Li Yongnan, Mizutani Yoichi, Shiraishi Takumi, Nakamura Terukazu, Mikami Kazuya, Takaha Natsuki, Okihara Koji, Kawauchi Akihiro, Sakai Toshiyuki, Miki Tsuneharu
Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
BJU Int. 2007 Mar;99(3):663-8. doi: 10.1111/j.1464-410X.2006.06606.x. Epub 2006 Nov 7.
To measure dihydropyrimidine dehydrogenase (DPD), an enzyme involved in the metabolism of 5-fluorouracil (5-FU), expression in prostate cancer and determine whether 5-chloro-2,4-dihydroxypyridine (CDHP), a potent inhibitor of DPD, enhances the antitumoral activity of 5-FU against prostate cancer.
PATIENTS, MATERIALS AND METHODS: In all, 44 prostate tissue specimens were obtained from men who had a radical prostatectomy alone for prostate cancer, and 38 specimens from men who had had neoadjuvant hormonal therapy. We analysed the cancerous tissue and normal prostate tissue for DPD expression using immunohistochemistry, and determined its prognostic significance. In cultured human prostate cancer lines (DU145 and LNCaP), we compared the cytotoxicity of 5-FU/CDHP with that of 5-FU alone. Finally, in experiments on immunodeficient mice, we studied the effect of oral administration of tegafur, a pro-drug for 5-FU, with or without CDHP on the growth of tumours introduced by injection of DU145 cells.
The expression of DPD was significantly higher in cancerous than normal prostate tissue; 36 of 44 (82%) specimens of prostate cancer expressed DPD, whereas only 25 of 44 (57%) specimens of normal prostate tissue expressed DPD. For men with prostate cancer who had radical prostatectomy alone, men with negative DPD expression tended to have a longer recurrence-free survival than those with positive expression; there were no recurrences in men with prostate cancer and negative DPD expression in the 5-year follow-up. DPD expression was significantly lower in men with prostate cancer who received neoadjuvant hormonal therapy. In vitro treatment of human prostate cancer cell lines with 5-FU/CDHP showed more cytotoxicity than with 5-FU treatment alone. Finally, DU145 tumours in mice treated with tegafur and CDHP were significantly smaller than in mice given tegafur alone.
The present study showed that DPD expression is elevated in prostate cancer, and indicate that DPD inhibitors might enhance the antitumour activity of 5-FU against prostate cancer.
检测参与5-氟尿嘧啶（5-FU）代谢的二氢嘧啶脱氢酶（DPD）在前列腺癌中的表达，并确定DPD的强效抑制剂5-氯-2,4-二羟基吡啶（CDHP）是否能增强5-FU对前列腺癌的抗肿瘤活性。
患者、材料与方法：共获取44例仅接受前列腺癌根治性切除术患者的前列腺组织标本，以及38例接受新辅助激素治疗患者的标本。我们采用免疫组织化学方法分析癌组织和正常前列腺组织中DPD的表达，并确定其预后意义。在培养的人前列腺癌细胞系（DU145和LNCaP）中，我们比较了5-FU/CDHP与单独使用5-FU的细胞毒性。最后，在免疫缺陷小鼠实验中，我们研究了口服替加氟（一种5-FU的前体药物）联合或不联合CDHP对注射DU145细胞所致肿瘤生长的影响。
癌组织中DPD的表达显著高于正常前列腺组织；44例前列腺癌标本中有36例（82%）表达DPD，而44例正常前列腺组织标本中只有25例（57%）表达DPD。对于仅接受前列腺癌根治性切除术的患者，DPD表达阴性的患者无复发生存期往往比表达阳性的患者更长；在5年随访中，DPD表达阴性的前列腺癌患者无复发。接受新辅助激素治疗的前列腺癌患者中DPD表达显著降低。用5-FU/CDHP对人前列腺癌细胞系进行体外处理显示出比单独使用5-FU治疗更强的细胞毒性。最后，用替加氟和CDHP治疗的小鼠中的DU145肿瘤明显小于仅给予替加氟的小鼠。
本研究表明前列腺癌中DPD表达升高，并提示DPD抑制剂可能增强5-FU对前列腺癌的抗肿瘤活性。
