Thymidylate synthase (TS) and ribonucleotide reductase (RNR) may be involved in acquired resistance to 5-fluorouracil (5-FU) in human cancer xenografts in vivo
Thymidylate synthase (TS) and ribonucleotide reductase (RNR) may be involved in acquired resistance to 5-fluorouracil (5-FU) in human cancer xenografts in vivo
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DOI：
10.1016/s0959-8049(01)00174-5
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发表时间：
2001-09-01
影响因子：
8.4
通讯作者：
Takechi, T
中科院分区：
文献类型：
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作者：
Fukushima, M;Fujioka, A;Takechi, T
对5-氟尿嘧啶（5-FU）耐药的人肿瘤亚系通过每天一次和每5次至少50次给予5-FU至裸鼠中的KM 12 C人结肠直肠异种移植物来建立。用5-FU处理的KM 12 C肿瘤显示对5-FU的敏感性较低，抑制率（IR）为7.9%，而未处理的肿瘤对5-FU高度敏感，IR为81.8%。为了阐明5-FU耐药的机制，测量了亲代和5-FU处理的KM 12 C肿瘤中参与5-FU代谢的各种酶的活性和基因表达。在5-FU耐药的KM 12 C肿瘤中观察到胸苷酸合成酶（TS）活性增加2- 3倍，核糖核苷酸还原酶（RNR）活性降低4- 5倍，而乳清酸磷酸核糖基转移酶（OPRT）胸苷和尿苷磷酸化酶（TP，UP）和胸苷激酶（TK）的活性没有明显变化，这是5-FU重复治疗KM 12 C肿瘤的结果。与亲本肿瘤相比，5-FU处理的肿瘤亚系（KM 12 C/5-FU）中TS mRNA的表达也根据TS活性的增加而扩增，但与亲本肿瘤相比，在5-FU耐药的肿瘤亚系中未检测到RNR R1和RNA-R2 mRNA的表达变化，这表明RNR可能存在转录后调节。此外，除了TS和OPRT之外，RNR似乎与人类癌症异种移植物中对5-FU的固有不敏感性有关。从这些结果可以得出结论，RNR活性是体内人类癌症异种移植物中对5-FU的获得性或固有抗性因素之一，包括TS。(C)2001爱思唯尔科技有限公司版权所有。
A human tumour sub-line resistant to 5-fluorouracil (5-FU) was established by once a day and every 5, with at least 50 administrations of 5-FU to KM12C human colorectal xenografts in nude mice. KM12C tumours treated with 5-FU showed less sensitivity to 5-FU with an inhibition rate (IR) of 7.9%, while non-treated tumours were highly sensitive to 5-FU with an IR of 81.8%. To clarify the mechanism of 5-FU-resistance, the activities of various enzymes and gene expressions involved in the metabolism of 5-FU in both parental and 5-FU-treated KM12C tumours were measured. A 2- to 3-fold increase in thymidylate synthase (TS) activity and 4- to 5-fold decrease in ribonucleotide reductase (RNR) activity were observed in 5-FU-resistant KM12C tumours, while the activities of orotate phosphoribosyltransferase (OPRT) thymidine and uridine phosphorylases (TP,UP) and thymidine kinase (TK) were not markedly changed as a consequence of repeated treatment of KM12C tumours with 5-FU. The expression of TS mRNA was also amplified in accordance with the increased TS activity in a 5-FU-treated tumour sub-line (KM12C/5-FU) compared with that in parental tumours, but changed expressions of both RNR-R1 and RNA-R2 mRNA could not be detected in the 5-FU-resistant tumour sub-line compared with the parental tumours, suggesting possible post-transcriptional regulation of RNR. Moreover, RNR, in addition to TS and OPRT, seemed to be related to the inherent insensitivity to 5-FU in human cancer xenografts. From these results, it may be concluded that RNR activity is one of the acquired or inherent resistant factors, including TS, to 5-FU in human cancer xenografts in vivo. (C) 2001 Elsevier Science Ltd. All rights reserved.