Роль фармакогенетических факторов в развитии побочных эффектов метотрексата при лечении злокачественных опухолей

Валиев Т.Т., Семенова В.В., Иконникова А.Ю., Петрова А.А., Белышева Т.С., Наседкина Т.В. Роль фармакогенетических факторов в развитии побочных эффектов метотрексата при лечении злокачественных опухолей. Современная Онкология. 2021;23(4):622–627. DOI: 10.26442/18151434.2021.4.201127

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Valiev TT, Semenova VV, Ikonnikova AY, Petrova AA, Belysheva TS, Nasedkina TV. Role of pharmacogenetic factors in the development of side effects of methotrexate in the treatment of malignant tumors: A review. Journal of Modern Oncology. 2021;23(4):622–627. DOI: 10.26442/18151434.2021.4.201127

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Аннотация

программ лечения острых лимфобластных лейкозов и неходжкинских лимфом. Обратной стороной высокой противоопухолевой активности МТХ являются побочные эффекты, для предупреждения которых требуется проведение сопроводительной терапии. Но даже современная сопроводительная терапия в ряде случаев не позволяет избежать развития тяжелых токсических повреждений со стороны кожи и слизистых оболочек, нервной системы, почек, печени. Фармакокинетика МТХ демонстрирует значительную индивидуальную вариабельность, что может быть отражением генетической изменчивости. Многочисленные фармакогенетические исследования оценивали влияние полиморфизма генов, участвующих в метаболизме MTX, на фармакокинетику МТХ и развитие токсических проявлений с целью улучшить результаты лечения пациентов и снизить токсичность препарата. В настоящем обзоре рассмотрен вклад в развитие токсичности МТХ полиморфных вариантов в ключевых генах метаболизма МТХ (ATIC, DHFR, GGH, FPGS, MTHFR, MTR, MTRR, TYMS) и генах белков-транспортеров (ABCB1, ABCG2, ABCC2, ABCC4, SLC19A1, SLCO1B1). Наибольшее влияние на фармакокинетику МТХ оказывают полиморфные маркеры в гене SLCO1B1.

Ключевые слова: метотрексат, фармакогенетика, генетический полиморфизм, фолатный цикл, побочные эффекты

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Methotrexate (MTX) is one of the main chemotherapeutic agents that has determined the high effectiveness of protocols for the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphomas. The reverse side of the high anti-tumor activity of MTX is the adverse reactions, which require accompanying preventive therapy. But even modern accompanying therapy in some cases does not avoid severe toxicity from the skin and mucous membranes, nervous system, kidneys, liver. MTX pharmacokinetics exhibits significant individual variability, which may be a reflection of genetic variability. Numerous pharmacogenetic studies have evaluated the effect of polymorphism of various genes involved in MTX metabolism on MTX pharmacokinetics and the development of toxic manifestations in order to improve patient outcomes and decrease drug toxicity. This review presents impact of key metabolic MTX genes (ATIC, DHFR, GGH, FPGS, MTHFR, MTR, MTRR, TYMS) and transporter proteins genes (ABCB1, ABCG2, ABCC2, ABCC4, SLC19A1, SLCO1B1) in the development of MTX side effects. Polymorphic markers in SLCO1B1 gene have the most influence with MTX pharmacokinetic.

Keywords: methotrexate, pharmacogenetics, genetic polymorphism, folate cycle, side effects

