Генотипирование полиморфизмов UGT1A1 и DPYD у пациентов с колоректальным раком

Тимошкина Н. Н., Петрусенко Н. А., Габричидзе П. Н., Черкес М. А., Пушкарева Т. Ф., Савченко Д. А. Генотипирование полиморфизмов UGT1A1 и DPYD у пациентов с колоректальным раком. Современная Онкология. 2023;25(4):447–453. DOI: 10.26442/18151434.2023.4.202514

© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.

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Timoshkina NN, Petrusenko NA, Gabrichidze PN, Cherkes MA, Pushkareva TF, Savchenko DA. Genotyping of UGT1A1 and DPYD polymorphisms in patients with colorectal cancer: A review. Journal of Modern Oncology. 2023;25(4): 447–453. DOI: 10.26442/18151434.2023.4.202514

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Аннотация

Основной схемой лечения пациентов с метастатическим колоректальным раком по-прежнему является курсовая химиотерапия фторпиримидинами в сочетании с оксалиплатином и/или иринотеканом. Для активности этих химиотерапевтических препаратов характерен преобладающий специфический способ метаболизма. В этом случае важное значение приобретают генетические особенности пациента как фактор прогноза возникновения и тяжести нежелательных явлений в ходе терапии. В обзоре рассмотрены современные представления о механизмах токсической активности иринотекана и фторпиримидинов, проанализированы результаты собственного фармакогенотипирования полиморфизмов UGT1A1, DPYD и опубликованных исследований, оценивавших связь генетических вариантов указанных генов и безопасности химиотерапии. Отмечено существенное влияние популяционной составляющей как в распределении частот аллелей генов, так и в их фенотипической реализации. Для ряда полиморфизмов DPYD установлены дозозависимые ассоциации с токсичностью 5‑фторурацила, и тем не менее они определяют только 1–8% случаев из 40–60% пациентов с нежелательными явлениями, у которых выявляют дефицит белка DPD, что, очевидно, связано с другими механизмами снижения активности фермента. Фармакологическое значение генетических вариаций UGT1A1 связывают не только с прогнозированием токсичности, но и с выделением группы пациентов для назначения более эффективной высокодозовой терапии иринотеканом. Приведена информация о состоянии фармакогенотипирования указанных маркеров с целью установления дозы лекарственных средств в различных национальных руководствах. На текущий момент неоднородность доступных фармакогенетических данных оставляет открытым вопрос об определении наиболее подходящих стратегий дозирования иринотекана и фторпиримидинов. Широкое внедрение в клиническую практику генотипирования UGT1A1 и DPYD балансирует между экономической целесообразностью и прогностической ценностью биомаркеров. Поскольку область фармакогеномики быстро развивается, дальнейшие более надежные исследования должны преодолеть существующие препятствия, что будет способствовать принятию персонализированных решений по дозировке лекарств.

Ключевые слова: фармакогенетика, уридин-дифосфат-глюкуронозил-трансфераза, UGT1A1, иринотекан, дигидро-пиримидин-дегидрогеназа, DPYD, фторпиримидины, полиморфизм

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The main treatment regimen for patients with metastatic colorectal cancer is still cycle-based chemotherapy with fluoropyridines combined with oxaliplatin and/or irinotecan. The activity of these chemotherapeutic agents depends on a predominant specific metabolism pathway. Therefore, the genetic features of the patient become important as a prognostic factor for the occurrence and severity of adverse events during therapy. The review addresses current views about the mechanisms of toxic activity of irinotecan and fluoropyrimidines, analyzes the results of pharmacogenotyping of UGT1A1 and DPYD polymorphisms, and published studies assessing the relationship between genetic variants of these genes and the safety of chemotherapy. A significant role of the population component is noted both in the distribution of gene allele frequencies and in their phenotypic expression. For some polymorphisms of the DPYD gene, dose-dependent associations with the toxicity of 5‑fluorouracil have been established. Nevertheless, they determine only 1–8% of cases out of 40–60% of patients with adverse events and DPD protein deficiency associated with other enzyme activity reduction mechanisms. The pharmacological significance of UGT1A1 genetic variations is associated with toxicity prediction and helps allocate patients for more effective high-dose irinotecan therapy. Data is presented on the pharmacogenotyping of these markers to establish the dose of drugs in various national guidelines. Currently, the heterogeneity of the available pharmacogenetic data leaves open the question of determining the most appropriate dosing strategies for irinotecan and fluoropyrimidines. The widespread introduction of UGT1A1 and DPYD genotyping into clinical practice balances the economic feasibility and predictive value of biomarkers. As pharmacogenomics evolves rapidly, more robust research would overcome existing hurdles and facilitate personalized drug dosage decisions.

