A simple and rapid method of measuring 5 alpha-reductase (5 alpha-R) activity and of determining the kinetic parameters (KM and Vmax) of the enzyme is described. The 5 alpha-R activity in the homogenate of the prostate of Wistar rats aged 8-12 weeks was established, and the effects of natural and synthetic steroids and of non-steroidal antiandrogens (IC50) upon the 5 alpha-R activity were studied. Of the natural steroids, 17-OH-progesterone was found to have the highest inhibitory effect (IC50 = 1.35 microM), followed in decreasing order by progesterone (IC50 = 5.0 microM) and 4-androstene-3,17-dione (IC50 = 21.6 microM). Oestradiol-17 beta had practically no inhibitory effect. Of the synthetic steroids, 4-MA had the highest inhibitory effect (IC50 = 0.068 microM), followed by nortestosterone (IC50 = 7.4 microM) and RU-486 (Mifepristone) (IC50 = 115 microM). Even at 1000 microM, cyproterone acetate exerted no inhibitory effect. Of the nonsteroidal compounds, ketoconazole proved a weak inhibitor (IC50 = 115 microM), while flutamide was practically ineffective.
For purposes of testosterone suppression, high doses of ketoconazole were administered to 18 patients with advanced cancer of the prostate for an average of 6 months. A well-evaluable response was observed both objectively and subjectively. The blood levels of the steroid hormones were measured during the treatment period and it was found that testosterone biosynthesis was blocked. Mild gastrointestinal symptoms occurred in the minority of the cases, and administration of the drug had to be stopped in one case because of jaundice. The possibility of the use of smaller doses is being investigated, which may lead to the development of an alternative to the endocrine treatment methods.
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