Reversal by Vitamin A Analogues (Retinoids) of Hyperplasia Induced by N-Methyl-N′-nitro-N-nitrosoguanidine in Mouse Prostate Organ Cultures2

Abstract

The antihyperplastic activity of beta-retinoic acid (RA) and nine synthetic analogues (retinoids) was examined in organ cultures of mouse prostate made hyperplastic by treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). After 8 or 10 days, when most explants developed hyperplasia, the carcinogen was withdrawn and explants were incubated in control medium and medium containing different concentrations of a retinoid. The antimitotic activity of retinoids was compared with that of RA. Different retinoids produced variable degrees of mitotic inhibition in the hyperplastic prostate epithelium. The methylketo cyclopentenyl and 1-methoxyethyl cyclopentenyl analogues of RA were at least 50-fold more active than RA in reversing MNNG-induced hyperplasia. The trimethylmethoxyphenyl analogue of RA and retinyl methyl ether were significantly more active than RA. Three analogues, N-acetyiretinylamine, retinal acetyl hydrazone, and retinal oxime, were as active as RA. The chlorotrimethylphenyl analogue showed less activity than RA, and alpha-retinyl acetate was completely devoid of mitotic inhibitory activity.

Effect of retinoic acid on prostatic development

“…In addition to inhibiting cancer development, retinoids also have antiproliferative and differentiation-inducing activity in cultured cell lines. Retinoids have effectively inhibited proliferation of tumor cells in culture and have reversed the anaplastic or hyperplastic changes induced in mouse prostatic epithelial cells by carcinogenic hydrocarbons [14]. Lasnitzki [20,21] and Lasnitzki and Goodman [22] showed that premalignant changes (squamous metaplasia and hyperplasia) of mouse prostate glands treated with 3-methylcholanthrene could be reversed by retinoids.…”

“…Lotan and Nicolson [12] studied the antiproliferative activity of retinoic acid and retinyl acetate in 31 different cell lines, and found growth to be inhibited in >60% of them. In the prostate, Chopra and Wilkoff [14] effectively inhibited proliferation of tumor cells in culture, and reversed the anaplastic or hyperplastic changes induced in mouse prostatic epithelial cells by carcinogenic hydrocarbons. Although the antitumor effects of retinoids have been tested in different cell cultures, their effect on prostatic ductal development and branching has not been determined.…”

Einflu� des Vitamin A auf die MNNG-induziert Cancerogenese im Dr�senmagen der Ratte

“…Aber auch Drtisenepithelien und das Epithel des Urogenital-und Verdauungstraktes scheinen Vitamin A-sensibel zu sein: so erwiesen sich Mammacarcinome [22], Tumoren der Harnblase [29] und der Prostata [6] als Vitamin A-empfindlich.…”

Study on Cytochrome P-450 Dependent Retinoic Acid Metabolism and its Inhibitors As Potential Agents for Cancer Therapy

“…ATRA is being used in differentiation therapy of cancer, in cancer chemoprevention and for the treatment of acne [3–5]. Recently, ATRA has proven useful in cancer chemotherapy [6–8]. One of the most impressive effects of ATRA is on acute promyelocytic leukaemia.…”