Abstract
Thymidine phosphorylase is a protein which may has a dual action: it is a rate-limiting enzyme in thymidine metabolism and it is similar to the platelet – derived endothelial cell growth factor (PD/ECGF). The enzyme catalyzes the reversible reaction of phosphorolytic cleavage of thymidine to thymine and deoxyribose-1-phosphate. It has been found that TP has higher activity in tumor tissues. Also it is involved in a proliferative process in a wide variety of chronic inflammatory diseases. Increased expression of PD/ECGF in many tumors is associated with aggressive disease and/or poor prognosis. Its known that high TP activity is related to malignant angiogenesis and invasion.
On the other hand, TP inhibits a hypoxia induced apoptotic pathway and enhances expression of various inflammatory cytokines and interferons. This apparent role of enzyme in tumor progression has prompted investigation a large number of TP inhibitors for applicability in chemotherapy backbone regimens. The enzymatic activity of PD/ECGF is being able to generate 5-fluorouracile from capecitabine and other precursors. Thus TP is identified as a prime target for developing novel anticancer therapies. The serum TP level in cancer patients provides useful prognostic information regarding both responses to chemotherapy and length of survival and should be used in planning appropriate therapy. TP could be suggested that control of individual enzyme activity in blood serum may be used as informative tool for monitoring of patients and treatment optimization.
References
Бакурова Е.М. Особенности генерации 2-дезокси-α-D-рибозо-1-фосфата опухолью, связь с продукцией активных форм кислорода // Актуальные вопросы биологической физики и химии. 2018;3(3):584-587 [Bakurova EM. The features of tumoral 2-deoxy-D-ribose-1-phosphate generation, association with production of reactive oxygen species // Russian Journal of Biological Physics and Chemistry. 2018;3(3):584-587 (in Russ.)].
Бакурова Е.М., Борзенко Б.Г., Василенко И.В. Тимидинфосфорилаза — перспективный маркер эпителиально-мезенхимальной трансформации опухоли // Медицинский алфавит. 2016;19(3):31-32 [Bakurova EM, Borzenko BG, Vasilenko IV. Thymidine phosphorylase as perspective marker of epithelialmesenchymal transition of tumor // Meditsinskiy alfavit. 2016;19(3):1-32 (in Russ.)].
Борзенко Б.Г., Бакурова Е.М. Нарушение метаболизма предшественников ДНК в слизистой оболочки желудка как показатель вероятного озлокачествления язвы этого органа // Вопросы онкологии. 2008;54(2):184-187 [Borzenko BG, Bakurova EM. Disturbed metabolism of gastric mucosa DNA precursors as prognosticator of neoplastic transformation of gastric ulcer // Vopr Onkol. 2008;54(2):184-187 (In Russ.)].
Клинические рекомендации по диагностике и лечению больных раком прямой кишки. М.: Ассоциация онкологов России, 2014 [Clinical guidelines for diagnosis and treatment of colorectal cancer. Moscow: association of oncologists of Russia, 2014 (In Russ.)].
Проект: медицинская методология оказания медицинской помощи пациентам, страдающим раком ободочной кишки / разраб. Кокушкин К.А. М., 2017 [Project: medical methodology for health care management of patients with colorectal cancer / Kokushkin K.A. Moscow, 2017 (in Russ.)].
Борзенко Б.Г., Верхова О.О, Помазан В.О. и др. Метаболізм аденозину та тимідину у здорових жінок різного віку та у жінок з мастопатією // Укр. Біохім. Журн. 1999;71(3):86-89 [Borzenko BG, Verkhova OO, Pomazan VO et al. Metabolism of adenosine and thymidine in healthy females of different ages and females with mastopathies // Ukr Biokhim Zh, 1999;71(3):86-9. (In Russ.)].
Almandil NB, Taha M, Farooq R et al. Synthesis of thymidine phosphorylase inhibitor based on quinoxaline derivatives and their molecular docking study // Molecules. 2019;24(1002):1-18.
Asai K, Nakanishi K, Isobe I et al. Neurotrophic action of gliostatin on cortical neurons. Identity of gliostatin and platelet-derived endothelial cell growth factor // Journal of Biological Chemistry. 1992;28(267):20311–20316.
Balzarini J, Gamboa AE, Esnouf R et al. 7-Deazaxanthine, a novel prototype inhibitor of thymidine phosphorylase // FEBS Letters. 1998;438(1-2):91–95.
Baynes JW. The role of AGEs in aging: Causation or correlation // Experimental Gerontology. 2001;36(9):1527–1537.
Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: Implications for new anticancer therapies // Journal of Pathology. 2002;3(196):254–265.
