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Enzymes involved in folate metabolism and its implication for cancer treatment

  • Kim, Sung-Eun (Department of Food and Nutrition, Sookmyung Women's University)
  • Received : 2020.01.31
  • Accepted : 2020.02.13
  • Published : 2020.04.01

Abstract

BACKGROUND/OBJECTIVES: Folate plays a critical role in DNA synthesis and methylation. Intracellular folate homeostasis is maintained by the enzymes folylpolyglutamate synthase (FPGS) and γ-glutamyl hydrolase (GGH). FPGS adds glutamate residues to folate upon its entry into the cell through a process known as polyglutamylation to enhance folate retention in the cell and to maintain a steady supply of utilizable folate derivatives for folate-dependent enzyme reactions. Thereafter, GGH catalyzes the hydrolysis of polyglutamylated folate into monoglutamylated folate, which can subsequently be exported from the cell. The objective of this review is to summarize the scientific evidence available on the effects of intracellular folate homeostasis-associated enzymes on cancer chemotherapy. METHODS: This review discusses the effects of FPGS and GGH on chemosensitivity to cancer chemotherapeutic agents such as antifolates, such as methotrexate, and 5-fluorouracil. RESULTS AND DISCUSSION: Polyglutamylated (anti)folates are better substrates for intracellular folate-dependent enzymes and retained for longer within cells. In addition to polyglutamylation of (anti)folates, FPGS and GGH modulate intracellular folate concentrations, which are an important determinant of chemosensitivity of cancer cells toward chemotherapeutic agents. Therefore, FPGS and GGH affect chemosensitivity to antifolates and 5-fluorouracil by altering intracellular retention status of antifolates and folate cofactors such as 5,10-methylenetetrahydrofolate, subsequently influencing the cytotoxic effects of 5-fluorouracil, respectively. Generally, high FPGS and/or low GGH activity is associated with increased chemosensitivity of cancer cells to methotrexate and 5-fluorouracil, while low FPGS and/or high GGH activity seems to correspond to resistance to these drugs. Further preclinical and clinical studies elucidating the pharmocogenetic ramifications of these enzyme-induced changes are warranted to provide a framework for developing rational, effective, safe, and customized chemotherapeutic practices.

Keywords

References

  1. Shane B. Folate chemistry and metabolism. In: Bailey LB, editor. Folate in Health and Disease. Boca Raton (FL): CRC Press; 2010. p.1-24.
  2. Gropper SAS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont (CA): Wadsworth/Cengage Learning; 2009.
  3. Kim YI. Role of folate in colon cancer development and progression. J Nutr 2003;133:3731S-3739S. https://doi.org/10.1093/jn/133.11.3731S
  4. Kim YI. Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 1999;10:66-88. https://doi.org/10.1016/S0955-2863(98)00074-6
  5. Kim YI. Folate and colorectal cancer: an evidence-based critical review. Mol Nutr Food Res 2007;51:267-92. https://doi.org/10.1002/mnfr.200600191
  6. Kim YI. Folic acid supplementation and cancer risk: point. Cancer Epidemiol Biomarkers Prev 2008;17:2220-5. https://doi.org/10.1158/1055-9965.EPI-07-2557
  7. Park YM, Youn J, Cho CH, Kim SH, Lee JE. Circulating folate levels and colorectal adenoma: a case-control study and a meta-analysis. Nutr Res Pract 2017;11:419-29. https://doi.org/10.4162/nrp.2017.11.5.419