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1. Mahonova LA. Sovremenie metody lechenya ostrogo limphoblastnogo leykoza u detey. Аvtoref. dis. … kand. med. nauk. Moscow, 1963; p. 14 (in Russian).
2. Demidowicz E, Pogorzała M, Łęcka M, et al. Outcome of pediatric acute lymphoblastic leukemia: sixty years of progress. Anticancer Res. 2019;39(9):5203‑7. DOI:10.21873/anticanres.13717
3. Valiev TT. Lymphoma Berkitta u detey: 30 let terapii. Pediatriya. Zhurnal im. GN Speranskogo. 2020;99(4):35-41 (in Russian).
4. Kara MK, Peter DC, Qinglin P, et al. Response-adapted Therapy for the Treatment of Children with Newly Diagnosed High risk Hodgkin lymphoma (AHOD0831): a report fr om the Children's Oncology Group. Br J Haematol. 2019;187(1):39-48. DOI:10.1111/bjh.16014
5. Sakura T, Hayakawa F, Sugiura I, et al. High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG. Leukemia. 2018;32(3):626-32. DOI:10.1038/leu.2017.283
6. ALL IC-BFM 2009. A randomized trial of the I-BFM-SG for the management of childhood non-B acute lymphoblastic leukemia final version of therapy protocol from August-14-2009. Available at: http://www.bialaczka.org/wp-content/uploads/2016/10/ALLIC_BFM_2009.pdf. Accessed: 28.02.2020 (in Russian)].
7. ALL–MB 2015. Режим доступа: https://fnkc.ru/docs/ALLMB2015.pdf. Ссылка активна на 22.09.2021 [ALL–MB 2015. Available at: https://fnkc.ru/docs/ALLMB2015.pdf. Accessed: 22.09.2021 (in Russian)].
8. Bhojwani D, Sabin ND, Pei D, et al. Methotrexate-induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia. J Clin Oncol. 2014;32(9):949-59. DOI:10.1200/JCO.2013.53.0808
9. Schmiegelow K, Klaus Müller K, Mogensen SS, et al. Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy. F1000Res. 2017;6:444. DOI:10.12688/f1000research.10768.1
10. Sajith M, Pawar A, Bafna V, et al. Serum methotrexate level and side effects of high dose methotrexate infusion in pediatric patients with acute lymphoblastic leukaemia (ALL). Indian J Hematol Blood Transfus. 2020;36(1):51-8.
DOI:10.1007/s12288-019-01144-3
11. Lima A, Sousa H, Monteiro J, et al. Genetic polymorphisms in low-dose methotrexate transporters: current relevance as methotrexate therapeutic outcome biomarkers. Pharmacogenomics. 2014;15(12):1611-35. DOI:10.2217/pgs.14.116
12. Fowler B. The folate cycle and disease in humans. Kidney Int Suppl. 2001;78:S221‑9. DOI:10.1046/j.1523-1755.2001.59780221.x
13. Suthandiram S, Gan GG, Zain SM, et al. Effect of polymorphisms within methotrexate pathway genes on methotrexate toxicity and plasma levels in adults with hematological malignancies. Pharmacogenomics. 2014;15(11):1479‑94. DOI:10.2217/pgs.14.97
14. Cao M, Guo M, Wu DQ, Meng L. Pharmacogenomics of Methotrexate: current status and future outlook. Curr Drug Metab. 2018;19(14):1182-7.
DOI:10.2174/1389200219666171227201047
15. Mikkelsen TS, Thorn CF, Yang JJ, et al. PharmGKB summary: methotrexate pathway. Pharmacogenet Genomics. 2011;21(10):679-86. DOI:10.1097/FPC.0b013e328343dd93
16. Inoue K, Yuasa H. Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9. DOI:10.2133/dmpk.dmpk-13-rv-119
17. Esmaili MA, Kazemi A, Faranoush M, et al. Polymorphisms within methotrexate pathway genes: relationship between plasma methotrexate levels, toxicity experienced and outcome in pediatric acute lymphoblastic leukemia. Iran J Basic Med Sci. 2020;23(6):800-9. DOI:10.22038/ijbms.2020.41754.9858
18. Lopez-Lopez E, Martin-Guerrero I, Ballesteros J, Garcia-Orad A. A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia. Pharmacogenomics J. 2013;13(6):498-506. DOI:10.1038/tpj.2012.44
19. Fukushima H, Fukushima T, Sakai A, et al. Polymorphisms of MTHFR associated with higher relapse/death ratio and delayed weekly MTX administration in pediatric lymphoid malignancies. Leuk Res Treatment. 2013;2013:238528. DOI:10.1155/2013/238528
20. Ezhilarasan D. Hepatotoxic potentials of methotrexate: understanding the possible toxicological molecular mechanisms. Toxicology. 2021;458:152840. DOI:10.1016/j.tox.2021.152840
21. Bernsen EC, Hagleitner MM, Kouwenberg TW, Hanff LM. Pharmacogenomics as a tool to lim it acute and long-term adverse effects of chemotherapeutics: an update in pediatric oncology. Front Pharmacol. 2020;11:1184.
DOI:10.3389/fphar.2020.01184
22. Stamp LK, Roberts RL. Effect of genetic polymorphisms in the folate pathway on methotrexate therapy in rheumatic diseases. Pharmacogenomics. 2011;12(10):1449-63. DOI:10.2217/pgs.11.86
