The significance of the expression of dihydropyrimidine dehydrogenase in prostate cancer
The significance of the expression of dihydropyrimidine dehydrogenase in prostate cancer
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DOI：
10.1111/j.1464-410x.2006.06606.x
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发表时间：
2007-03-01
影响因子：
4.5
通讯作者：
Miki, Tsuneharu
中科院分区：
文献类型：
--
作者：
Li, Yongnan;Mizutani, Yoichi;Miki, Tsuneharu
为了检测二氢嘧啶脱氢酶（DPD）在前列腺癌中的表达，并确定DPD的有效抑制剂5-氯-2，4-二羟基吡啶（CDHP）是否能增强5-氟尿嘧啶（5-FU）对前列腺癌的抗肿瘤活性。和38例来自接受过新辅助激素治疗的男性的标本。我们用免疫组化方法分析了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（DU 145和LNCaP）中，我们比较了5-FU/CDHP与单独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5-FU的前体药物替加氟（tegafur）与CDHP或不与CDHP联合应用对DU 145细胞移植瘤生长的影响，结果表明，DPD在癌组织中的表达显著高于正常前列腺组织; 44例前列腺癌组织中36例（82%）表达DPD，而44例正常前列腺组织中仅25例（57%）表达DPD。对于仅行根治性前列腺切除术的前列腺癌患者，DPD表达阴性的患者的无复发生存期往往比阳性表达的患者更长;在5年随访中，DPD表达阴性的前列腺癌患者没有复发。DPD表达在接受新辅助激素治疗的前列腺癌患者中显著降低。在体外治疗的人前列腺癌细胞系与5-FU/CDHP显示出更大的细胞毒性比5-FU单独治疗。最后，DU 145肿瘤与替加氟和CDHP治疗的小鼠显着小于在小鼠给tegafur单独。本研究表明，DPD表达升高的前列腺癌，并表明DPD抑制剂可能会增强5-FU对前列腺癌的抗肿瘤活性。
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.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.