Homma Y, Kaneko M, Kondo Y, Kawabe K, Kakizoe T
Department of Urology, Faculty of Medicine, The University of Tokyo, Japan.
J Natl Cancer Inst. 1997 Jun 4;89(11):803-7. doi: 10.1093/jnci/89.11.803.
Androgen levels in the prostate may influence carcinogenesis in this organ. Inhibitors of the enzyme 5alpha-reductase block conversion of testosterone to the more active androgen dihydrotestosterone. The use of a 5alpha-reductase inhibitor, finasteride, in the chemoprevention of prostate cancer is being evaluated in a clinical trial.
This study was conducted to determine if a 5alpha-reductase inhibitor, FK143, inhibits the development of prostate cancer in rats.
Male ACI/Seg rats, which spontaneously develop prostate cancer, were randomly assigned at 80 weeks of age to receive one of three diets (n = 35/group) containing 0 (i.e., control group), 20, or 200 ppm FK143. At 140 weeks of age, the animals were killed, and the prostates were removed and examined for histopathologic features in addition to being assayed for androgen concentrations. Two-sided statistical tests were used to calculate all P values.
The incidence of prostate carcinoma in the control group was 62.9% (22 of 35 rats); in the group fed the 20 ppm FK143-containing diet, it was 45.7% (16 of 35); and in the group fed the 200 ppm FK143-containing diet, it was 67.6% (23 of 34) (overall, P = .153). The corresponding incidences of macroscopic lesions were 17.1% (six of 35 rats), 0% (none of 35), and 23.5% (eight of 34), respectively (overall, P = .004). The incidence of macroscopic lesions in the prostates of rats in the 20-ppm diet group was significantly lower than that in the control group (P = .029) or that in the 200-ppm diet group (P = .003). Intraprostatic dihydrotestosterone content was significantly lower in rats in the groups fed diets containing 20 or 200 ppm FK143 (mean values: 4.51 and 4.33 pg/mg wet weight of prostate tissue, respectively) than in the control group (6.10 pg/mg) (overall, P<.001); by contrast, testosterone was higher in the 200-ppm diet group (2.09 pg/mg) than in the control group (1.08 pg/mg) or the 20-ppm diet group (1.21 pg/mg) (overall, P<.001).
FK143, when fed to rats at 20 or 200 ppm, significantly reduced the level of dihydrotestosterone in their prostate tissue. However, the incidence of macroscopic cancer in the prostate was suppressed in rats consuming the 20 ppm FK143-containing diet but not in those consuming the 200-ppm diet. The lack of dose dependence for the chemopreventive activity of FK143 may be explained by the reciprocal increase of tissue testosterone in the 200-ppm diet group.
The 5alpha-reductase inhibitor FK143 may, at specific doses, reduce the incidence of spontaneously developing prostate cancer; however, whether these findings in rats will apply to humans remains to be determined.
前列腺中的雄激素水平可能会影响该器官的致癌作用。5α-还原酶抑制剂可阻止睾酮转化为活性更强的雄激素双氢睾酮。一项临床试验正在评估5α-还原酶抑制剂非那雄胺在前列腺癌化学预防中的应用。
本研究旨在确定5α-还原酶抑制剂FK143是否能抑制大鼠前列腺癌的发生。
雄性ACI/Seg大鼠会自发发生前列腺癌，在80周龄时将其随机分为三组（每组n = 35只），分别给予三种饮食之一，其中一种饮食不含FK143（即对照组），另外两种饮食分别含有20 ppm或200 ppm的FK143。在140周龄时，处死动物，取出前列腺，检查其组织病理学特征，并测定雄激素浓度。使用双侧统计检验计算所有P值。
对照组前列腺癌的发生率为62.9%（35只大鼠中有22只）；在喂食含20 ppm FK143饮食的组中，发生率为45.7%（35只中有16只）；在喂食含200 ppm FK143饮食的组中，发生率为67.6%（34只中有23只）（总体而言，P = 0.153）。相应的宏观病变发生率分别为17.1%（35只中有6只）、0%（35只中无）和23.5%（34只中有8只）（总体而言，P = 0.004）。喂食含20 ppm FK143饮食的大鼠前列腺中宏观病变的发生率显著低于对照组（P = 0.029）或含200 ppm饮食的组（P = 0.003）。喂食含20或200 ppm FK143饮食的组大鼠前列腺内双氢睾酮含量显著低于对照组（平均值：前列腺组织湿重分别为4.51和4.33 pg/mg）（总体而言，P<0.001）；相比之下，含200 ppm饮食组的睾酮水平高于对照组（1.08 pg/mg）或含20 ppm饮食组（1.21 pg/mg）（总体而言，P<0.001）。
当以20或200 ppm的剂量喂食大鼠时，FK143可显著降低其前列腺组织中双氢睾酮的水平。然而，喂食含20 ppm FK143饮食的大鼠前列腺中宏观癌症的发生率受到抑制，而喂食含200 ppm饮食的大鼠则未受抑制。FK143化学预防活性缺乏剂量依赖性可能是由于含200 ppm饮食组中组织睾酮的相应增加所致。
5α-还原酶抑制剂FK143在特定剂量下可能会降低自发发生前列腺癌的发生率；然而，这些在大鼠中的发现是否适用于人类仍有待确定。
