therapy to patients with advanced disease in whom previous tamoxifen therapy had failed. In addition, formestane produced a response rate, duration of response and overall survival rate that was not significantly different from that of oral tamoxifen when administered as first-line endocrine therapy to patients with advanced disease, but tamoxifen was superior in some measures. Further investigation of these 2 agents, including the higher dosage of formestane (500mg), is necessary to confirm their relative efficacies. Formestane is well tolerated by the majority of patients; adverse events rarely necessitate cessation of therapy. The most common adverse events are local reactions at the injection site and systemic events usually related to the effect of the drug on the hormonal milieu. The systemic tolerability of formestane is similar to that of tamoxifen but better than that of megestrol. Thus, formestane is effective and well tolerated as first-line endocrine therapy for advanced disease. However, at present, it is unlikely to challenge tamoxifen in this indication, based on recent findings from a large comparative study and the fact that formestane requires intramuscular administration. Nonetheless, formestane, which appears to have a better tolerability profile than other currently available second-line agents (including megestrol and the aromatase inhibitor aminoglutethimide), is a valuable drug for the second-line treatment of postmenopausal women with advanced breast cancer.

Synthesis and Bioconversions of Formestane

“…The oxidation of testosterone (2) with Jones reagent 13 afforded androst-4-ene-3,17-dione (3). 14 Hydroxylation of 3 with OsO 4 /H 2 O 2 followed by alkaline dehydration of the resultant diols 4 gave formestane (1). 15 The identity of formestane (1) was confirmed by comparison of its mass spectral ([M + H] + = 303.42) and 1 H and 13 C NMR data (Figures S1 and S2) with those of an authentic standard.…”

“…IR data also revealed the disappearance of the C4−C5 double bond. Comparison of the 1 H and 13 C NMR data of this metabolite (Figures S3 and S4) with those of formestane (1) and literature data confirmed the product as 4β,5α-dihydroxyandrostane-3,17-dione (5) (Figure 1). 17 The biotransformation of formestane (1) by B. bassiana afforded three metabolites.…”

“…F ormestane (1), like exemestane, is a steroidal aromatase inhibitor that is used in the treatment of breast and ovarian cancers in postmenopausal women. It suppresses the production of estrogen by inhibiting the aromatase enzyme that converts androgens into estrogens.…”

“…Of the aforementioned aromatase inhibitors, our group is focused on improving the efficacy and low bioavailability [1][2][3]7 of formestane (1). As such, analogues 8,9 of formestane (1) were prepared by microbial means with the prolific steroid transformers Beauveria bassiana 10,11 and Rhizopus oryzae, 12 in the hopes of finding new aromatase inhibitors with enhanced biological activities. An improved synthetic route from testosterone (2) to formestane (1) is included.…”

Synthetic Androgens as Designer Supplements

“…The inhibition of the enzyme complex aromatase is therapeutically used in estrogen depending cancer [ 96 ]. In combination with anabolic steroids they are administered in order to reduce side effects like gynocomastia resulting from estrogenic metabolites [ 91 ].…”