  8. Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, Burke CA, McKeown-Eyssen GE, Baron JA. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst 2009;101:432-5. https://doi.org/10.1093/jnci/djp019
  9. Hirsch S, Sanchez H, Albala C, de la Maza MP, Barrera G, Leiva L, Bunout D. Colon cancer in Chile before and after the start of the flour fortification program with folic acid. Eur J Gastroenterol Hepatol 2009;21:436-9. https://doi.org/10.1097/MEG.0b013e328306ccdb
  10. Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007;16:1325-9. https://doi.org/10.1158/1055-9965.EPI-07-0329
  11. Bailey RL, Dodd KW, Gahche JJ, Dwyer JT, McDowell MA, Yetley EA, Sempos CA, Burt VL, Radimer KL, Picciano MF. Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-2006. Am J Clin Nutr 2010;91:231-7. https://doi.org/10.3945/ajcn.2009.28427
  12. Shakur YA, Tarasuk V, Corey P, O'Connor DL. A comparison of micronutrient inadequacy and risk of high micronutrient intakes among vitamin and mineral supplement users and nonusers in Canada. J Nutr 2012;142:534-40. https://doi.org/10.3945/jn.111.149450
  13. Velicer CM, Ulrich CM. Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review. J Clin Oncol 2008;26:665-73. https://doi.org/10.1200/JCO.2007.13.5905
  14. Holmes RS, Zheng Y, Baron JA, Li L, McKeown-Eyssen G, Newcomb PA, Stern MC, Haile RW, Grady WM, Potter JD, Le Marchand L, Campbell PT, Figueiredo JC, Limburg PJ, Jenkins MA, Hopper JL, Ulrich CM; Colon Cancer Family Registry. Use of folic acid-containing supplements after a diagnosis of colorectal cancer in the Colon Cancer Family Registry. Cancer Epidemiol Biomarkers Prev 2010;19:2023-34. https://doi.org/10.1158/1055-9965.EPI-09-1097
  15. Satia JA, Campbell MK, Galanko JA, James A, Carr C, Sandler RS. Longitudinal changes in lifestyle behaviors and health status in colon cancer survivors. Cancer Epidemiol Biomarkers Prev 2004;13:1022-31.
  16. Sandler RS, Halabi S, Kaplan EB, Baron JA, Paskett E, Petrelli NJ. Use of vitamins, minerals, and nutritional supplements by participants in a chemoprevention trial. Cancer 2001;91:1040-5. https://doi.org/10.1002/1097-0142(20010301)91:5<1040::AID-CNCR1095>3.0.CO;2-N
  17. Assaraf YG. The role of multidrug resistance efflux transporters in antifolate resistance and folate homeostasis. Drug Resist Updat 2006;9:227-46. https://doi.org/10.1016/j.drup.2006.09.001
  18. Hooijberg JH, de Vries NA, Kaspers GJ, Pieters R, Jansen G, Peters GJ. Multidrug resistance proteins and folate supplementation: therapeutic implications for antifolates and other classes of drugs in cancer treatment. Cancer Chemother Pharmacol 2006;58:1-12.
  19. Porcelli L, Assaraf YG, Azzariti A, Paradiso A, Jansen G, Peters GJ. The impact of folate status on the efficacy of colorectal cancer treatment. Curr Drug Metab 2011;12:975-84. https://doi.org/10.2174/138920011798062274
  20. Assaraf YG. Molecular basis of antifolate resistance. Cancer Metastasis Rev 2007;26:153-81. https://doi.org/10.1007/s10555-007-9049-z
  21. Moran RG. Roles of folylpoly-gamma-glutamate synthetase in therapeutics with tetrahydrofolate antimetabolites: an overview. Semin Oncol 1999;26:24-32.
  22. Kamen B. Folate and antifolate pharmacology. Semin Oncol 1997;24:S18-30-S18-39.
  23. Zhao R, Goldman ID. Resistance to antifolates. Oncogene 2003;22:7431-57. https://doi.org/10.1038/sj.onc.1206946
  24. Calvert H. An overview of folate metabolism: features relevant to the action and toxicities of antifolate anticancer agents. Semin Oncol 1999;26:3-10.