Borzenko BG, Bakurova EM, Popovich YuA et al. Activity of thymidilate «salvage pathway» enzymes in human gastric cancer and blood serum: Correlation with treatment modalities // Experimental Oncology. 2013;1(35):37–40.
Bronckaers A, Gago F, Balzarini Jan, Liekens S. The dual role of thymidine phosphorylase in cancer development and chemotherapy // Medicinal Research Reviews. 2009;29(6):903–953.
Brown NS, Jones A, Fujiyama C et al. Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors // Cancer Research. 2000;22(60):6298–6302.
Brown NS, Bicknell R. Thymidine phosphorylase, 2-deoxy-D-ribose and angiogenesis // Biochemical Journal. 1998(334):1–8.
Cao D, Russell RL, Zhang D et al. Uridine phosphorylase (-/-) murine embryonic stem cells clarify the key role of this enzyme in the regulation of the pyrimidine salvage pathway and in the activation of fluoropyrimidines // Cancer Research. 2002;62(8):2313–2317.
Creamer D, Jaggar R, Allen M et al. Overexpression of the angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase in psoriatic epidermis // British Journal of Dermatology. 1997;137(6):851–855.
de Bruin M, Temmink O, Hoekman K et al. Role of platelet derived endothelial cell growth factor / thymidine phosphorylase in health and disease // Cancer Therapy. 2006;4):99–124.
Desgranges C, Razaka G, Rabaud M, Bricaud H. Catabolism of thymidine in human blood platelets purification and properties of thymidine phosphorylase // BBA Section Nucleic Acids And Protein Synthesis. 1981;654(2):211–218.
Desgranges C, Razaka G, Rabaud M et al. Phosphorolysis of (E)-5-(2-bromovinyl)-2’-deoxyuridine (BVDU) and other 5-substituted-2’-deoxyuridines by purified human thymidine phosphorylase and intact blood platelets // Biochemical Pharmacology. 1983;32(23):3583–3590.
Elamin YY, Rafee S, Osman N et al. Thymidine Phosphorylase in Cancer; Enemy or Friend? // Cancer Microenvironment. 2016;9(1):33–43.
Fox SB, Moghaddam A, Westwood M et al. Platelet‐derived endothelial cell growth factor/thymidine phosphorylase expression in normal tissues: An immunohistochemical study // The Journal of Pathology. 1995;176(2):183–190.
Friedkin M, Roberts D. The enzymatic synthesis of nucleosides: I. Thymidine phosphorylase in mammalian tissue // J. Biol. Chem. 1954(207):245–256.
Fujimoto J, Sakaguchi H, Hirose R et al. Expression of platelet-derived endothelial cell growth factor (PD-ECGF) and its mRNA in uterine cervical cancers // British Journal of Cancer. 1999;79(7/8):1249–1254.
Fujimoto K, Hosotani R, Wada M et al. Expression of two angiogenic factors, vascular endothelial growth factor and platelet-derived endothelial cell growth factor in human pancreatic cancer, and its relationship to angiogenesis // European Journal of Cancer. 1998;34(9):1439–1447.
Fujiwaki R, Hata K, Iida K et al. Co-expression of vascular endothelial growth factor and thymidine phosphorylase in endometrial cancer // Acta Obstet Gynecol Scand. 1999;78:728–734.
Fukushima M, Suzuki N, Emura T et al. Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2′-deoxyribonucleosides // Biochemical Pharmacology. 2000;59(10):1227–1236.
Furukawa T, Yoshimura A, Sumizawa T et al. Angiogenic factor // Nature. 1992;23 (356):668.
Giatromanolaki A, Sivridis E, Maltezos E et al. Upregulated hypoxia inducible factor-1alpha and -2alpha pathway in rheumatoid arthritis and osteoarthritis // Arthritis research & therapy. 2003. Vol. 5(4):193–201.
Goto H, Kohno K, Sone S et al. Interferon γ-dependent induction of thymidine phosphorylase/platelet-derived endothelial growth factor through γ-activated sequence-like element in human macrophages // Cancer Research. 2001;61(2):469–473.
Hagiwara K, Stenman G, Honda H et al. Organization and chromosomal localization of the human platelet-derived endothelial cell growth factor gene // Molecular and Cellular Biology. 1991;11(4):2125–2132.
Haraguchi M, Furukawa T, Sumizawa T et al. Sensitivity of Human KB Cells Expressing Platelet-Derived Endothelial Cell Growth Factor to Pyrimidine Antimetabolites // Cancer Research. 1993;53(23):5680–5682.
