Nio Y, Kimura H, Tsubono M, Tseng C C, Kawabata K, Masai Y, Hayashi H, Meyer C, Fukumoto M, Tobe T
First Department of Surgery, Kyoto University Faculty of Medicine, Japan.
Anticancer Res. 1992 Jul-Aug;12(4):1141-6.
5'-Deoxy-5-fluorouridine (5'-DFUR) is believed to be metabolized to 5-fluorouracil (5-FU) by pyrimidine nucleoside phosphorylase (PyNPase). PyNPase activity is reported to be higher in neoplastic tissues than in normal tissues, and this has been proposed as an explanation for the selective cytotoxicity of 5'-DFUR against tumors. In the present study, PyNPase activity was measured in 95 neoplastic and normal specimens from human digestive organ tissues. In specimens from the esophagus, stomach, intestine and pancreas, PyNPase activity was higher in neoplastic tissues than in normal tissues. However, PyNPase activity in non-malignant liver tissues, especially cirrhotic liver tissues, was much higher than in the normal tissues of the other digestive organs. PyNPase activity in non-malignant liver tissues was a high as in primary liver tumors, and PyNPase activity in metastatic liver tumors was lower than in primary tumors and non-malignant cirrhotic tissues. The in vivo antitumor activities of oral 5'-DFUR and intravenous 5-FU were also assessed in 6 human digestive organ cancer xenograft lines transplanted subcutaneously in nude mice, and the relationship between the in vivo antitumor effects of 5'-DFUR and PyNPase activity in the tumors was assessed. However, there was no statistically significant correlation between them. Although the in vivo antitumor effect of intravenous 5-FU correlated significantly with the in vitro sensitivity of the tumors to 5-FU (assessed by DNA synthesis inhibition assay), the in vivo effects of 5'-DFUR did not correlate with the in vitro sensitivity to 5-FU. It is suggested that: (a) the liver may be the major site for metabolizing 5'-DFUR to 5-FU, and (b) measuring PyNPase activity in the tumor may not be a useful indicator for chemotherapy with 5'-DFUR.
5'-脱氧-5-氟尿苷（5'-DFUR）被认为可通过嘧啶核苷磷酸化酶（PyNPase）代谢为5-氟尿嘧啶（5-FU）。据报道，肿瘤组织中的PyNPase活性高于正常组织，这被认为是5'-DFUR对肿瘤具有选择性细胞毒性的原因。在本研究中，检测了95例取自人体消化器官组织的肿瘤和正常标本中的PyNPase活性。在取自食管、胃、肠和胰腺的标本中，肿瘤组织中的PyNPase活性高于正常组织。然而，非恶性肝组织，尤其是肝硬化肝组织中的PyNPase活性远高于其他消化器官的正常组织。非恶性肝组织中的PyNPase活性与原发性肝癌中的活性一样高，而转移性肝癌中的PyNPase活性低于原发性肿瘤和非恶性肝硬化组织。还在6种皮下移植到裸鼠体内的人消化器官癌异种移植瘤模型中评估了口服5'-DFUR和静脉注射5-FU的体内抗肿瘤活性，并评估了5'-DFUR的体内抗肿瘤作用与肿瘤中PyNPase活性之间的关系。然而，它们之间没有统计学上的显著相关性。尽管静脉注射5-FU的体内抗肿瘤作用与肿瘤对5-FU的体外敏感性（通过DNA合成抑制试验评估）显著相关，但5'-DFUR的体内作用与对5-FU的体外敏感性无关。研究表明：（a）肝脏可能是将5'-DFUR代谢为5-FU的主要部位，（b）检测肿瘤中的PyNPase活性可能不是5'-DFUR化疗的有用指标。
