Inhibition of metastasis of tumor cells overexpressing thymidine phosphorylase by 2-deoxy-L-ribose
Inhibition of metastasis of tumor cells overexpressing thymidine phosphorylase by 2-deoxy-L-ribose
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DOI：
10.1158/0008-5472.can-03-2597
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发表时间：
2004-03-01
期刊：
影响因子：
11.2
通讯作者：
Akiyama, S
中科院分区：
文献类型：
--
作者：
Nakajima, Y;Gotanda, T;Akiyama, S
胸苷磷酸化酶（TP）催化胸苷可逆转化为胸腺嘧啶，从而产生2-脱氧-D-核糖-1-磷酸，其在去磷酸化后形成2-脱氧-D-核糖（D-dRib），这是胸苷的降解产物。我们先前已经表明，D-dRib促进血管生成和内皮细胞的趋化性，并且还在一些癌细胞系中赋予对缺氧诱导的细胞凋亡的抗性。D-dRib的立体异构体2-脱氧-L-核糖（L-dRib）能抑制D-dRib的抗凋亡作用，并能抑制移植于裸鼠体内的过表达TP的KB细胞（KB/TP细胞）的生长。在这项研究中，我们使用两种不同的转移模型检测了L-dRib抑制KB/TP细胞转移的能力。首先在接种KB/TP细胞的裸鼠肝转移模型中研究了L-dRib的抗转移作用。以20 mg/kg/天的剂量口服给予L-dRib 28天，显著减少了肝脏中转移性结节的数量，抑制了KB/TP转移性结节中的血管生成并增强了细胞凋亡。接下来，我们比较了L-dRib和替加氟单独或组合减少接受皮下注射的裸鼠腹腔器官中转移性结节数量的能力。KB/TP细胞的数量。L-dRib（20 mg/kg/天）在减少腹腔器官中转移性结节数量方面比替加氟（100 mg/kg/天）显著（P < 0.05）更有效。体外侵袭实验表明，L-dRib能明显减少KB/TP细胞的侵袭。L-dRib的抗侵袭活性可能是通过其抑制TP和D-dRib对培养的KB细胞中血管内皮生长因子和白细胞介素-8的mRNA和蛋白表达的增强作用的能力来介导的。这些发现表明，L-dRib可能在临床环境中用于抑制表达TP的肿瘤细胞的转移。
Thymidine phosphorylase (TP) catalyzes the reversible conversion of thymidine to thymine, thereby generating 2-deoxy-D-ribose-1-phosphate, which upon dephosphorylation forms 2-deoxy-D-ribose (D-dRib), a degradation product of thymidine. We have previously shown that D-dRib promotes angiogenesis and chemotaxis of endothelial cells and also confers resistance to hypoxia-induced apoptosis in some cancer cell lines. 2-Deoxy-L-ribose (L-dRib), a stereoisomer of D-dRib, can inhibit D-dRib antiapoptotic effects and suppressed the growth of KB cells overexpressing TP (KB/TP cells) transplanted into nude mice. In this study, we examined the ability of L-dRib to suppress metastasis of KB/TP cells using two different models of metastasis. The antimetastatic effect of L-dRib was first investigated in a liver-metastasis model in nude mice inoculated with KB/TP cells. Oral administration of L-dRib for 28 days at a dose of 20 mg/kg/day significantly reduced the number of metastatic nodules in the liver and suppressed angiogenesis and enhanced apoptosis in KB/TP metastatic nodules. Next, we compared the ability of L-dRib and tegafur alone or in combination to decrease the number of metastatic nodules in organs in the abdominal cavity in nude mice receiving s.c. of KB/TP cells into their backs. L-dRib (20 mg/kg/day) was significantly (P < 0.05) more efficient than tegafur (100 mg/kg/day) in decreasing the number of metastatic nodules in organs in the abdominal cavity. By in vitro invasion assay, L-dRib also reduced the number of invading KB/TP cells. L-dRib anti-invasive activity may be mediated by its ability to suppress the enhancing effect of TP and D-dRib on both mRNA and protein expression of vascular endothelial growth factor and interleukin-8 in cultured KB cells. These findings suggest that L-dRib may be useful in a clinical setting for the suppression of metastasis of tumor cells expressing TP.