  25. Kremer JM. Toward a better understanding of methotrexate. Arthritis Rheum 2004;50:1370-82. https://doi.org/10.1002/art.20278
  26. Grem JL. 5-Fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs 2000;18:299-313. https://doi.org/10.1023/A:1006416410198
  27. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003;3:330-8. https://doi.org/10.1038/nrc1074
  28. Radparvar S, Houghton PJ, Houghton JA. 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 1989;38:335-42. https://doi.org/10.1016/0006-2952(89)90046-4
  29. Cho RC, Cole PD, Sohn KJ, Gaisano G, Croxford R, Kamen BA, Kim YI. Effects of folate and folylpolyglutamyl synthase modulation on chemosensitivity of breast cancer cells. Mol Cancer Ther 2007;6:2909-20. https://doi.org/10.1158/1535-7163.MCT-07-0449
  30. Kim SE, Cole PD, Cho RC, Ly A, Ishiguro L, Sohn KJ, Croxford R, Kamen BA, Kim YI. ${\gamma}$-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate. Br J Cancer 2013;109:2175-88. https://doi.org/10.1038/bjc.2013.579
  31. Sakamoto E, Tsukioka S, Oie S, Kobunai T, Tsujimoto H, Sakamoto K, Okayama Y, Sugimoto Y, Oka T, Fukushima M, Oka T. Folylpolyglutamate synthase and gamma-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity. Biochem Biophys Res Commun 2008;365:801-7. https://doi.org/10.1016/j.bbrc.2007.11.043
  32. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010;31:27-36. https://doi.org/10.1093/carcin/bgp220
  33. McGuire JJ, Bertino JR. Enzymatic synthesis and function of folylpolyglutamates. Mol Cell Biochem 1981;38:19-48. https://doi.org/10.1007/BF00235686
  34. Cichowicz DJ, Shane B. Mammalian folylpoly-gamma-glutamate synthetase. 2. Substrate specificity and kinetic properties. Biochemistry 1987;26:513-21. https://doi.org/10.1021/bi00376a025
  35. Cook JD, Cichowicz DJ, George S, Lawler A, Shane B. Mammalian folylpoly-gamma-glutamate synthetase. 4. In vitro and in vivo metabolism of folates and analogues and regulation of folate homeostasis. Biochemistry 1987;26:530-9. https://doi.org/10.1021/bi00376a027
  36. Kim JS, Lowe KE, Shane B. Regulation of folate and one-carbon metabolism in mammalian cells. IV. Role of folylpoly-gammaglutamate synthetase in methotrexate metabolism and cytotoxicity. J Biol Chem 1993;268:21680-5. https://doi.org/10.1016/S0021-9258(20)80595-X
  37. Aghi M, Kramm CM, Breakefield XO. Folylpolyglutamyl synthetase gene transfer and glioma antifolate sensitivity in culture and in vivo. J Natl Cancer Inst 1999;91:1233-41. https://doi.org/10.1093/jnci/91.14.1233
  38. Pizzorno G, Mini E, Coronnello M, McGuire JJ, Moroson BA, Cashmore AR, Dreyer RN, Lin JT, Mazzei T, Periti P, Berlino JR. Impaired polyglutamylation of methotrexate as a cause of resistance in CCRF-CEM cells after short-term, high-dose treatment with this drug. Cancer Res 1988;48:2149-55.
  39. McCloskey DE, McGuire JJ, Russell CA, Rowan BG, Bertino JR, Pizzorno G, Mini E. Decreased folylpolyglutamate synthetase activity as a mechanism of methotrexate resistance in CCRF-CEM human leukemia sublines. J Biol Chem 1991;266:6181-7. https://doi.org/10.1016/S0021-9258(18)38101-8
  40. Mauritz R, Peters GJ, Priest DG, Assaraf YG, Drori S, Kathmann I, Noordhuis P, Bunni MA, Rosowsky A, Schornagel JH, Pinedo HM, Jansen G. Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis. Biochem Pharmacol 2002;63:105-15. https://doi.org/10.1016/S0006-2952(01)00824-3
  41. Liani E, Rothem L, Bunni MA, Smith CA, Jansen G, Assaraf YG. Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines. Int J Cancer 2003;103:587-99. https://doi.org/10.1002/ijc.10829
  42. Zhao R, Titus S, Gao F, Moran RG, Goldman ID. Molecular analysis of murine leukemia cell lines resistant to 5, 10-dideazatetrahydrofolate identifies several amino acids critical to the function of folylpolyglutamate synthetase. J Biol Chem 2000;275:26599-606. https://doi.org/10.1074/jbc.M002580200
  43. Roy K, Egan MG, Sirlin S, Sirotnak FM. Posttranscriptionally mediated decreases in folylpolyglutamate synthetase gene expression in some folate analogue-resistant variants of the L1210 cell. Evidence for an altered cognate mRNA in the variants affecting the rate of de novo synthesis of the enzyme. J Biol Chem 1997;272:6903-8. https://doi.org/10.1074/jbc.272.11.6903
  44. Romanini A, Lin JT, Niedzwiecki D, Bunni M, Priest DG, Bertino JR. Role of folylpolyglutamates in biochemical modulation of fluoropyrimidines by leucovorin. Cancer Res 1991;51:789-93.
