Analysis of the mechanisms for biological activities of thymidine phosphorylase

2-脱氧-D-核糖（2dR）是胸苷在胸苷磷酸化酶（TP）作用下的代谢产物之一。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气囊实验中发现，2dR的光学异构体21 R能抑制TP或2dR诱导的内皮细胞小管形成、牛主动脉内皮细胞迁移和血管生成。2001年我们发现21 R能抑制TP诱导的裸鼠移植瘤的生长和小鼠肝转移模型的转移，这些结果提示某些识别2dR分子结构的分子可能在2dR的生物学效应中起重要作用。21 R或其类似物有可能成为一种新型的抗肿瘤药物。2dR可抑制缺氧条件下HIFla的稳定和p38（MAP激酶）的激活。本研究建立了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苷的分子。这些基因敲除小鼠是可生育的，形态正常，没有体重减轻的迹象。UPKO除肝脏外，其它各器官的胸苷降解活性均较低，TPKO肝脏和TP/UPKO各器官的胸苷降解活性均较低。TPKO组和TP/UPKO组血清胸苷浓度分别为对照组的20倍和50倍。1999年，Nishino等人报道TP是MNGIE（线粒体神经胃肠脑肌病）的原因。10月龄小鼠肌肉MNGIE未见明显改变，而TP/UPKO小鼠脑MRI T2区出现高信号影。提示TP/UPKO可作为脑损伤的动物模型

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