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Cancer Chemotherapy and Pharmacology

, Volume 84, Issue 6, pp 1157–1166 | Cite as

Dihydropyrimidine dehydrogenase in the metabolism of the anticancer drugs

  • Vinay Sharma
  • Sonu Kumar Gupta
  • Malkhey VermaEmail author
Review Article

Abstract

Cancer caused by fundamental defects in cell cycle regulation leads to uncontrolled growth of cells. In spite of the treatment with chemotherapeutic agents of varying nature, multiple resistance mechanisms are identified in cancer cells. Similarly, numerous variations, which decrease the metabolism of chemotherapeutics agents and thereby increasing the toxicity of anticancer drugs have been identified. 5-Fluorouracil (5-FU) is an anticancer drug widely used to treat many cancers in the human body. Its broad targeting range is based upon its capacity to act as a uracil analogue, thereby disrupting RNA and DNA synthesis. Dihydropyrimidine dehydrogenase (DPD) is an enzyme majorly involved in the metabolism of pyrimidines in the human body and has the same metabolising effect on 5-FU, a pyrimidine analogue. Multiple mutations in the DPD gene have been linked to 5-FU toxicity and inadequate dosages. DPD inhibitors have also been used to inhibit excessive degradation of 5-FU for meeting appropriate dosage requirements. This article focusses on the role of dihydropyrimidine dehydrogenase in the metabolism of the anticancer drug 5-FU and other associated drugs.

Keywords

Cancer Anticancer drugs Dihydropyrimidine dehydrogenase (DPD) 5-Fluorouracil (5-FU) Drug resistance Drug metabolism 

Notes

Acknowledgements

The authors acknowledge the support received from the Central University of Punjab, Bhatinda, India, in writing this manuscript. We thank Dr Dinesh Babu, Assistant Professor, Department of English for reading and grammatically improving the manuscript.

Compliance with ethical standards

Conflict of interest

Authors declare no conflicting interests.