Keywords: pharmacogenetics, uridine diphosphate-glucuronosyl transferase, UGT1A1, irinotecan, dihydro-pyrimidine dehydrogenase, DPYD, fluoropyrimidines, polymorphism

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1. Fedenko AA, Triakin AA, Zhukova LG, et al. Natsional’noe rukovodstvo po lekarstvennomu lecheniiu zlokachestvennykh opukholei. Pod red. AD Kaprina. Moscow, 2020 (in Russian).
2. Takano M, Sugiyama T. UGT1A1 polymorphisms in cancer: impact on irinotecan treatment. Pharmgenomics Pers Med. 2017;10:61‑8. DOI:10.2147/PGPM.S108656
3. Pfizer: CAMPTOSAR® (irinotecan HCl) Prescribing Information, 2014. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020571s048lbl.pdf. Accessed: 30.11.2022.
4. Tam VC, Rask S, Koru-Sengul T, Dhesy-Thind S. Generalizability of toxicity data from oncology clinical trials to clinical practice: Toxicity of irinotecan-based regimens in patients with metastatic colorectal cancer. Curr Oncol. 2009;16(6):13‑20. DOI:10.3747/co.v16i6.426
5. Shulman K, Cohen I, Barnett-Griness O, et al. Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients. Cancer. 2011;117(14):3156‑62. DOI:10.1002/cncr.25735
6. Karas S, Innocenti F. All You Need to Know About UGT1A1 Genetic Testing for Patients Treated With Irinotecan: A Practitioner-Friendly Guide. JCO Oncol Pract. 2022;18(4):270‑7. DOI:10.1200/OP.21.00624
7. Fuchs CS, Moore MR, Harker G, et al. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003;21(5):807‑14. DOI:10.1200/JCO.2003.08.058
8. Kweekel D, Guchelaar HJ, Gelderblom H. Clinical and pharmacogenetic factors associated with irinotecan toxicity. Cancer Treat Rev. 2008;34(7):656‑69.
DOI:10.1016/j.ctrv.2008.05.002
9. Wasserman E, Myara A, Lokiec F, et al. Severe CPT‑11 toxicity in patients with Gilbert’s syndrome: two case reports. Ann Oncol. 1997;8(10):1049‑51. DOI:10.1023/A:1008261821434
10. Williams JA, Hyland R, Jones BC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004;32(11):1201‑8. DOI:10.1124/dmd.104.000794
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12. Cerny MA. Prevalence of Non-Cytochrome P450-Mediated Metabolism in Food and Drug Administration – Approved Oral and Intravenous Drugs: 2006‑2015. Drug Metab Dispos. 2016;44(8):1246‑52. DOI:10.1124/dmd.116.070763
13. Meng CL, Zhao W, Zhong DN. Epigenetics and microRNAs in UGT1As. Hum Genomics. 2021;15(1):30. DOI:10.1186/s40246‑021‑00331‑6
14. Sara JD, Kaur J, Khodadadi R, et al. 5‑fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol. 2018;10:1758835918780140. DOI:10.1177/1758835918780140
15. Van Kuilenburg ABP, Meinsma R, Zoetekouw L, Van Gennip AH. 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. 2002;101(3):253‑8. DOI:10.1002/ijc.10599
16. Johnson MR, Diasio RB. Importance of dihydropyrimidine dehydrogenase (DPD) deficiency in patients exhibiting toxicity following treatment with 5‑fluorouracil. Adv Enzyme Regul. 2001;41:151‑7. DOI:10.1016/s0065‑2571(00)00011‑x
17. Mikhail SE, Sun JF, Marshall JL. Safety of capecitabine: a review. Expert Opin Drug Saf. 2010;9(5):831‑41. DOI:10.1517/14740338.2010.511610
18. Pallet N, Hamdane S, Garinet S, et al. A comprehensive population-based study comparing the phenotype and genotype in a pretherapeutic screen of dihydropyrimidine dehydrogenase deficiency. Br J Cancer. 2020;123(5):811‑8. DOI:10.1038/s41416‑020‑0962‑z
