Vol. 17 No. 2 (2024), LYMPHOID TUMORS
Vol. 17 No. 2 (2024)
LYMPHOID TUMORS

The Role of Polymorphic Variants of Р450 Cytochrome Genes as well as Genes GSTP1 and MDR1 in Toxic Complications of Program Drug Chemotherapy for Classical Hodgkin Lymphoma

Published 01.04.2024
Yana Yurevna Shebunyaeva
Novosibirsk State Medical University, 52 Krasnyi pr-t, Novosibirsk, Russian Federation, 630091
PDF_2024-17-2_141-153 (Russian)

Keywords

classical Hodgkin lymphoma
hepatotoxicity
cardiotoxicity
gene polymorphism
cytochromes Р450
genes MDR1
GSTP1

How to Cite

1.
Shebunyaeva Y.Y. The Role of Polymorphic Variants of Р450 Cytochrome Genes as well as Genes GSTP1 and MDR1 in Toxic Complications of Program Drug Chemotherapy for Classical Hodgkin Lymphoma. Клиническая онкогематология. 2024;17(2):141-153. doi:10.21320/2500-2139-2024-17-2-141-153
ACM ACS APA ABNT Chicago Harvard IEEE MLA Turabian Vancouver AMA ГОСТ

Download Citation

Endnote/Zotero/Mendeley (RIS) BibTeX

Keywords

Abstract

Background. Although considerable progress has been achieved in the treatment of classical Hodgkin lymphoma (cHL), toxic complications of program drug chemotherapy remain an issue. Standard cytostatic agents used in cHL therapy are metabolized in liver by the enzymes with Р450 cytochrome and GSTP1 gene-controlled synthesis. At the same time, the excretion of active metabolites of antitumor drugs is mediated by MDR1 coded P-glycoprotein. Polymorphisms[1] of these genes may change the processes of antitumor drug biotransformation and their metabolite excretion. Additionally, they may result in organo-toxic complications, disablement of patients, and even death.

Aim. To assess the role of polymorphisms in cytochrome genes Р450 as well as genes GSTP1 and MDR1 in organ toxicity dynamics during program chemotherapy (CT) in cHL patients.

Materials & Methods. The study enrolled 122 cHL patients treated with first-line regimens (ABVD, BEACOPP) of program drug chemotherapy. The patients were aged 18–78 years (median 35 years); there were 67 (54.9 %) women and 55 (45.1 %) men. In compliance with the NCCN CTC (2003) criteria of hepatotoxicity and practical recommendations for correcting cardiovascular toxicity of chemotherapy (2021), the signs of toxic liver and heart damage were assessed in all patients. PCR was used to analyze polymorphisms in cytochrome genes Р450 as well as genes GSTP1 and MDR1, their association with toxic complications of CT was analyzed.

Results. Drug-induced liver damage on program CT was identified in 80 % of cHL patients. The toxicity was increasing from CT cycle 1 to cycle 6 both on ABVD and BEACOPP. Complications grade 3/4 were observed only in BEACOPP recipients. Significant (p < 0.05) associations were found between hepatotoxic complications with increased cytolytic (AST, ALT) and cholestatic (ALP) values and polymorphic variants of MDR1. Significant (p < 0.05) reduction of left ventricle myocardium contractility in cHL patients was associated with Т-allele presence in genotypes CYP2D6*10 (rs1065852), CYP2C9*2 (rs1799853) and A-allele deletion in genotype CYP2D6_3 (rs4986774).

Conclusion. The identification of genetic predictors for toxic effects of program CT in cHL patients at the baseline examination can minimize the risks of drug chemotherapy-related adverse events and allow these patients to maintain a satisfactory quality of life.

 

[1] Gene polymorphism is a structural difference between alternative variants of a gene. Alternative variants of genes result from mutations.

PDF_2024-17-2_141-153 (Russian)