Haraguchi M, Miyadera K, Uemura K et al. Angiogenic activity of enzymes // Nature. 1994;368(6468):198.
Heidelberger C, Chaudhuri NK, Danneberg P et al. Fluorinated Pyrimidines, A New Class of Tumour-Inhibitory Compounds // Nature. 1957;179:663–666.
Hotchkiss KA, Ashton AW, Klein RS et al. Mechanisms by which tumor cells and monocytes expressing the angiogenic factor thymidine phosphorylase mediate human endothelial cell migration // Cancer Research. 2003;63(2):527–533.
Ikeda R. et al. Molecular basis for the inhibition of hypoxia-induced apoptosis by 2-deoxy-D-ribose // Biochemical and Biophysical Research Communications. 2002;291(4):806–812.
Ikeda R, Furukawa T, Kitazono M et al. Thymidine phosphorylase inhibits the expression of proapoptotic protein BNIP3 // Biochemical and Biophysical Research Communications. 2008;370(2):220–224.
Ishikawa F, Miyazono K, Hellman U et al. Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor // Nature. 1989;338:557–562.
Ishitsuka H. Capecitabine: Preclinical pharmacology studies // Investigational New Drugs. 2000;18(4):343–354.
Javaid S, Saad SM, Zafar H et al. Thymidine phosphorylase and prostrate cancer cell proliferation inhibitory activities of synthetic 4-hydroxybenzohydrazides: In vitro, kinetic, and in silico studies // PLoS ONE. 2020;15(1).
Kimura Y, Morohashi S, Yoshizawa T et al. Clinicopathological significance of vascular endothelial growth factor, thymidine phosphorylase and microvessel density in colorectal cancer // Molecular Medicine Reports. 2016;13(2):1551–1557.
Kitazono M, Takebayashi Y, Ishitsuka K et al. Prevention of hypoxia-induced apoptosis by the angiogenic factor thymidine phosphorylase // Biochem Biophys Res Commun. 1998;23(3):797–803.
Kobashi N, Matsumoto H, Zhao S et al. The thymidine phosphorylase imaging agent 123I-IIMU predicts the efficacy of capecitabine // Journal of Nuclear Medicine. 2016;57(8):1276–1281.
Kono A, Hara Y, Sugata S et al. Activation of 5’-deoxy-5-fluorouridine by thymidine phosphorylase in human tumors // Chem. Pharm. Bull. 1983;31(1):175–178.
Kouni MH, Naguib FNM, Naguib FNM. Differences in Activities and Substrate Specificity of Human and Murine Pyrimidine Nucleoside Phosphorylases: Implications for Chemotherapy with 5-Fluoropyrimidines // Cancer Research. 1993;53(16):3687–3693.
Lee SJ, Yeo JS, Lee HJ et al. Thymidine phosphorylase influences [18F] fluorothymidine uptake in cancer cells and patients with non-small lung cancer // European Journal of Nuclear Medicine and Molecular Imaging. 2014;41(7):1327–1335.
Liu H, Liu Z, Du J et al. Thymidine phosphorylase exerts complex effects on bone resorption and formation in myeloma // Science Translational Medicine. 2016;8(353):1–11.
Maeda K, Kang SM, Ogawa M et al. Combined analysis of vascular endothelial growth factor and platelet- derived endothelial cell growth factor expression in gastric carcinoma // International Journal of Cancer. 1997;74(5):545–550.
Makower D, Wadler S, Haynes H, Schwartz L. Interferon Induces Thymidine Phosphorylase/Platelet-derived Endothelial Cell Growth Factor Expression in Vivo // Clinical Cancer Research. 1997;3(6):923–929.
Marchetti S, Chazal M, Dubreuil A et al. Impact of thymidine phosphorylase surexpression on fluoropyrimidine activity and on tumour angiogenesis // British Journal of Cancer. 2001. Vol. 85(3):439–445.
Matsuura T, Kuratate I, Teramachi K et al. Thymidine phosphorylase expression is associated with both increase of intratumoral microvessels and decrease of apoptosis in human colorectal carcinomas // Cancer Research. 1999;59(19):5037–5040.
Miwa M, Ura M, Nishida M et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5 fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue // European Journal of Cancer. 1998;34(8):1274–1281.
Miyazono K, Okabe T, Urabe A et al. Purification and properties of an endothelial cell growth factor from human platelets // Journal of Biological Chemistry. 1987;262(9):4098–4103.
Moghaddam A, Bicknell R. Expression of Platelet-Derived Endothelial Cell Growth Factor in Escherichia coli and Confirmation of Its Thymidine Phosphorylase Activity // Biochemistry. 1992;31(48):12141–12146.