19. Zhang X, Li L, Fourie J, et al. The role of Sp1 and Sp3 in the constitutive DPYD gene expression. Biochim Biophys Acta (BBA) – Gene Structure and Expression. 2006;1759(5):247‑56.nDOI:10.1016/j.bbaexp.2006.05.001
20. Hirota T, Date Y, Nishibatake Y, et al. Dihydropyrimidine dehydrogenase (DPD) expression is negatively regulated by certain microRNAs in human lung tissues. Lung Cancer. 2012;77(1):16‑23. DOI:10.1016/j.lungcan.2011.12.018
21. Toren W, Ansari D, Andersson B, et al. Thymidylate synthase: a predictive biomarker in resected colorectal liver metastases receiving 5-FU treatment. Future Oncol. 2018;14(4):343‑51. DOI:10.2217/fon‑2017‑0431
22. Abbasian MH, Ansarinejad N, Abbasi B, et al. The Role of Dihydropyrimidine Dehydrogenase and Thymidylate Synthase Polymorphisms in Fluoropyrimidine-Based Cancer Chemotherapy in an Iranian Population. Avicenna J Med Biotechnol. 2020;12(3):157‑64.
23. Kit OI, Maksimov AYu, Dzhenkova EA, Timoshkina NN. The role of molecular genetic studies in current oncology. Annals of the Russian Academy of Medical Sciences. 2022;77(3):214‑24 (in Russian).
24. Vodolazhsky DI, Dvadnenko KV, Timoshkina NN, et al. UGT1A1 gene polymorphism in patients with colorectal cancer living in the South of Russia: results of a pilot study. Molecular Medicine. 2017;15(1):61‑4 (in Russian).
25. Timoshkina NN, Bogomolova OA, Zhuzhelenko IA, et al. Study of UGT1A1 and DPYD gene polymorphisms in patients with colorectal cancer. Siberian Journal of Oncology. 2018;17(6):49‑56 (in Russian). DOI:10.21294/1814‑4861‑2018‑17‑6-49‑56
26. Chen X, Liu L, Guo Z, et al. UGT1A1 polymorphisms with irinotecan-induced toxicities and treatment outcome in Asians with Lung Cancer: a meta-analysis. Cancer Chemother Pharmacol. 2017;79(6):1109‑17. DOI:10.1007/s00280‑017‑3306‑9
27. Zhang X, Yin JF, Zhang J, et al. UGT1A1*6 Polymorphisms are Correlated With Irinotecan-Induced Neutropenia: A Systematic Review and Meta-Analysis. Cancer Chemother Pharmacol. 2017;80(1):135‑49. DOI:10.1007/s00280‑017‑3344‑3
28. Liu X, Cheng D, Kuang Q, et al. Association of UGT1A1*28 polymorphisms with irinotecan-induced toxicities in colorectal cancer: a meta-analysis in Caucasians. Pharmacogenomics J. 2014;14(2):120‑9. DOI:10.1038/tpj.2013.10
29. Yang Y, Zhou M, Hu M, et al. UGT1A1*6 and UGT1A1*28 polymorphisms are correlated with irinotecan-induced toxicity: A meta-analysis. Asia Pac J Clin Oncol. 2018;14(5):e479‑89. DOI:10.1111/ajco.13028
30. Cremolini C, Del Re M, Antoniotti C, et al. DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer. Oncotarget. 2018;9(8):7859‑66. DOI:10.18632/oncotarget.23559
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Авторы

Н. Н. Тимошкина*, Н. А. Петрусенко, П. Н. Габричидзе, М. А. Черкес, Т. Ф. Пушкарева, Д. А. Савченко

ФГБУ «Национальный медицинский исследовательский центр онкологии» Минздрава России, Ростов-на-Дону, Россия
*timoshkinann@rnioi.ru

________________________________________________

Natalia N. Timoshkina*, Natalia A. Petrusenko, Petr N. Gabrichidze, Mariia A. Cherkes, Tatiana F. Pushkareva, Dmitry A. Savchenko

National Medical Research Center for Oncology, Rostov-on-Don, Russia
*timoshkinann@rnioi.ru

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