References

  1. Демина Е.А. Руководство по лечению лимфомы Ходжкина. М.: Ремедиум, 2021. [Demina EA. Rukovodstvo po lecheniyu limfomy Khodzhkina. (Guidelines on Hodgkin lymphoma treatment.) Moscow: Remedium Publ.; 2021. (In Russ)]
  2. Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Под ред. И.В. Поддубной, В.Г. Савченко. М.: Буки Веди, 2018. 324 с. [Poddubnaya IV, Savchenko VG, eds. Rossiiskie klinicheskie rekomendatsii po diagnostike i lecheniyu limfoproliferativnykh zabolevanii. (Russian clinical guidelines on diagnosis and treatment of lymphoproliferative disorders.) Moscow: Buki Vedi Publ.; 2018. 324 р. (In Russ)]
  3. Ansell SM. Hodgkin lymphoma: A 2020 update on diagnosis, risk-stratification, and management. Am J Hematol. 2020;95(8):978–89. doi: 10.1002/ajh.25856.
  4. Даниленко А.А. Отдаленные последствия лучевой и химиолучевой терапии первичных больных лимфомой Ходжкина: Автореф. дис. … канд. мед. наук. Обнинск, 2017. [Danilenko AA. Otdalennye posledstviya luchevoi i khimioluchevoi terapii pervichnykh bol’nykh limfomoi Khodzhkina. (Long-term effects of radiation and chemoradiotherapy in primary patients with Hodgkin lymphoma.) [dissertation] Obninsk; 2017. (In Russ)]
  5. Nangalia J, Smith H, Wimperis JZ. Isolated neutropenia during ABVD chemotherapy for Hodgkin lymphoma does not require growth factor support. Leuk Lymphoma. 2008;49(8):1530–6. doi: 10.1080/10428190802210718.
  6. Yang J, Bogni A, Schuetz EG, et al. Etoposide pathway. Pharmacogenet Genomics. 2009;19(7):552–3. doi: 10.1097/FPC.0b013e32832e0e7f.
  7. Timm R, Kaiser R, Lotsch J, et al. Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19. Рharmacogenomics J. 2005;5(6):365–73. doi: 10.1038/sj.tpj.6500330.
  8. Muniz P, Andres-Zayas C, Carbonell D, et al. Association between gene polymorphisms in the cyclophosphamide metabolism pathway with complications after haploidentical hematopoieticstem cell transplantation. Front Immunol. 2022;13:1002959. doi: 10.3389/fimmu.2022.1002959.
  9. Ларионова В.Б., Снеговой А.В. Возможности коррекции лекарственной печеночной токсичности при лечении больных с опухолями системы крови. Онкогематология. 2020;15(4):65–81. doi: 10.17650/1818-8346-2020-15-4-65-81. [Larionova VB, Snegovoy AV. Correction possibilities of drug-induced liver toxicity in the treatment of patients with blood system tumors. Oncohematology. 2020;15(4):65–81. doi: 10.17650/1818-8346-2020-15-4-65-81. (In Russ)]
  10. Songbo M, Lang H, Xinyong C, et al. Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol Lett. 2019;307:41–8. doi: 10.1016/j.toxlet.2019.02.013.
  11. Kovacs ER, Toth S, Erdelyi DJ. Epigenetic effects affecting etoposide distribution and metabolism in the human body. Orv Hetil. 2018;159(32):1295–302. Hungarian. doi: 10.1556/650.2018.31162.
  12. Rendic S, Guengerich FP. Survey of Human Oxidoreductases and Cytochrome P450 Enzymes Involved in the Metabolism of Xenobiotic and Natural Chemicals. Chem Res Toxicol. 2015;28(1):38–42. doi: 10.1021/tx500444e.
  13. Zhuo X, Zheng N, Felix CA, Blair IA. Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos. 2004;32:993–1000.
  14. Wen Z, Tallman MN, Ali SY, Smith PC. UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for etoposide glucuronidation in human liver and intestinal microsomes: structural characterization of phenolic and alcoholic glucuronides of etoposide and estimation of enzyme kinetics. Drug Metab Dispos. 2007;35(3):371–80. doi: 10.1124/dmd.106.012732.
  15. Christ O, Lucke K, Imren S, et al. Improved purification of hematopoietic stem cells based on their elevated aldehyde dehydrogenase activity. Haematologica. 2007;92(9):1165–72. doi: 10.3324/haematol.11366.
  16. Zelcer N, Saeki T, Reid G, et al. Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem. 2001;276(49):46400–7. doi: 10.1074/jbc.M107041200.
  17. Jedlitschky G, Leier I, Buchholz U, et al. Transport of glutathione, glucuronate, and sulfate conjugates by the MRP gene-encoded conjugate export pump. Cancer Res. 1996;56(5):988–94.
