Rudolph O. Neri

Biological studies on an anti-androgen (SH 714)

Abstract The biological properties of the anti-androgen, SH 714 (Cyproterone acetate) were determined. This compound is strongly anti-androgenic in testosterone-stimulated, orchiectomized rats and in intact male rats when administered either subcutaneously or orally. The steroid is also androgenic, progestational, anti-estrogenic, and at high doses, possesses anti-gonadotropin activity. It is devoid of anti-inflammatory activity. SH 714 also exhibited an anti-fertility effect, probably due to its potent progestational activity. When administered to orchiectomized, testosterone-stimulated orchiectomized or intact male rats, adrenal atrophy occured, and in intact animals, this atrophy was accompanied by a decrease in plasma corticosterone levels. The adrenal effects are probably due to pituitary ACTH suppression. Hypercholesterolemia also occured in treated male rats.

Antiandrogens: Preclinical and clinical studies

Abstract Objectives To describe biological and clinical properties of antiandrogens. To demonstrate their usefulness in prostatic diseases, specifically in prostatic carcinoma. Methods Intact and orchiectomized rats were used to characterize antiandrogenic efficacy of the test agent, administered orally, for reducing ventral prostate weight. For clinical studies, the antiandrogens were orally administered, as monotherapy, in patients with advanced prostatic carcinoma. Results Flutamide (Schering-Plough), nilutamide (Roussel), and casodex (Zeneca) were all effective in advanced prostate cancer. Complete and partial remissions were observed following the daily administration of each of these antiandrogens. The flutamide results represent the first clinical study of a “pureantiandrogen. When compared with 1 mg diethystilbestrol (DES), response rates and survival with flutamide were similar, but higher toxicity rates were observed with DES. In 26 patients with advanced prostate cancer, nilutamide had a response rate of 38.5%with a median progression-free survival and overall survival of 9 and 23 months, respectively. The overall objective response rate of casodex (50 mg) in a study of 127 patients was50%, representing 33% with stable disease and the remaining 17% showing progression. Conclusions The nonsteroidal antiandrogens such as flutamide, nilutamide, and casodex have shown efficacy in animal trials. In previously untreated patients with advanced prostatic cancer these antiandrogens were also effective in ameliorating the disease.

Biological Properties of Flutamide

Great interest has been generated in the past few years to uncover agents which inhibit the actions of androgens. This interest is based on the inference that such agents would be therapeutically useful in human benign prostatic hyperplasia and adenocarcinoma, hirsutism, and acne.

Drug Evaluation: Oncologic, Endocrine & Metabolic: Toremifene

Toremifene is a triphenylethylene antioestrogenic derivative, chemically and pharmacologically related to tamoxifen. In animals, toremifene blocks the uterotrophic effect of oestradiol and, in intact animals, uterine weights are reduced, demonstrating the antioestrogenic activity of the compound. Such antioestrogenic effects are believed to underlie the antitumour actions of toremifene in breast cancer, i.e., it competes with oestrogen for binding sites in the cancer, thus preventing the growth-stimulating effects of oestrogen. The drug is well absorbed following oral administration and the mean elimination half-life is 5 days. Toremifene is extensively metabolised and the main metabolite in human serum is N-demethyltoremifene. This metabolite has a longer half-life (10 days) than toremifene and its steady state serum concentration is about 2 times higher than that of the parent compound.Unlike tamoxifen, toremifene is not a genotoxic carcinogen in rodent studies and, similarly, is not associated with end...

BIOLOGICAL ASPECTS OF ANTIANDROGENS

Flutamide (α,α,α-trifluoro-2-methyl-4′-nitro-m-propionotoluidide) at daily doses from 1–50 mg/kg reduced seminal vesicle and ventral prostate weights of intact male rats. A comparative study in castrated rats revealed that flutamide was equipotent to cyproterone acetate (CPA) as an antiandrogen. These potencies were substantiated by a newly developed assay measuring DNA synthesis rate (Sufrin and Coffey). No androgenic, estrogenic, anti-estrogenic, corticoid, progestational, anti-progestational, or antigonadotrophic activities were observed. Flutamide, given per os daily for either 6 weeks or 1 year to aged dogs with benign prostatic hyperplasia, reduced prostatic size in 6 weeks and the prostate remained reduced at 3, 6 and 12 months after the initiation of drug therapy. Flutamide, given im three times weekly for 4 weeks reduced the size of the baboon prostate (Muntzing et al.). In testosterone propionate-treated castrated rats CPA and flutamide inhibited 3H-testosterone uptake and retention by prostate and prostate nuclei. In a study in 18 patients with far-advanced carcinoma of the prostate, there were seven positive responders, 10 failures and one inconclusive report, following the daily administration of flutamide (Stoliar and Albert). In a similar study, 9 of 12 patients in stage D prostatic carcinoma responded favorably (Prout and Irwin).