  45. Wang FS, Aschele C, Sobrero A, Chang YM, Bertino JR. Decreased folylpolyglutamate synthetase expression: a novel mechanism of fluorouracil resistance. Cancer Res 1993;53:3677-80.
  46. Cheradame S, Etienne MC, Chazal M, Guillot T, Fischel JL, Formento P, Milano G. Relevance of tumoral folylpolyglutamate synthetase and reduced folates for optimal 5-fluorouracil efficacy: experimental data. Eur J Cancer 1997;33:950-9. https://doi.org/10.1016/S0959-8049(97)00028-2
  47. Sohn KJ, Smirnakis F, Moskovitz DN, Novakovic P, Yates Z, Lucock M, Croxford R, Kim YI. Effects of folylpolyglutamate synthetase modulation on chemosensitivity of colon cancer cells to 5-fluorouracil and methotrexate. Gut 2004;53:1825-31. https://doi.org/10.1136/gut.2004.042713
  48. Backus HH, Pinedo HM, Wouters D, Padron JM, Molders N, van Der Wilt CL, van Groeningen CJ, Jansen G, Peters GJ. Folate depletion increases sensitivity of solid tumor cell lines to 5-fluorouracil and antifolates. Int J Cancer 2000;87:771-8. https://doi.org/10.1002/1097-0215(20000915)87:6<771::AID-IJC2>3.0.CO;2-V
  49. Zhao R, Gao F, Goldman ID. Marked suppression of the activity of some, but not all, antifolate compounds by augmentation of folate cofactor pools within tumor cells. Biochem Pharmacol 2001;61:857-65. https://doi.org/10.1016/S0006-2952(01)00532-9
  50. Odin E, Wettergren Y, Nilsson S, Willen R, Carlsson G, Spears CP, Larsson L, Gustavsson B. Altered gene expression of folate enzymes in adjacent mucosa is associated with outcome of colorectal cancer patients. Clin Cancer Res 2003;9:6012-9.
  51. Wettergren Y, Odin E, Nilsson S, Willen R, Carlsson G, Gustavsson B. Low expression of reduced folate carrier-1 and folylpolyglutamate synthase correlates with lack of a deleted in colorectal carcinoma mRNA splice variant in normal-appearing mucosa of colorectal carcinoma patients. Cancer Detect Prev 2005;29:348-55. https://doi.org/10.1016/j.cdp.2005.06.006
  52. Oppeneer SJ, Ross JA, Koh WP, Yuan JM, Robien K. Genetic variation in folylpolyglutamate synthase and gamma-glutamyl hydrolase and plasma homocysteine levels in the Singapore Chinese Health Study. Mol Genet Metab 2012;105:73-8. https://doi.org/10.1016/j.ymgme.2011.09.035
  53. van der Straaten RJ, Wessels JA, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Allaart CF, Bogaartz J, Tiller M, Huizinga TW, Guchelaar HJ. Exploratory analysis of four polymorphisms in human GGH and FPGS genes and their effect in methotrexate-treated rheumatoid arthritis patients. Pharmacogenomics 2007;8:141-50. https://doi.org/10.2217/14622416.8.2.141
  54. Liu SG, Gao C, Zhang RD, Jiao Y, Cui L, Li WJ, Chen ZP, Wu MY, Zheng HY, Zhao XX, Yue ZX, Li ZG. FPGS rs1544105 polymorphism is associated with treatment outcome in pediatric B-cell precursor acute lymphoblastic leukemia. Cancer Cell Int 2013;13:107. https://doi.org/10.1186/1475-2867-13-107