References

  1. 1.
    Cooper GM, Hausman RE (2016) Chapter 19 Cancer. In: Cooper GM, Hausman RE (eds) The cell A molecular approach. Sunnderland, Sinauer Associates USA Inc, Massachusetts, pp 723–726Google Scholar
  2. 2.
    Nussbaumera S, Bonnabrya P, Veuthey JL, Fleury-Souveraina S (2011) Analysis of anticancer drugs; a review. Talanta 85(5):2265–2289Google Scholar
  3. 3.
    Miura K, Kinouchi M, Ishida K, Fujibuchi W, Naitoh T et al (2010) 5-FU metabolism in cancer and orally-administrable 5-FU drugs. Cancers 2(3):1717–1730PubMedPubMedCentralGoogle Scholar
  4. 4.
    Grem JL (2000) 5-Fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs 18(4):299–313PubMedGoogle Scholar
  5. 5.
    Cordier P-Y, Nau A, Ciccolini J, Oliver M, Mercier C, Lacarelle B, Peytel E (2011) 5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases. Cancer Chemother Pharmacol 68(3):823–826PubMedGoogle Scholar
  6. 6.
    Wohlhueter RM, Scott MR, Plagemann PG (1980) Facilitated transport of uracil and 5-fluorouracil, and permeation of orotic acid into cultured mammalian cells. J Cell Physiol 104(3):309–319PubMedGoogle Scholar
  7. 7.
    Heggie G, Sommadossi J-P, Cross DS, Huster WJ, Diasio RB (1987) Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Can Res 47(8):2203–2206Google Scholar
  8. 8.
    Longley DB, Harkin DP, Johnston PG (2003) 5-Fluorouracil: mechanisms of action and clinical strategies. Cancer 3(5):330PubMedGoogle Scholar
  9. 9.
    Houghton JA, Morton CL, Adkins DA, Rahman A (1993) Locus of the interaction among 5-fluorouracil, leucovorin, and interferon-alpha 2a in colon carcinoma cells. Can Res 53(18):4243–4250Google Scholar
  10. 10.
    Kufe DW, Major PP (1981) 5-Fluorouracil incorporation into human breast carcinoma RNA correlates with cytotoxicity. J Biol Chem 256(19):9802–9805PubMedGoogle Scholar
  11. 11.
    Glazer RI, Lloyd LS (1982) Association of cell lethality with incorporation of 5-fluorouracil and 5-fluorouridine into nuclear RNA in human colon carcinoma cells in culture. Mol Pharmacol 21(2):468–473PubMedGoogle Scholar
  12. 12.
    Kanamaru R, Kakuta H, Sato T, Ishioka C, Wakui A (1986) The inhibitory effects of 5-fluorouracil on the metabolism of preribosomal and ribosomal RNA in L-1210 cells in vitro. Cancer Chemother Pharmacol 17(1):43–46PubMedGoogle Scholar
  13. 13.
    Santi DV, Hardy LW (1987) Catalytic mechanism and inhibition of tRNA (uracil-5-) methyltransferase: evidence for covalent catalysis. Biochemistry 26(26):8599–8606PubMedGoogle Scholar
  14. 14.
    Randerath K, Tseng WC, Harris JS, Lu LJW (1983) Specific effects of 5-fluoropyrimidines and 5-azapyrimidines on modification of the 5 position of pyrimidines, in particular the synthesis of 5-methyluracil and 5-methylcytosine in nucleic acids. Book series (RECENTCANCER, vol 84) Modified Nucleosides and Cancer, pp 283–297Google Scholar
  15. 15.
    Sommer H, Santi DV (1974) Purification and amino acid analysis of an active site peptide from thymidylate synthetase containing covalently bound 5-fluoro-2′-deoxyuridylate and methylenetetrahydrofolate. Biochem Biophys Res Commun 57(3):689–695PubMedGoogle Scholar
  16. 16.
    Santi DV, McHenry CS, Sommer H (1974) Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry 13(3):471–481PubMedGoogle Scholar
  17. 17.
    Aherne GW, Hardcastle A, Raynaud F, Jackman AL (1996) Immunoreactive dUMP and TTP pools as an index of thymidylate synthase inhibition; effect of tomudex (ZD1694) and a non-polyglutamated quinazoline antifolate (CB30900) in L1210 mouse leukaemia cells. Biochem Pharmacol 51(10):1293–1301PubMedGoogle Scholar
  18. 18.
    Mitrovski B, Pressacco J, Mandelbaum S, Erlichman C (1994) Biochemical effects of folate-based inhibitors of thymidylate synthase in MGH-U1 cells. Cancer Chemother Pharmacol 35(2):109–114PubMedGoogle Scholar
  19. 19.
    Matherly LH, Czajkowski CA, Muench SP, Psiakis JT (1990) Role for cytosolic folate-binding proteins in the compartmentation of endogenous tetrahydrofolates and the 5-formyl tetrahydrofolate-mediated enhancement of 5-fluoro-2′-deoxyuridine antitumor activity in vitro. Can Res 50(11):3262–3269Google Scholar
  20. 20.
