The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2.
The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2.
复制标题
胞苷类似物氟环戊烯基胞嘧啶 (RX-3117) 由尿苷-胞苷激酶 2 激活。
DOI：
10.1371/journal.pone.0162901
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Peters GJ
中科院分区：
文献类型：
--
作者：
Sarkisjan D;Julsing JR;Smid K;de Klerk D;van Kuilenburg AB;Meinsma R;Lee YB;Kim DJ;Peters GJ
氟环戊基胞嘧啶（Fluorocyclopentenylcytosine, RX-3117）是一种口服胞苷类似物，目前处于I期临床试验阶段。RX-3117在包括吉西他滨耐药肿瘤在内的多种人类肿瘤异种移植物中具有良好的抗肿瘤活性。RX-3117被尿嘧啶-胞苷激酶（UCK）激活。由于UCK以UCK1和UCK2两种形式存在，我们研究了哪种形式负责RX-3117的磷酸化。为此，我们用uck - sirna转染了A549和SW1573细胞系。转染UCK1-siRNA能有效下调UCK1-mRNA的表达，但不能下调UCK2-mRNA的表达，并且不影响对RX-3117的敏感性。然而，转染UCK2-siRNA完全下调UCK2-mRNA和蛋白，并保护A549和SW1573免受RX-3117的侵害。两组肿瘤细胞系和异种移植细胞的UCK酶活性仅与UCK2-mRNA表达相关（r分别为0.803和0.915），而与UCK1-mRNA表达无关。此外，RX-3117核苷酸的积累与UCK2的表达相关。综上所述，RX-3117可被UCK2激活，UCK2可用于筛选对RX-3117潜在敏感的患者。
Fluorocyclopentenylcytosine (RX-3117) is an orally available cytidine analog, currently in Phase I clinical trial. RX-3117 has promising antitumor activity in various human tumor xenografts including gemcitabine resistant tumors. RX-3117 is activated by uridine-cytidine kinase (UCK). Since UCK exists in two forms, UCK1 and UCK2, we investigated which form is responsible for RX-3117 phosphorylation. For that purpose we transfected A549 and SW1573 cell lines with UCK-siRNAs. Transfection of UCK1-siRNA efficiently downregulated UCK1-mRNA, but not UCK2-mRNA expression, and did not affect sensitivity to RX-3117. However, transfection of UCK2-siRNA completely downregulated UCK2-mRNA and protein and protected both A549 and SW1573 against RX-3117. UCK enzyme activity in two panels of tumor cell lines and xenograft cells correlated only with UCK2-mRNA expression (r = 0.803 and 0.915, respectively), but not with UCK1-mRNA. Moreover, accumulation of RX-3117 nucleotides correlated with UCK2 expression. In conclusion, RX-3117 is activated by UCK2 which may be used to select patients potentially sensitive to RX-3117.
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DOI：
10.1111/j.1349-7006.2002.tb01325.x
发表时间：
2002-07
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Shimamoto Y;Koizumi K;Okabe H;Kazuno H;Murakami Y;Nakagawa F;Matsuda A;Sasaki T;Fukushima M
通讯作者：
Fukushima M
影响因子：
--
作者：
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通讯作者：
van Beusechem, Victor W.
影响因子：
3.5
作者：
Schumacher, Fredrick R.;Wang, Zhaoming;McGlynn, Katherine A.
通讯作者：
McGlynn, Katherine A.
影响因子：
64.5
作者：
Okano, M;Bell, DW;Li, E
通讯作者：
Li, E
影响因子：
7.3
作者：
Choi, Won Jun;Chung, Hwa-Jin;Jeong, Lak Shin
通讯作者：
Jeong, Lak Shin