23. Trevino LR, Shimasaki N, Yang W, et al. Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol. 2009;27(35):5972-8. DOI:10.1200/JCO.2008.20.4156
24. Ramsey LB, Panetta JC, Smith C, et al. Genome-wide study of methotrexate clearance replicates SLCO1B. Blood. 2013;121(6):898-904.
DOI:10.1182/blood-2012-08-452839
25. Ramsey LB, Bruun GH, Yang W, et al. Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition. Genome Res. 2012;22(1):1-8. DOI:10.1101/gr.129668.111
26. Spyridopoulou KP, Dimou NL, Hamodrakas SJ, Bagos PG. Methylene tetrahydrofolate reductase gene polymorphisms and their association with methotrexate toxicity: a meta-analysis. Pharmacogenet Genomics. 2012;22(2):117‑33. DOI:10.1097/FPC.0b013e32834ded2a
27. Campbell JM, Bateman E, Stephenson MD, et al. Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Cancer Chemother Pharmacol. 2016;78(1):27-39. DOI:10.1007/s00280-016-3043-5
28. Umerez M, Gutierrez-Camino Á, Muñoz-Maldonado C, et al. MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy. Pharmgenomics Pers Med. 2017;10:69-78. DOI:10.2147/PGPM.S107047
29. Yao P, He X, Zhang R, et al. The influence of MTHFR genetic polymorphisms on adverse reactions after methotrexate in patients with hematological malignancies: a meta-analysis. Hematology. 2019;24(1):10-9.
DOI:10.1080/10245332.2018.1500750
30. Lee YH, Bae SC. Association of the ATIC 347 C/G polymorphism with responsiveness to and toxicity of methotrexate in rheumatoid arthritis: a meta-analysis. Rheumatol Int. 2016;36(11):1591-9. DOI:10.1007/s00296-016-3523-2
31. Cheng Y, Chen MH, Zhuang Q, et al. Genetic factors involved in delayed methotrexate elimination in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2021;68(5):e28858. DOI:10.1002/pbc.28858
32. Gervasini G, de Murillo SG, Jiménez M, et al. Dihydrofolate reductase genetic polymorphisms affect methotrexate dose requirements in pediatric patients with acute lymphoblastic leukemia on maintenance therapy. J Pediatr Hematol Oncol. 2017;39(8):589-95. DOI:10.1097/MPH.0000000000000908
33. Wang SM, Sun LL, Zeng WX, et al. Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2014;74(2):283-9. DOI:10.1007/s00280-014-2507-8
34. Hegyi M, Arany A, Semsei AF, et al. Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma. Oncotarget. 2017;8(6):9388-98. DOI:10.18632/oncotarget.11543
35. Uhlen M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. DOI:10.1126/science.1260419
36. Huang Z, Tong HF, Li Y, et al. Effect of the polymorphism of folylpolyglutamate synthetase on treatment of high-dose methotrexate in pediatric patients with acute lymphocytic leukemia. Med Sci Monit. 2016;22:4967-73. DOI:10.12659/msm.899021
37. Taylor ZL, Vang J, Lopez-Lopez E, et al. Systematic review of pharmacogenetic factors that influence high-dose methotrexate pharmacokinetics in pediatric Malignancies. Cancers (Basel). 2021;13(11):2837. DOI:10.3390/cancers13112837
38. den Hoed MA, Lopez-Lopez E, te Winkel ML, et al. Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenomics J. 2015;15(3):248-54. DOI:10.1038/tpj.2014.63
39. Maagdenberg H, Oosterom N, Zanen J, et al. Genetic variants associated with methotrexate-induced mucositis in cancer treatment: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2021;161:103312. DOI:10.1016/j.critrevonc.2021.103312
40. Sorich MJ, Pottier N, Pei D, et al. In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile. PLoS Med. 2008;5(4):e83. DOI:10.1371/journal.pmed.0050083
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Авторы

Т.Т. Валиев*1,2, В.В. Семенова1,3, А.Ю. Иконникова3, А.А. Петрова3, Т.С. Белышева1, Т.В. Наседкина3

1 ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, Москва, Россия;
2 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия;
3 ФГБУН «Институт молекулярной биологии им. В.А. Энгельгардта» РАН, Москва, Россия
*timurvaliev@mail.ru

________________________________________________

Timur T. Valiev*1,2, Vera V. Semenova1,3, Anna Yu. Ikonnikova3, Alisa A. Petrova3, Tatiana S. Belysheva1, Tatiana V. Nasedkina3

1 Blokhin National Medical Research Center of Oncology, Moscow, Russia;
2 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia;
3 Engelhardt Institute of Molecular Biology, Moscow, Russia
*timurvaliev@mail.ru

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