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Analysis of the mechanisms for biological activities of thymidine phosphorylase

胸苷磷酸化酶生物活性机制分析

基本信息

批准号：
12670144
负责人：
FURUKAWA Tatsuhiko
金额：
$ 2.18万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670144/
关键词：
thymidine phosphorylase 2deoxy-D-ribose 2deoxy-I-ribose angipgenesis apoptosis hypoxia metastasis knock-out mouse

项目摘要

2-Deoxy-D-ribose (2dR) is one of metabolites of thymidine With thymidinephosphorylase (TP). We reported that 2dR has angiogenic activity before. In 2000 we found that 2deoxy L-ribose (21R), optical isomer of 2dR, can inhibit TP or 2dR induced tube formation of endotherial cells, migration of bovine aortic endotherial cells and anigogenesis in rat corneal assay and mouse dorsal air sac method. In 2001 we found that 21R can inhibit TP induced tumor growth in nude mouse xenograft model and metastasis in a liver metastasis model of mouse.These results indicated that some molecule that can recognize the molecular structure of 2dR may play important roles in the biological effect of 2dR. Furthermore 21R or analog of 21R can be a new type ahti-cancer drug.We investigated the mechanism of inhibitory effect with TP arid 2dR hypoxia induced apoptosis. 2dR could inhibit the stabilization of HIFla and the activation of p38 (MAP kinase) under hypoxic conditions. Now we are trying to find out the molecule that can directly interact with 2dR.We produced TP knockout mouse (TPKO) and TP / uridine phosphorylase (UP) double knock out mouse (TP/UPKO). UP is another molecule that can degrade thymidine. These knock out mice is fertile, morphologically normal and no signs of weight loss. Thymidine degradation activities were low in all organs except for liver of UPKO, in liver of TPKO and in all organs of TP/UPKO. Thymidine concentration in serum was 2times and 5times higher in TPKO and TP/UPKO respectively. In 1999 Nishino et al. reported that TP is a cause of MNGIE (Mitochondrial Neurogastrointestional Encephalomyopathy). We could detect no significant change as MNGIE in muscle of lOmonth-old mice, however we found the high intensity image in T2 of MRI in the brain of TP/UPKO. That may indicate TP/UPKO is useful as a model animals with encephalopathy

2-脱氧-D-核糖(2dR)是胸腺嘧啶核苷与胸苷磷酸化酶(TP)的代谢产物之一。我们以前报道过2dR具有血管生成活性。2000年，我们在大鼠角膜实验和小鼠背部气囊法中发现，2dR的光学异构体--2脱氧L核糖(21R)能抑制TP或2dR诱导的血管内皮细胞管形成、牛主动脉内皮细胞迁移和致畸作用。2001年，我们发现21R能够抑制茶多酚诱导的裸鼠移植瘤生长和小鼠肝转移模型的转移，提示一些识别2dR分子结构的分子可能在2dR的生物学效应中发挥重要作用。此外，21R或其类似物可能是一种新型的抗癌药物。我们研究了茶多酚和2dR缺氧诱导细胞凋亡的抑制机制。2DR可抑制缺氧条件下HIFla的稳定和p38(MAP-K)的激活。现在我们正在努力寻找与2DR直接相互作用的分子，我们培育了TP基因敲除小鼠(TPKO)和TP/尿苷磷酸化酶(UP)双基因敲除小鼠(TP/UPKO)。UP是另一种可以降解胸腺嘧啶核苷的分子。这些基因敲除的小鼠是可生育的，形态正常，没有体重减轻的迹象。除UPKO的肝脏外，TPKO的肝脏和TP/UPKO的所有器官的胸腺嘧啶核苷降解活性均较低。TPKO组和TP/UPKO组血清胸腺嘧啶核苷浓度分别是TPKO组的2倍和5倍。1999年，Nishino et al.据报道，TP是引起线粒体神经胃肠病(MNGIE)的原因之一。在1月龄小鼠肌肉中未检测到明显的MNGIE改变，而在TP/UPKO小鼠脑组织中可见MRI的T2高信号图像。提示TP/UPKO可作为脑病动物模型。