Mori SI, Takao S, Ikeda R et al. Thymidine phosphorylase suppresses Fas-induced apoptotic signal transduction independent of its enzymatic activity // Biochemical and Biophysical Research Communications. 2002;295(2):300–305.
Osaki M, Sakatani T, Okamoto E et al. Thymidine phosphorylase expression results in a decrease in apoptosis and increase in intratumoral microvessel density in human gastric carcinomas // Virchows Archiv. 2000;437:31–36.
Pinedo HM, Peters GJ. Fluorouracil: biochemistry and pharmacology // Journal of Clinical Oncology. 1988;6(10):1653–1664.
Piper AA, Fox RM. Biochemical Basis for the Differential Sensitivity of Human T– and B-Lymdhocvte Lines to 5-Fluorouracil // Cancer Research. 1982;42(9):3753–3760.
Pugmire MJ, Cook WJ, Jasanoff A et al. Structural and theoretical studies suggest domain movement produces an active conformation of thymidine phosphorylase // Journal of Molecular Biology. 1998;281(2):285–299.
Schröter D, Höhn A. Role of Advanced Glycation End Products in Carcinogenesis and their Therapeutic Implications // Current Pharmaceutical Design. 2019;24(44):5245–5251.
Schwartz EL, Wan E, Wang FS, Baptiste N. Regulation of expression of thymidine phosphorylase/platelet-derived endothelial cell growth factor in human colon carcinoma cells // Cancer Research. 1998;58(7):1551–1557.
Schwartz M. Thymidine Phosphorylase from Escherichia coli Properties and Kinetics // Eur. J. Biochem. 1971;21(2):191–198.
Spadari S, Ciarrocchi G, Focher F et al. 5-Iodo-2’-deoxy-L-uridine and (E)-5-(2-bromovinyl)-2’-deoxy-L-uridine: Selective phosphorylation by herpes simplex virus type 1 thymidine kinase, antiherpetic activity, and cytotoxicity studies // Molecular Pharmacology. 1995;47(6):1231–1238.
Spraggon G, Stuart D, Ponting C et al. Crystallization and X-ray diffraction study of recombinant platelet-derived endothelial cell growth factor // Journal of Molecular Biology. 1993;234(3):879–880.
Tabata S, Ikeda R, Yamamoto M et al. Thymidine phosphorylase enhances reactive oxygen species generation and interleukin-8 expression in human cancer cells // Oncology Reports. 2012;28(3):895–902.
Tabata S, Yamamoto M, Goto H et al. Thymidine Catabolism as a Metabolic Strategy for Cancer Survival // Cell Reports. 2017;19(7):1313–1321.
Tabata S, Yamamoto M, Goto H et al. Thymidine catabolism promotes NADPH oxidase-derived reactive oxygen species (ROS) signalling in KB and yumoto cells // Scientific Reports. 2018;8(1):1–8.
Toi M, Bando H, Horiguchi S et al. Modulation of thymidine phosphorylase by neoadjuvant chemotherapy in primary breast cancer // British Journal of Cancer. 2004;90(12):2338–2343.
Uboha N, Hochster HS. Tas-102: A novel antimetabolite for the 21st century // Future Oncology. 2016;12(2):153–163.
Usuki K, Norberg L, Larsson E et al. Localization of platelet-derived endothelial cell growth factor in human placenta and purification of an alternatively processed form // Molecular Biology of the Cell. 1990;1(8):577–584.
Usuki K, Saras J, Waltenberger J et al. Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity // Biochemical and Biophysical Research Communications. 1992;184(3):1311–1316.
Verri A, Focher F, Duncombe RJ et al. Anti-(herpes simplex virus) activity of 4’-thio-2’-deoxyuridines: A biochemical investigation for viral and cellular target enzymes // Biochemical Journal. 2000;351(2):319–326.
Wadler S, Wersto R, Weinberg V et al. Interaction of Fluorouracil and Interferon in Human Colon Cancer Cell Lines: Cytotoxic and Cytokinetic Effect // Cancer Research. 1990;50):5735–5739.
Walter MR, Cook WJ, Cole LB et al. Three-dimensional Strycture of Thymidine Phosphorylase from Escherichia coli at 2.8 A Resolution* // The Journal of biological chemistry. 1990; 265(23):14016–14022.
Zhu GH, Lenzi M, Schwartz EL. The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells // Oncogene. 2002;21(55):8477–8485.
![Creative Commons License](http://i.creativecommons.org/l/by-nc-nd/4.0/88x31.png)
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
© АННМО «Вопросы онкологии», Copyright (c) 2021