    Park JG, Collins JM, Gazdar AF, Allegra CJ, Steinberg SM, Greene RF et al (1988) Enhancement of fluorinated pyrimidine induced cytotoxicity by leucovorin in human colorectal carcinoma cell lines. J Natl Cancer Inst 80(19):1560–1564PubMedGoogle Scholar
  21. 21.
    Nadal J, Van GC, Pinedo H, Peters G (1988) In vivo potentiation of 5-fluorouracil by leucovorin in murine colon carcinoma. Biomed Pharmacother 42(6):387–393Google Scholar
  22. 22.
    Dolnick BJ, Cheng YC (1978) Human thymidylate synthetase. II. Derivatives of pteroylmono- and -polyglutamates as substrates and inhibitors. J Biol Chem 253(10):3563–3567PubMedGoogle Scholar
  23. 23.
    Radparvar S, Houghton PJ, Houghton JA (1988) Effect of polyglutamylation of 5,10-methylenetetrahydrofolate on the binding of 5-fluoro-2′-deoxyuridylate to thymidylate synthase purified from a human colon adenocarcinoma xenograft. Biochem Pharmacol 38(2):335–342Google Scholar
  24. 24.
    Adjei AA (2001) A review of the pharmacology and clinical activity of new chemotherapy agents for the treatment of colorectal cancer. Br J Clin Pharmacol 48(3):265–277Google Scholar
  25. 25.
    Spector T, Cao S, Rustum YM, Harrington JA, Porter DJ (1995) Attenuation of the antitumor activity of 5-fluorouracil by (R)-5-fluoro-5,6-dihydrouracil. Can Res 55(6):1239–1241Google Scholar
  26. 26.
    Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K et al (1998) Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34(8):1274–1281PubMedGoogle Scholar
  27. 27.
    Cao D, Russell RL, Zhang D, Leffert JJ, Pizzorno G (2002) 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. Can Res 62(8):2313–2317Google Scholar
  28. 28.
    Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Maroun MK et al (2001) Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19(8):2282–2292PubMedGoogle Scholar
  29. 29.
    Gorlick R, Bertino JR (1999) Clinical pharmacology and resistance to dihydrofolate reductase inhibitors. In: Jackman AL (ed) Antifolate Drugs in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJGoogle Scholar
  30. 30.
    Cadman E, Heimer R, Benz C (1981) The influence of methotrexate pretreatment on 5-fluorouracil metabolism in L1210 cells. J Biol Chem 256(4):1695–1704PubMedGoogle Scholar
  31. 31.
    Wolmark N, Bryant J, Smith R, Jean G, Allegra C, Hyams D et al (1998) Adjuvant 5 fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: national Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst 90(23):1810–1816PubMedGoogle Scholar
  32. 32.
    Shirasaka T, Nakano K, Takechi T, Satake H, Uchida J, Fujioka A et al (1996) Antitumor activity of 1 m Tegafur-0.4 m 5-chloro-2,4-dihydroxypyridine-1 m potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res 56(11):2602–2606PubMedGoogle Scholar
  33. 33.
    Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K et al (1996) Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 7(5):548–557PubMedGoogle Scholar
  34. 34.
    Shirasaka T, Shimamoto Y, Fukushima M (1993) Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Can Res 53(17):4004–4009Google Scholar
  35. 35.
    Omura K (2003) Clinical implications of dihydropyrimidine dehydrogenase (DPD) activity in 5-FU-based chemotherapy: mutations in the DPD gene, and DPD inhibitory fluoropyrimidines. Int J Clin Oncol 8(3):132–138PubMedGoogle Scholar
  36. 36.
    Meyerhardt JA, Mayer RJ (2005) Systemic therapy for colorectal cancer. N Engl J Med 352(5):476–487PubMedGoogle Scholar
  37. 37.
    Twelves C, Wong A, Nowacki MP, Abt M, Burris H, Carrato A et al (2005) Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352(26):2696–2704PubMedGoogle Scholar
  38. 38.
    Wigmore P, Mustafa S, El-Bettagy M, Lyons L, Umka J, Bennett G (2010) Effects of 5-FU. Adv Exp Med Biol 6:871–881Google Scholar
  39. 39.
    Diasio RB (1998) The role of dihydropyrimidine dehydrogenase (DPD) modulation in 5-FU pharmacology. Cancer Network 12(10):23–27Google Scholar
  40. 40.
    Alsanosi SM, Skiffington C, Padmanabhan S (2014) Chapter 17—pharmacokinetic pharmacogenomics. Handbook Pharmacogenomics Stratified Med 341-364Google Scholar
  41. 41.