  55. Sharma S, Das M, Kumar A, Marwaha V, Shankar S, Singh P, Raghu P, Aneja R, Grover R, Arya V, Dhir V, Gupta R, Kumar U, Juyal RC, K TB. Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among north Indians. Pharmacogenet Genomics 2009;19:823-8. https://doi.org/10.1097/FPC.0b013e328331b53e
  56. Leclerc GJ, Sanderson C, Hunger S, Devidas M, Barredo JC. Folylpolyglutamate synthetase gene transcription is regulated by a multiprotein complex that binds the TEL-AML1 fusion in acute lymphoblastic leukemia. Leuk Res 2010;34:1601-9. https://doi.org/10.1016/j.leukres.2010.05.012
  57. Leclerc GJ, Mou C, Leclerc GM, Mian AM, Barredo JC. Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy. Leukemia 2010;24:552-62. https://doi.org/10.1038/leu.2009.282
  58. Kim SE, Hinoue T, Kim MS, Sohn KJ, Cho RC, Weisenberger DJ, Laird PW, Kim YI. Effects of folylpolyglutamate synthase modulation on global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells. J Nutr Biochem 2016;29:27-35. https://doi.org/10.1016/j.jnutbio.2015.10.019
  59. Waltham MC, Li WW, Gritsman H, Tong WP, Bertino JR. gamma-Glutamyl hydrolase from human sarcoma HT-1080 cells: characterization and inhibition by glutamine antagonists. Mol Pharmacol 1997;51:825-32. https://doi.org/10.1124/mol.51.5.825
  60. Longo GS, Gorlick R, Tong WP, Ercikan E, Bertino JR. Disparate affinities of antifolates for folylpolyglutamate synthetase from human leukemia cells. Blood 1997;90:1241-5. https://doi.org/10.1182/blood.v90.3.1241.1241_1241_1245
  61. Rots MG, Pieters R, Peters GJ, Noordhuis P, van Zantwijk CH, Kaspers GJ, Hahlen K, Creutzig U, Veerman AJ, Jansen G. Role of folylpolyglutamate synthetase and folylpolyglutamate hydrolase in methotrexate accumulation and polyglutamylation in childhood leukemia. Blood 1999;93:1677-83. https://doi.org/10.1182/blood.v93.5.1677.405a16_1677_1683
  62. Li WW, Waltham M, Tong W, Schweitzer BI, Bertino JR. Increased activity of gamma-glutamyl hydrolase in human sarcoma cell lines: a novel mechanism of intrinsic resistance to methotrexate (MTX). Adv Exp Med Biol 1993;338:635-8. https://doi.org/10.1007/978-1-4615-2960-6_131
  63. Pizzorno G, Moroson BA, Cashmore AR, Russello O, Mayer JR, Galivan J, Bunni MA, Priest DG, Beardsley GP. Multifactorial resistance to 5,10-dideazatetrahydrofolic acid in cell lines derived from human lymphoblastic leukemia CCRF-CEM. Cancer Res 1995;55:566-73.
  64. Rhee MS, Wang Y, Nair MG, Galivan J. Acquisition of resistance to antifolates caused by enhanced gamma-glutamyl hydrolase activity. Cancer Res 1993;53:2227-30.
  65. Schneider E, Ryan TJ. Gamma-glutamyl hydrolase and drug resistance. Clin Chim Acta 2006;374:25-32. https://doi.org/10.1016/j.cca.2006.05.044
  66. Yao R, Rhee MS, Galivan J. Effects of gamma-glutamyl hydrolase on folyl and antifolylpolyglutamates in cultured H35 hepatoma cells. Mol Pharmacol 1995;48:505-11.
