Preview

Успехи молекулярной онкологии

Расширенный поиск

Фармакогенетическое тестирование аллельных вариантов гена CYP2D6 при гормоноположительном раке молочной железы

https://doi.org/10.17650/2313-805X-2017-4-3-57-66

Полный текст:

Аннотация

Тамоксифен является препаратом выбора при эндокринотерапии гормоноположительного рака молочной железы у женщин в репродуктивном возрасте. Метаболическая активность тамоксифена в организме определяется активностью фермента CYP2D6, кодируемого одноименным геном: под действием фермента тамоксифен переходит в метаболически активную форму – эндоксифен. Фармакогенетическое тестирование гена CYP2D6 у пациентов с гормоноположительным раком молочной железы поможет прогнозировать эффективность терапии и оценить риск развития побочных эффектов в целях улучшения отдаленных результатов лечения.

Об авторах

Л. Н. Любченко
ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России.
Россия
115478 Москва, Каширское шоссе, 24.


М. Г. Филиппова
ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России.
Россия
115478 Москва, Каширское шоссе, 24.


Т. А. Шендрикова
ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России.
Россия
115478 Москва, Каширское шоссе, 24.


Л. Г. Жукова
ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России.
Россия
115478 Москва, Каширское шоссе, 24.


Н. И. Мехтиева
ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России.
Россия
115478 Москва, Каширское шоссе, 24.


О. В. Крохина
ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России.
Россия
115478 Москва, Каширское шоссе, 24.


С. М. Портной
ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России.
Россия
115478 Москва, Каширское шоссе, 24.


Список литературы

1. Статистика злокачественных новообразований в России и странах СНГ в 2012 г. Под ред. М.И. Давыдова, Е.М. Аксель М.: Издательская группа РОНЦ, 2014. 226 с. [Statistics of malignant neoplasms in Russia and CIS countries in 2012. Eds.: M.I. Davydov, E.M. Axel’. Moscow: Izdatel’skaya gruppa RONTS, 2014. 226 p. (In Russ.)].

2. McGraw J., Waller D. Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Metab Toxicol 2012;8(3):371–82.

3. Gonzalez F.J., Mackenzie P.I., Kimura S., Nebert D.W. Isolation and characterization of mouse full-length cDNA and genomic clones of 3-methylcholanthreneinducible cytochrome P1-450 and P3-450. Gene 1984;29(3):281–92.

4. Nebert D.W., Adesnik M., Coon M.J. et al. The P450 gene superfamily: recommended nomenclature. DNA 1987;6(1):1–11.

5. Nelson D.R. Cytochrome P450 gene superfamily. Available at: drnelson.utmem. edu/cytochromeP450.html (Accessed July 10, 2002).

6. Phillips K.A., Veenstra D.L., Oren E. et al. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 2001;286(18):2270–9.

7. Andersson T., Flockhart D.A., Goldstein D.B. et al. Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther 2005;78(6):559–81.

8. Franceschi M., Scarcelli C., Niro V. et al. Prevalence, clinical features and avoidability of adverse drug reactions as cause of admission to a geriatric unit: a prospective study of 1756 patients. Drug Saf 2008;31(6):545–56.

9. Lazarou J., Pomeranz B.H., Corey P.N. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279(15):1200–5.

10. Goldhirsch А., Wood W.C., Gelber R.D. et. al Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer. Ann Oncol 2007;18(7):1133–44.

11. Davies C., Pan H., Godwin J. et al. Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomized trial. Lancet 2013;381(9869):805–16.

12. Gray R.G., Rea D.W., Handley K. et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 2013;31(18S):5.

13. Lim Y.C., Desta Z., Flockhart D.A., Skaar T.C. Endoxifen (4-hydroxy-N-desmethyltamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxytamoxifen. Cancer Chemother Pharmacol 2005;55(5):471–8.

14. Crewe H.K., Ellis S.W., Lennard M.S., Tucker GT. Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem Pharmacol 1997;53(2):171–8.

15. Murdter T.E., Schroth W., Bacchus-Gerybadze L. et al. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma. Clin Pharmacol Ther 2011;89(5):708–17.

16. Wu X., Hawse J.R., Subramaniam M. et al. The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res 2009;69(5):1722–7.

17. de Vries Schultink A.H., Zwart W., Linn S.C. et al. Effects of pharmacogenetics on the pharmacokinetics and pharmacodynamics of tamoxifen. Clin Pharmacokinet 2015;54(8):797–810.