    Daher GC, Harris BE, Diasio RB (1990) Metabolism of pyrimidine analogues and their nucleosides. Pharmacol Ther 48(2):189–222PubMedGoogle Scholar
  42. 42.
    Diasio RB, Johnson MR (1999) Dihydropyrimidine dehydrogenase: its role in 5-fluorouracil clinical toxicity and tumor resistance. Clin Cancer Res 5(10):2672–2673PubMedGoogle Scholar
  43. 43.
    Etienne MC, Lagrange JL, Dassonville O, Fleming R, Thyss A, Schneider NR et al (1994) Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol 12(11):2248–2253PubMedGoogle Scholar
  44. 44.
    Lu Z, Zhang R, Diasio RB (1993) Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Can Res 53(22):5433–5438Google Scholar
  45. 45.
    Tuchman M, Stoeckeler JS, Kiang DT, O’Dea RF, Ramnaraine ML, Mirkin BL (1985) Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity. N Engl J Med 313(4):245–249PubMedGoogle Scholar
  46. 46.
    Diasio RB, Beavers TL, Carpenter JT (1988) Familial deficiency of dihydropyrimidine dehydrogenase Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. J Clin Investig 81(1):47–51PubMedGoogle Scholar
  47. 47.
    Pathania S, Bhatia R, Baldi A, Singh R, Rawal RK (2018) Drug metabolizing enzymes and their inhibitor’s role in cancer resistance. Biomed Pharmacol 105:53–65Google Scholar
  48. 48.
    Gonzalez FJ, Fernander-Salguero P (1995) Diagnostic analysis, clinical importance and molecular basis of dihydropyrimidine dehydrogenase deficiency. Trends Pharmacol Sci 16(10):325–327PubMedGoogle Scholar
  49. 49.
    Wasternack C (1980) Degradation of pyrimidines and pyrimidine analogs—pathways and mutual influences. Pharmacol Ther 8(3):629–651PubMedGoogle Scholar
  50. 50.
    Bakkere J, De Abreu R, Sengers R, Gabreëls F, Maas J, Renier W (1984) Elevated urine, blood and cerebrospinal fluid levels of uracil and thymine in a child with dihydrothymine dehydrogenase deficiency. Clin Chim Acta 140(3):247–256Google Scholar
  51. 51.
    Brockstedt M, Jakobs C, Smit LM, Gennip AH, Berger R (1990) A new case of dihydropyrimidine dehydrogenase deficiency. J Inherit Metab Dis 13(1):121–124PubMedGoogle Scholar
  52. 52.
    Meulendijks D, Henricks LM, Sonke GSJ, Deenem MJ, Froehlich TK, Amstutz U (2015) Clinical relevance of DPYD variants c.1679T > G, c.1236G > A/HapB3, and c.1601G > A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol 16(16):1639–1650PubMedGoogle Scholar
  53. 53.
    Naguib FN, Kouni MH, Cha S (1985) Enzymes of uracil catabolism in normal and neoplastic human tissues. Cancer Research 45(11 Part 1):5405–5412PubMedGoogle Scholar
  54. 54.
    Harris B, Song R, Diasio R (1990) Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Can Res 50(1):197–201Google Scholar
  55. 55.
    Uchida K, Danenberg PV, Danenberg KD, Grem JL (2008) Thymidylate synthase, dihydropyrimidine dehydrogenase, ERCC1, and thymidine phosphorylase gene expression in primary and metastatic gastrointestinal adenocarcinoma tissue in patients treated on a phase I trial of oxaliplatin and capecitabine. BMC Cancer 8(1):386PubMedPubMedCentralGoogle Scholar
  56. 56.
    Yamashita T, Kato K, Long NK, Makita H, Yonemoto K, Iida K et al (2013) Effects of smoking and alcohol consumption on 5-fluorouracil-related metabolic enzymes in oral squamous cell carcinoma. Mol Clin Oncol 2(3):429–434Google Scholar
  57. 57.
    Shin JG, Kang T, Cheong H, Shin H, Park H, Na H et al (2015) Determination of DPYD enzyme activity in korean population. Ther Drug Monit 37(2):147–151PubMedGoogle Scholar
  58. 58.
    Li G-Y, Duan J-F, Li W-J, Liu T (2016) DPYD*2A/*5A/*9A and UGT1A1*6/*28 polymorphisms in Chinese colorectal cancer patients. J Cancer Res Therapeutics 12(2):782Google Scholar
  59. 59.
    Caudle K, Thorn C, Klein T, Swen J, McLeod H, Diasio R, Schwab M (2013) Clinical pharmacogenetics implementation consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Therapeutics 94(6):640–645Google Scholar
  60. 60.
    Ruzzo A, Grazianp F, Galli F, Galli FR, Lonardi S, Ranzoni M et al (2017) Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients. Br J Cancer 117(9):1269PubMedPubMedCentralGoogle Scholar
  61. 61.
    Kuilenburg AB, Abreu RA, Gennip AH (2003) Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency. Ann Clin Biochem 40(1):41–45PubMedGoogle Scholar
