Analysis of the mechanisms for biological activities of thymidine phosphorylase

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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