2001 Fiscal Year Final Research Report Summary
Analysis of the mechanisms for biological activities of thymidine phosphorylase
| Project/Area Number |
12670144
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Kagoshima University |
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Principal Investigator |
FURUKAWA Tatsuhiko Kagoshima University, Faculty of Medicine, Research Associate, 医学部, 助手 (40219100)
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| Co-Investigator(Kenkyū-buntansha) |
AKIYAMA Shin-ichi Kagoshima University, Faculty of Medicine, Professor, 医学部, 教授 (60117413)
SUMIZAWA Tomoyuki Kagoshima University, Faculty of Medicine, Research Associate, 医学部, 助手 (90206582)
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| Project Period (FY) |
2000 – 2001
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| Keywords | thymidine phosphorylase / 2deoxy-D-ribose / 2deoxy-I-ribose / angipgenesis / apoptosis / hypoxia / metastasis / knock-out mouse |
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| Research Abstract |
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
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Research Products
(29 results)
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[Publications] Nishimoto,K., Matsune,S., Miyadera,K., Takebayashi,Y., Furukawa,T., Sumizawa,T., Akiyama,S.I. and KuronoY.: "Tne role of thymidine phosphorylase in the pathogenesis of allergic rhinitis"Acta Otolaryngol. 120. 644-648 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Arima,J., Imazono,Y., Takebayashi,Y., Nishiyama,K., Shirahama,T., Akiba,S., Furukawa,T., Akiyama,S. and Ohi,Y.: "Expression of thymidine phosphorylase as an indicator of poor prognosis for patients with transitional cell carcinoma! of the bladder"Cancer. 88. 1131-1138 (2000)
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[Publications] Okumura,H., Natsugoe,S., Nakashima,S., Matsumoto,M., Sakita,H., Nakano,S., Kusano,C., Baba,M,, Takao,S., Furukawa,T., Akiyama,S.I, and Aikou,T.: "Apoptosis and cell proliferation in esophageal sqamous cell carcinoma treated by chemotherapy"Cancer Lett. 158. 211-216 (2000)
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[Publications] Okumura,H., Chen,Z.S., Sakou,M., Sumizawa,T., Furukawa,T., Komatsu,M., Ikeda,R., Suzuki,H., Hirota,K., Aikou,T. and Akiyama,S.I.: "Reyersal of P-glycoprotein and multidrug-resistance protein-mediated drug resistance, in KB cells by 5-0-benzoylated taxinine K"Mol Pharmacol. 58. 1563-1569 (2000)
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[Publications] Kitazono,M., Okumura,H., Ikeda,R., Sumizawa,T., Furukawa,T., Nagayama,S., Seto,K., Aikou,T. and Akiyama,S.: "Reversal of LRP-associated drug resistance in colon carcinoma SW-620 cells"Int J Cancer. 91. 126-131 (2001)
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[Publications] Tsujikawa,K., Kawakami,N., Uchino,Y., Ichijo,T., Furukawa,T., Saito,H. and Yamamoto,H.: "Distinct functions of the tyvo protein tyrosine phosphatase domains of LAR )leukocyte common antigen-related) on tyrosine dephosphorylation of insulin receptor"Mol Endocrinol. 15. 271-280 (2001)
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[Publications] Ohno,N., Tani,A., Uozumi,K., Hanada,S., Furukawa,T., Akiba,S., Sumizawa,T., Utsunomiya,A., Arima,T. and Akiyama,S.: "Expression of functional lung resistance-related protein predicts poor putcome in adult T-cell leukemia"Blood. 98. 1160-1165 (2001)
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[Publications] Ohno,N., Tani,A., Chen,Z.S., Uozumi,K., Hanada,S., Akiba,S., Ren,X.Q., Furukawa,T., Sumizawa,T., Arima,T. and Akiyama,S.I.: "Prognostic significance of multidrug resistance protein in adult T-cell leukemia"Clin Cancer Res. 7. 3120-3126 (2001)
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[Publications] Qiao,S., Iwashita,T., Furukawa,T., Yamamoto,M., Sobue,G. and Takahashi,M.: "Differential effects of leukocyte common antigen-related protein on biochemical and biological activities of RET-MEN2A and RET-MEN2B mutant proteins"J Biol Chem. 276. 9460-9467 (2001)
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[Publications] Chen,Z.S., Aoki,S., Komatsu,M., Ueda,K., Sumizawa,T., Furukawa,T.. Okumura,H., Ren,X.Q., Belinsky,M.G., Lee K., Kruh,G.D., Kobayashi,M. and Akiyaraa,S.: "Reversal of drug resistance mediated by multidrug resistance protein )MRP) 1 by dual effects of agosterol A on MRP1 function"Int J Cancer. 93. 107-113 (2001)
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[Publications] Ren,X.Q., Furukawa,T., Aoki,S., Nakajima,T., Sumizawa,T., Haraguchi,M., Chen,Z.S., Kobayashi,M. and kiyama,S.: "Glutathione-dependent binding of a photoaffinity analog of agosterol A to the C-terminal half of human multidrug resistance protein"J Biol Chem. 276. 23197-23206 (2001)
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[Publications] Ikeda,R., Furukawa,T., Kitazono,M., Ishitsuka,K., Okumura,H. Tani,A., Sumizawa,T., Haraguchi,M., Komatsu,M., Uchimiya,H., Ren,X.Q., Motoya,T., Ymamada,K. and Akiyama,S.: "Molecular basis for the inhibition of hypoxia-induced apoptosis by 2-deoxy-D-ribose"Biochem Biophys Res Commun. 291. 806-812 (2002)
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[Publications] Aoki,S., Naka,Y., Itoh,T., Furukawa,T., Rachmat,R., Akiyama,S. and Kobayashi,M.: "Lembehsterols A and B, novel sulfated sterols inhibiting thymidine phosphorylase, from the marine sponge petrosia strongylata cham"Pharm Bull. (in press). (2002)
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[Publications] Ohno,N., Kreitman,R.J., Saito,T., Uozumi,K., Hanada,S., Furukawa,T., Sumizawa,T., Arima,T. and Akiyama,S.: "Augmentation of the cytotoxic activity of an immunotoxin, anti-Tac)Fv)-PE40KDEL, in adult T leukemia cells"Leukemia Lymphoma. (in press). (2002)
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[Publications] Uchimiya,H., Furukawa,T., Okamoto,M., Nakajima,Y., Matsushita,S., Ikeda,R., Gotanda,T., Haraguchi,M., Sumizawa,T,, Ono,M., Kuwano,M., Kanzaki,T. and Akiyama,S.: "Suppression of thymidine phosphorylase-inedaitaed angiogenesis and tumor growth by2-deoxy-L-ribose."Cancer Res. (in press). (2002)
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[Publications] Haraguchi,M., Tsujimoto,H., Fukushima,M., Higuchi,I., Kuribaashi,H., Utsumi,H., Nakayama,A., Hashizume,Y., Hirato,J., Yoshida,H., Kara,H., Hamano S., Kawaguchi H., Furukawa,T., Miyazono,K., Ishikawa,F., Toyoshima,H., Kaname,T., Komatsu,M., Chen,Z-S., Gotanda1,T., Tachiwada,T., Sumizawa,T., Miyadera,K., Osame,M., Yoshida1,H., Noda,T., Yamada,Y. and Akiyama,S.: "Targeted Deletion of both Thymidine Phosphorylase and Oridine Phospshorylase and consequent disorders in mice"Mol. Cell. Bio.. (in press). (2002)
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