  62. 62.
    Sulzyc-Bielicka V, Binczak-Kuleta A, Pioch W, Kladny J, Gziut K, Bielicki D et al (2008) 5-Fluorouracil toxicity-attributable IVS14 + 1G > A mutation of the dihydropyrimidine dehydrogenase gene in Polish colorectal cancer patients. Pharmacol Rep 60(238):238–242PubMedGoogle Scholar
  63. 63.
    Mattison L, Johnson M, Diasio RB (2002) A comparative analysis of translated dihydropyrimidine dehydrogenase cDNA; conservation of functional domains and relevance to genetic polymorphisms. Pharmacogenet Genomics 12(2):133–144Google Scholar
  64. 64.
    Baskin Y, Amirfallah A, Unal OU, Calibasi G, Oztop I (2015) Dihydropyrimidine dehydrogenase 85T > C mutation is associated with ocular toxicity of 5-fluorouracil: a case report. Am J Ther 22(2):36–39Google Scholar
  65. 65.
    Milano G, Etienne MC (1994) Potential importance of dihydropyrimidine dehydrogenase (DPD) in cancer chemotherapy. Pharmacogenet Genomics 4(6):301–306Google Scholar
  66. 66.
    Teh LK, Hamzah S, Hashim H, Bannur Z, Zakaria ZA, Hasbullani Z (2013) Potential of Dihydropyrimidine Dehydrogenase Genotypes in Personalizing 5-Fluorouracil Therapy Among Colorectal Cancer Patients. Ther Drug Monit 35(5):624–630PubMedGoogle Scholar
  67. 67.
    Seck K, Riemer S, Kates R, Ullrich T, Lutz V, Harbeck N et al (2005) Analysis of the DPYD gene implicated in 5-Fluorouracil catabolism in a cohort of caucasian individuals. Clin Cancer Res 11(16):5886–5892PubMedGoogle Scholar
  68. 68.
    He YF, Wei W, Zhang X, Li YHS, Wang FH, Jiang WQ (2008) Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in chinese cancer patients. J Clin Pharm Ther 33(3):307–314PubMedGoogle Scholar
  69. 69.
    Khallaf HH, He M, Wittenauer A, Woolley EE, Cunto M, Pervaiz MA (2013) An incidental case of dihydropyrimidine dehydrogenase deficiency: one case, multiple challenges. Indian J Hum Genetics 19(4):483Google Scholar
  70. 70.
    Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, Lenthe HV, Abreu RA et al (2000) Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res 6(12):4705–4712PubMedGoogle Scholar
  71. 71.
    Ezzeldin H, Diasio R (2004) Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration. Clin Colorectal Cancer 4(3):181–189PubMedGoogle Scholar
  72. 72.
    Collie-Duguid E, Johnston SJ, Powrie R, Milano G, Etienne MC, Rochat B et al (2000) Cloning and initial characterization of the human DPYD gene promoter. Biochem Biophys Res Commun 271(1):28–35PubMedGoogle Scholar
  73. 73.
    Kuilenburg AB, Meinsma R, Zoetekouw L, Gennip AH (2002) Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: high prevalence of the IVS14 + 1g > a mutation. Int J Cancer 101(3):253–258PubMedGoogle Scholar
  74. 74.
    Mattison L, Soong R, Diasio RB (2002) Implications of dihydropyrimidine dehydrogenase on 5-fluorouracil pharmacogenetics and pharmacogenomics. Pharmacogenomics 3(4):485–492PubMedGoogle Scholar
  75. 75.
    Kouwaki M, Hamajima N, Sumi S, Nonaka M, Sasaki M, Dobashi K et al (1998) Identification of novel mutations in the dihydropyrimidine dehydrogenase gene in a Japanese patient with 5-fluorouracil toxicity. Clin Cancer Res 4(12):2999–3004PubMedGoogle Scholar
  76. 76.
    Vreken P, Kuilenburg AB, Meinsma R, van Gennip AH (1997) Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W. Hum Genet 101(3):333–338PubMedGoogle Scholar
  77. 77.
    Loriot MA, Ciccolini J, Thomas F, Barin-Le-Guellec C, Royer B, Milano G et al (2018) Dihydropyrimidine déhydrogenase (DPD) deficiency screening and securing of fluoropyrimidine-based chemotherapies: update and recommendations of the French GPCO-Unicancer and RNPGx networks. Bull Cancer 105(4):397–407Google Scholar
  78. 78.
    Morrison G, Bastian A, Dela Rosa T, Diasio RT (1997) Dihydropyrimidine dehydrogenase deficiency: a pharmacogenetic defect causing severe adverse reactions to 5-fluorouracil-based chemotherapy. Oncol Nurs Forum 24(1):83–88PubMedGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biochemistry and Microbial Sciences, School of Basic and Applied SciencesCentral University of PunjabBathindaIndia

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