Maruyama S, Nagasue N, Dhar D K, Yamanoi A, El-Assal O N, Satoh K, Okita K
Second Department of Surgery, Shimane Medical University, Izumo 693-8501, Japan.
Clin Cancer Res. 2001 Jul;7(7):2096-104.
The incidence of hepatocellular carcinoma (HCC) is more prevalent in males than in females. 5alpha-Dihydrotestosterone is the most potent form of androgen and is converted from testosterone by 5alpha-reductase. The antitumor effect of a 5alpha-reductase inhibitor (FK143) was evaluated in a rat chemical hepatocarcinogenesis model (Solt-Farber). Male Fischer 344 rats were used in three groups: (a) control group; (b) low-dose FK143 (FKL) group (20 ppm FK143); and (c) high-dose FK143 (FKH) group (200 ppm FK143). The numbers of both glutathione S-transferase placental form-positive foci (P < 0.05) and hyperplastic nodules (HNs; P < 0.01) in the liver were significantly lower in the FKL group than in the control group. The numbers (P < 0.05) and tumor volume (P < 0.01) of HCCs per liver were significantly lower in the FKL group when compared with the control group. All HCCs were well differentiated in the FKL group, whereas 38% and 36% of HCCs were moderate to poorly differentiated in the control group and the FKH group, respectively. The proliferating cell nuclear antigen labeling index:apoptotic index ratios of enzyme-altered foci, HNs, and HCCs were significantly lower in the FKL group than in the control group. Serum 5alpha-dihydrotestosterone was significantly lower in both the FKL and FKH groups. However, a high dose of FK143 (200 ppm) provided no protection against hepatocarcinogenesis, and the level of serum testosterone was elevated in this group when compared with that in the control group. The low dose of FK143 significantly suppressed the formation of enzyme-altered foci, HNs, and HCCs in rat hepatocarcinogenesis. This may indicate that 5alpha-dihydrotestosterone enhances hepatocarcinogenesis. We conclude that an optimal dose of FK143 may have a suppressive effect on hepatocarcinogenesis.
肝细胞癌（HCC）的发病率在男性中比在女性中更为普遍。5α-双氢睾酮是最具活性的雄激素形式，由睾酮通过5α-还原酶转化而来。在大鼠化学性肝癌发生模型（索尔-法伯模型）中评估了5α-还原酶抑制剂（FK143）的抗肿瘤作用。雄性费希尔344大鼠被分为三组：（a）对照组；（b）低剂量FK143（FKL）组（20 ppm FK143）；（c）高剂量FK143（FKH）组（200 ppm FK143）。FKL组肝脏中谷胱甘肽S-转移酶胎盘型阳性灶（P < 0.05）和增生性结节（HNs；P < 0.01）的数量均显著低于对照组。与对照组相比，FKL组每只肝脏中HCC的数量（P < 0.05）和肿瘤体积（P < 0.01）均显著降低。FKL组所有HCC均为高分化，而对照组和FKH组分别有38%和36%的HCC为中分化至低分化。FKL组酶改变灶、HNs和HCC的增殖细胞核抗原标记指数与凋亡指数之比显著低于对照组。FKL组和FKH组的血清5α-双氢睾酮均显著降低。然而，高剂量的FK143（200 ppm）对肝癌发生没有保护作用，与对照组相比，该组血清睾酮水平升高。低剂量的FK143显著抑制大鼠肝癌发生过程中酶改变灶、HNs和HCC的形成。这可能表明5α-双氢睾酮增强了肝癌发生。我们得出结论，最佳剂量的FK143可能对肝癌发生具有抑制作用。