  67. O'Connor BM, Rotundo RF, Nimec Z, McGuire JJ, Galivan J. Secretion of gamma-glutamyl hydrolase in vitro. Cancer Res 1991;51:3874-81.
  68. Nimec Z, Galivan J. Regulatory aspects of the glutamylation of methotrexate in cultured hepatoma cells. Arch Biochem Biophys 1983;226:671-80. https://doi.org/10.1016/0003-9861(83)90337-5
  69. Galivan J. Hormonal alteration of methotrexate and folate polyglutamate formation in cultured hepatoma cells. Arch Biochem Biophys 1984;230:355-62. https://doi.org/10.1016/0003-9861(84)90118-8
  70. Galivan J, Rhee MS. Insulin-dependent suppression in glutamyl hydrolase activity and elevated cellular methotrexate polyglutamates. Biochem Pharmacol 1995;50:1659-63. https://doi.org/10.1016/0006-2952(95)02064-0
  71. Samowitz WS, Albertsen H, Herrick J, Levin TR, Sweeney C, Murtaugh MA, Wolff RK, Slattery ML. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 2005;129:837-45. https://doi.org/10.1053/j.gastro.2005.06.020
  72. Iacopetta B, Kawakami K, Watanabe T. Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the CpG island methylator phenotype the 5-fluorouracil-responsive subgroup? Int J Clin Oncol 2008;13:498-503. https://doi.org/10.1007/s10147-008-0854-3
  73. Kawakami K, Ooyama A, Ruszkiewicz A, Jin M, Watanabe G, Moore J, Oka T, Iacopetta B, Minamoto T. Low expression of gammaglutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype. Br J Cancer 2008;98:1555-61. https://doi.org/10.1038/sj.bjc.6604346
  74. Chave KJ, Ryan TJ, Chmura SE, Galivan J. Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms. Gene 2003;319:167-75. https://doi.org/10.1016/S0378-1119(03)00807-2
  75. Hashiguchi M, Shimizu M, Hakamata J, Tsuru T, Tanaka T, Suzaki M, Miyawaki K, Chiyoda T, Takeuchi O, Hiratsuka J, Irie S, Maruyama J, Mochizuki M. Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population. J Pharm Health Care Sci 2016;2:35. https://doi.org/10.1186/s40780-016-0069-0
  76. Dervieux T, Kremer J, Lein DO, Capps R, Barham R, Meyer G, Smith K, Caldwell J, Furst DE. Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics 2004;14:733-9. https://doi.org/10.1097/00008571-200411000-00004
  77. Kim K, Kang SB, Chung HH, Kim JW, Park NH, Song YS. XRCC1 Arginine194Tryptophan and GGH-401Cytosine/Thymine polymorphisms are associated with response to platinum-based neoadjuvant chemotherapy in cervical cancer. Gynecol Oncol 2008;111:509-15. https://doi.org/10.1016/j.ygyno.2008.08.034
  78. Cheng Q, Wu B, Kager L, Panetta JC, Zheng J, Pui CH, Relling MV, Evans WE. A substrate specific functional polymorphism of human gamma-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells. Pharmacogenetics 2004;14:557-67. https://doi.org/10.1097/00008571-200408000-00009
  79. Cheng Q, Cheng C, Crews KR, Ribeiro RC, Pui CH, Relling MV, Evans WE. Epigenetic regulation of human gamma-glutamyl hydrolase activity in acute lymphoblastic leukemia cells. Am J Hum Genet 2006;79:264-74. https://doi.org/10.1086/505645
  80. Li Y, Liu S, Wang H, Mai H, Yuan X, Li C, Chen X, Wen F. Methylation level of CpG islands in GGH gene promoter in pediatric acute leukemia. PLoS One 2017;12:e0173472. https://doi.org/10.1371/journal.pone.0173472
  81. Kim SE, Hinoue T, Kim MS, Sohn KJ, Cho RC, Cole PD, Weisenberger DJ, Laird PW, Kim YI. ${\gamma}$-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells. Genes Nutr 2015;10:444. https://doi.org/10.1007/s12263-014-0444-0

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