Crucial roles of thymidine kinase 1 and deoxyUTPase in incorporating the antineoplastic nucleosides trifluridine and 2'-deoxy-5-fluorouridine into DNA.
Crucial roles of thymidine kinase 1 and deoxyUTPase in incorporating the antineoplastic nucleosides trifluridine and 2'-deoxy-5-fluorouridine into DNA.
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DOI：
10.3892/ijo.2015.2974
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发表时间：
2015
影响因子：
5.2
通讯作者：
Matsuo K
中科院分区：
文献类型：
--
作者：
Sakamoto K;Yokogawa T;Ueno H;Oguchi K;Kazuno H;Ishida K;Tanaka N;Osada A;Yamada Y;Okabe H;Matsuo K
三氟吡啶（FTD）和2 ' -脱氧-5-氟吡啶（FdUrd）是5-氟尿嘧啶（5-FU）的衍生物，是抑制胸苷酸合成酶活性的抗肿瘤药物，它们的核苷酸被并入DNA。然而，很明显，与这些核苷类似物相关的潜在抗肿瘤机制存在一些差异。最近，TAS-102（由FTD和盐酸替吡拉西组成，TPI）被证明可以延长中位数为2次既往治疗（包括5-FU）的结直肠癌患者的生存期。TAS-102最近在日本被批准临床使用。这些数据表明，TAS-102和5-FU的抗肿瘤活性通过不同的机制进行。因此，我们分析了它们在胸腺嘧啶回收途径利用方面的特性，包括膜转运蛋白、核苷激酶、核苷酸去磷酸化酶和DNA聚合酶α。FTD与DNA的结合效率高于FdUrd。FTD和FdUrd均通过ENT1和ENT2转运到细胞中，并被胸苷激酶1磷酸化，表明FTD的催化活性高于FdUrd。脱氧utpase （DUT）不识别dTTP和ftd -三磷酸（F3dTTP），而脱氧尿苷-三磷酸（dUTP）和fdurd -三磷酸（FdUTP）被DUT有效降解。DNA聚合酶α将F3dTTP和FdUTP结合到DNA对链上与腺嘌呤对齐的位点上。与fdurd处理的细胞相比，ftd处理的细胞表现出不同的核形态。这些发现表明，由于TK1和DUT的底物特异性不同，FTD和FdUrd以不同的效率并入DNA，导致大量FTD并入DNA。
Trifluridine (FTD) and 2′-deoxy-5-fluorouridine (FdUrd), a derivative of 5-fluorouracil (5-FU), are antitumor agents that inhibit thymidylate synthase activity and their nucleotides are incorporated into DNA. However, it is evident that several differences occur in the underlying antitumor mechanisms associated with these nucleoside analogues. Recently, TAS-102 (composed of FTD and tipiracil hydrochloride, TPI) was shown to prolong the survival of patients with colorectal cancer who received a median of 2 prior therapies, including 5-FU. TAS-102 was recently approved for clinical use in Japan. These data suggest that the antitumor activities of TAS-102 and 5-FU proceed via different mechanisms. Thus, we analyzed their properties in terms of thymidine salvage pathway utilization, involving membrane transporters, a nucleoside kinase, a nucleotide-dephosphorylating enzyme, and DNA polymerase α. FTD incorporated into DNA with higher efficiency than FdUrd did. Both FTD and FdUrd were transported into cells by ENT1 and ENT2 and were phosphorylated by thymidine kinase 1, which showed a higher catalytic activity for FTD than for FdUrd. deoxyUTPase (DUT) did not recognize dTTP and FTD-triphosphate (F3dTTP), whereas deoxyuridine-triphosphate (dUTP) and FdUrd-triphosphate (FdUTP) were efficiently degraded by DUT. DNA polymerase α incorporated both F3dTTP and FdUTP into DNA at sites aligned with adenine on the opposite strand. FTD-treated cells showed differing nuclear morphologies compared to FdUrd-treated cells. These findings indicate that FTD and FdUrd are incorporated into DNA with different efficiencies due to differences in the substrate specificities of TK1 and DUT, causing abundant FTD incorporation into DNA.
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影响因子：
3
作者：
Parsels, LA;Parsels, JD;Maybaum, J
通讯作者：
Maybaum, J
影响因子：
46.9
作者：
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影响因子：
5.7
作者：
Temmink, Olaf H.;Bijnsdorp, Irene V.;Peters, Godefridus J.
通讯作者：
Peters, Godefridus J.
影响因子：
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作者：
Fukushima, M;Suzuki, N;Asao, T
通讯作者：
Asao, T
影响因子：
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作者：
HEIDELBERGER, C;CHAUDHURI, NK;SCHEINER, J
通讯作者：
SCHEINER, J