  18. Кукес В.Г. Клиническая фармакология: Учебник для вузов. М.: ГЭОТАР-Медиа, 2009. 1056 с. [Kukes VG. Klinicheskaya farmakologiya: Uchebnik dlya vuzov. (Clinical pharmacology: textbook for universities.) Moscow: GEOTAR-Media Publ.; 2009. 1056 р. (In Russ)]
  19. Dennison JB, Kulanthaivel P, Barbuch RJ, et al. Selective metabolism of vincristine in vitro by CYP3A5. Drug Metab Dispos. 2006;34(8):1317–27. doi: 10.1124/dmd.106.009902.
  20. Ивашкин В.Т., Райхельсон К.Л., Пальгова Л.К. и др. Лекарственные поражения печени у онкологических пациентов. Онкогематология. 2020;15(3):80–94. doi: 10.17650/1818-8346-2020-15-3-80-94. [Ivashkin VT, Raikhelson KL, Palgova LK, et al. Drug-induced liver injury in cancer patients. Oncohematology. 2020;15(3):80–94. doi: 10.17650/1818-8346-2020-15-3-80-94. (In Russ)]
  21. Алыева А.А., Никитин И.Г., Архипов А.В. Сопроводительная терапия острого лекарственного повреждения печени на фоне химиотерапевтического лечения у пациенток с раком молочной железы. Лечебное дело. 2018;2:78–84. [Alyeva AA, Nikitin IG, Arkhipov AV. Accompanying therapy of acute drug-induced liver damage during chemotherapy treatment in patients with breast cancer. Lechebnoe delo. 2018;2:78–84. (In Russ)]
  22. Ткаченко П. Е., Ивашкин В. Т., Маевская М. В. Клинические рекомендации по коррекции гепатотоксичности, индуцированной противоопухолевой терапией. Злокачественные опухоли. Практические рекомендации RUSSCO. 2021;11(3s2):64–77. doi: 10.18027/2224-5057-2021-11-3s2-40. [Tkachenko PE, Ivashkin VT, Maevskaya MV. Clinical recommendations for the correction of hepatotoxicity induced by antitumor therapy. Malignant tumors. Practical Recommendations RUSSCO. 2021;11(3s2):64–77. doi: 10.18027/2224-5057-2021-11-3s2-40. (In Russ)]
  23. De Jonge ME, Huitema AD, Rodenhuis S, Beijnen JH. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet. 2005;44(11):1135–64. doi: 10.2165/00003088-200544110-00003.
  24. Morittu L, Earl HM, Souhami RL, et al. Patients at risk of chemotherapy-associated toxicity in small cell lung cancer. Br J Cancer. 1989;59(5):801–4. doi: 10.1038/bjc.1989.167.
  25. Srivastava S, Jones D, Wood LL, et al. A phase I trial of high-dose clofarabine, etoposide, and cyclophosphamide and autologous peripheral blood stem cell transplantation in patients with primary refractory and relapsed and refractory non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2011;17(7):987–94. doi: 10.1016/j.bbmt.2010.10.016.
  26. Гендлин Г.Е., Емелина Е.И., Никитин И.Г., Васюк Ю.А. Современный взгляд на кардиотоксичность химиотерапии онкологических заболеваний, включающей антрациклиновые антибиотики. Российский кардиологический журнал. 2017;3:145–54. doi: 10.15829/1560-4071-2017-3-145-154. [Gendlin GE, Emelina EI, Nikitin IG, Vasyuk YuA. Modern view on cardiotoxicity of chemotherapeutics in oncology including anthracyclines Russian journal of cardiology. 2017;3:145–54. doi: 10.15829/1560-4071-2017-3-145-154. (In Russ)]
  27. Abdel-Daim MM, Kilany OE, Khalifa HA, Ahmed AAM. Allicin ameliorates doxorubicin-induced cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis. Cancer Chemother Pharmacol. 2017;80(4):745–53. doi: 10.1007/s00280-017-3413-7.
  28. Vejpongsa P, Yeh ETH. Prevention of Anthracycline-Induced Cardiotoxicity: Challenges and Opportunities. J Am Coll Cardiol. 2014;64(9):938–45. doi: 10.1016/j.jacc.2014.06.1167.
  29. Hande KR. Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer. 1998;34(10):1514–21. doi: 10.1016/s0959-8049(98)00228-7.
  30. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf. 2000;22(4):263–302. doi: 10.2165/00002018-200022040-00002.
  31. Ghielmini M, Zappa F, Menafoglio A, et al. The high-dose sequential (Milan) chemotherapy/PBSC transplantation regimen for patients with lymphoma is not cardiotoxic. Ann Oncol. 1999;10(5):533–7. doi: 10.1023/a:1026434732031.
