Androgen receptors in experimentally induced colon carcinogenesis

Abstract

Sex hormones may play a role in colonic carcinogenesis, as evidenced by epidemiologic and experimental data showing different tumor rates in males and females. We investigated the effects of hormonal manipulation on tumor development and on androgen receptor binding in both colonic wall and experimentally induced tumors in male rats. Five of six groups, each with 40 animals, were given 10 weekly s.c. injections of azoxymethane (AOM), 7.5 mg/kg body weight. Group-I served as normal controls. Group-II received AOM only. Group-III was castrated 2 weeks prior to carcinogen treatment. Group-IV was castrated similarly and then hormone substituted with testosterone propionate. Group-V was chemically castrated with the anti androgen cyproterone acetate. Group-VI was castrated and given hormone vehicle. Scatchard analysis for androgen receptors in cytosol from normal colonic wall and tumor was performed with 3H-methyltrienolone as the ligand. Androgens were found to have an inhibitory effect on carcinogenesis: chemical castration increased colonic tumor development (P less than 0.05 for multiplicity), and testosterone administration produced a borderline statistically significant reduction in tumor incidence in surgically castrated rats (P less than 0.053), particularly in the right colon. Specific binding sites for androgen with high affinity and low capacity were found in the colonic wall of all groups. Receptor density was not altered by AOM administration, but increased after surgical castration. Receptor density was markedly lower in tumors than in normal colonic wall. Receptor binding sites in tumors were not altered by the various hormonal manipulations. Our study demonstrated that although cytoplasmic androgen receptors are present in colonic wall and in experimental tumors, AOM-induced colonic carcinogenesis appears to be only mildly affected by manipulation of androgens.

Effects of androgen manipulations on chemically induced colonic tumours and on macroscopically normal colonic mucosa in male Sprague-Dawley rats

“…In recent years these experimental carcinogenesis models were used to evaluate the effects of steroid hormones, including androgens, and of hormonal manipulations on chemically induced tumours. Whereas some authors were able to demonstrate promoting effects of androgens (Moon & Fricks, 1977;Izbicki et al, 1983;Mehta et al, 1978), other authors presented conflicting results with protective effects of androgens against experimental colon carcinogenesis (Izbicki et al, 1986).…”

“…In addition, hormonal manipulations have been reported to influence tumour yield (Balish et al, 1977;Moon & Fricks, 1977;Mehta et al, 1978;Izbicki et al, 1983). These findings seemed to support a possible role of androgens in colonic carcinogenesis.Recently, we reported the effects of hormonal manipulations on chemically induced colonic carcinogenesis and androgen receptors in macroscopically normal mucosa and colonic tumours (Izbicki et al, 1986). In the present publication we present our evaluation of the mechanisms of the observed effects.…”

“…Recently, we reported the effects of hormonal manipulations on chemically induced colonic carcinogenesis and androgen receptors in macroscopically normal mucosa and colonic tumours (Izbicki et al, 1986). In the present publication we present our evaluation of the mechanisms of the observed effects.…”

“…At week 23, hormone dose was reduced to I mg per kg body weight due to toxic effects, as expressed by a lethality of 40% in the castrated and testosterone-substituted group. Hormone preparations were as described previously (Izbicki et al, 1986). Briefly, steroid suspensions were prepared daily in 0.9% NaCl solution containing 0.85 g 1' Myri 53 as vehicle.…”

“…The rats were fed ad libitum with a standard rat chow (Altromin R 1324, Lage, FRG) and water. All groups were given the carcinogen azoxymethane (AOM), as described elsewhere (Izbicki et al, 1986). Briefly, all animals received 7.5 mg AOM per kg body weight subcutaneously (s.c.) once weekly for 10 weeks, starting at 10 weeks of age.…”