  32. Емелина Е.И., Шуйкова К.В., Гендлин Г.Е. и др. Поражение сердца при лечении современными противоопухолевыми препаратами и лучевые повреждения сердца у больных с лимфомами. Клиническая онкогематология. 2009;2(2):152–60. [Emelina EI, Shuikova KV, Gendlin GE, et al. Cardiac damage after modern chemo- and radiotherapy in patients with lymphomas. Klinicheskaya onkogematologiya. 2009;2(2):152–60. (In Russ)]
  33. Ozkan HA, Bal C, Gulbas Z. Assessment and comparison of acute cardiac toxicity during high-dose cyclophosphamide and high-dose etoposide stem cell mobilization regimens with N-terminal pro-B-type natriuretic peptide. Transfus Apher Sci. 2014;50(1):46–52. doi: 10.1016/j.transci.2013.12.001.
  34. Banerjee SK, Borden A, Christensen RB, et al. SOS-dependent replication past a single trans-syn T-T cyclobutane dimer gives a different mutation spectrum and increased error rate compared with replication past this lesion in uniduced cell. J Bacteriol. 1990;172(4):2105–12. doi: 10.1128/jb.172.4.2105-2112.1990.
  35. Смирнов В.В. Определение активности ферментов метаболизма лекарственных средств — перспектива использования в клинической практике. Ведомости научного центра экспертизы средств медицинского применения. 2016;4:28–32. [Smirnov VV. Determination of the activity of drug-metabolizing enzymes — the prospects for their use in clinical practice. Vedomosti nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya. 2016;4:28–32. (In Russ)]
  36. Скворцова Н.В. Цитокиновый профиль больных лимфомами в динамике полихимиотерапии: Автореф. дис. … канд. мед. наук. Новосибирск, 2005. [Skvortsova NV. Tsitokinovyi profil bolnykh limfomami v dinamike polikhimioterapii. (Cytokine profile of lymphoma patients in the dynamics of polychemotherapy.) [dissertation] Novosibirsk; 2005. (In Russ)]
  37. Slaviero KA, Clarke SJ, Rivory LP. Inflammatory response: an unrecognised source of variability in the pharmacokinetics and pharmacodynamics of cancer chemotherapy. Lancet Oncol. 2003;4(4):224–32. doi: 10.1016/s1470-2045(03)01034-9.
  38. Kacevska M, Robertson GR, Clarke SJ, Liddle C. Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: Impact and implications for chemotherapeutic drug dosing. Expert Opin Drug Metab Toxicol. 2008;4(2):137–49. doi: 10.1517/17425255.4.2.137.
  39. Morgan ET, Goralski KB, Piquette-Miller M, et al. Regulation of drug metabolizing enzymes and transporters in infection, inflammation, and cancer. Drug Metab Dispos. 2008;36(2):205–16. doi: 10.1124/dmd.107.018747.
  40. Krasniqi V, Dimovski A, Domjanovic IK, et al. How polymorphisms of the cytochrome P450 genes affect ibuprofen and diclofenac metabolism and toxicity. Arh Hig Rada Toksikol. 2016;67(1):1–8. doi: 10.1515/aiht-2016-67-2754.
  41. Arafa MH, Atteia HH. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6) are associated with long term tramadol treatment-induced oxidative damage and hepatotoxicity. Toxicol Appl Pharmacol. 2018;346:37–44. doi: 10.1016/j.taap.2018.03.019.
  42. Kim HJ, Im SA, Keam B, et al. ABCB1 polymorphism as prognostic factor in breast cancer patients treated with docetaxel and doxorubicin neoadjuvant chemotherapy. Cancer Sci. 2015;106(1):86–93. doi: 10.1111/cas.12560.
  43. Bagdasaryan AA, Chubarev VN, Smolyarchuk EA, et al. Pharmacogenetics of Drug Metabolism: The Role of Gene Polymorphism in the Regulation of Doxorubicin Safety and Efficacy. Cancers (Basel). 2022;14(21):5436. doi: 10.3390/cancers14215436.
  44. Bray J, Sludden J, Griffin MJ, et al. Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer. 2010;102(6):1003–9. doi: 10.1038/sj.bjc.6605587.
  45. Wang X, Sun CL, Quinones-Lombrana A, et al. CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children’s Oncology Group Genome-Wide Association Study. J Clin Oncol. 2016;34(8):863–70. doi: 10.1200/JCO.2015.63.4550.
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Copyright (c) 2024 Clinical Oncohematology