18. Mwinyi J., Vokinger K., Jetter A. et al. Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy. Cancer Chemother Pharmacol 2014;73(6):1181–8.

19. Eichelbaum M., Ingelman-Sundberg M., Evans W.E. Pharmacogenomics and individualized drug therapy. Annu Rev Med 2006;57:119–37.

20. Evans W.E., Relling M.V. Pharmacogenomics: translating functional genomics into rational therapeutics. Science1999;286(5439):487–91.

21. Nebert D.W., Jorge-Nebert L.F. Pharmacogenetics and pharmacogenomics. In book: Emery and rimoin’s principles and practice of medical genetics. 4th edn. Eds.: D.L. Rimoin, J.M. Connor, R.E . Pyeritz, B.R. Korf. Edinburgh: Harcourt Brace, 2002. Pp. 590–631.

22. Crewe H.K., Notley L.M., Wunsch R.M. et al. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 40 -hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metabolism Dispos 2002;30(8):869–74.

23. Desta Z., Ward B.A., Soukhova N.V., Flockhart D.A. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 2004;310(3):1062–75.

24. Maximov P.Y., McDaniel R.E., Fernandes D.J. et al. Simulation with cells in vitro of tamoxifen treatment in premenopausal breast cancer patients with different CYP2D6 genotypes. Br J Pharmacol 2014;171(24):5624–35.

25. Johnson M.D., Zuo H., Lee K.H. et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 2004;85(2):151–9.

26. Bradford L.D. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 2001;3(2):229–43.

27. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005;5(1):6–13.

28. Zanger U.M., Raimundo S., Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 2004;369(1):23–37.

29. Goetz M.P., Rae J.M., Suman V.J. et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005;23(36):9312–8.

30. Human cytochrome P450 (CYP) allele nomenclature T. The Human Cytochrome P450 (CYP) Allele Nomenclature Data base. Available at: www.cypalleles.ki.se/cyp2d6.htm. (Accessed Dec 28, 2014).

31. Gaikovitch E.A., Cascorbi I., Mrozikiewicz P.M. et al. Polymorphisms of drugmetabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol 2003;59(4):303–12.

32. Кольман Я., Рём К.Г. Наглядная биохимия. М.: Мир, 2000. 470 c. [Kohl’mann I., Rem K.G. Visible biochemistry. Moscow: Mir, 2000. 470 p. (In Russ.)].

33. Сычев Д.А., Миронова Н.А. Фармакогенетическое тестирование по CYP2D6 и CYP2C19: значение для персонализации применения лекарственных средств в клинической практике. Лаборатория 2012;(4):11–3. [Sychev D.A., Mironova N.A. Pharmacogenetic testing for CYP2D6 and CYP2C19: a value for personalizing the use of drugs in clinical practice. Laboratoriya = Laboratory 2012;(4):11–3. (In Russ.)].

34. Zhou S.F. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet 2009;48(12):761–804.

35. Borges S., Desta Z., Li L. et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol 2006;80(1):61–74.

36. Lim H.S., Ju Lee H., Seok Lee K. et al. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 2007;25(25):3837–45.

37. Madlensky L., Natarajan L., Tchu S. et al. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther 2011;89(5):718–25.

38. Schroth W., Goetz M.P., Hamann U. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA 2009;302(13):1429–36.

39. Regan M., Leyland-Jones B., Bouzyk M. et al. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial. J Natl Cancer Inst 2012;104(6):441–51.

40. Rae J.M., Drury S., Hayes D.F. et al. ATAC trialists: CYP2D6and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst 2012;104(6):452–60.

41. Nakamura Y., Ratain M.J., Cox N.J. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial. J Natl Cancer Inst 2012;104(16):1264.

42. Dezentjé V.O., van Schaik R.H., VletterBogaartz J.M. et al. CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvantmultinational (TEAM) trial. Breast Cancer Res Treat 2013;140(2):363–73.

43. Goetz M.P., Suman V.J., Hoskin T.L. et al. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res 2013;19(2):500–7.

44. Karle J., Bolbrinker J., Vogl S. et al. Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer. Breast Cancer Res Treat 2013;139(2):553–60.

45. Zeng Z., Liu Y., Liu Z. CYP2D6 polymorphisms influence tamoxifen treatment outcomes in breast cancer patients: a metaanalysis. Cancer Chemother Pharmacol 2013;72(2):287–303.

46. Irvin W.J. Jr, Walko C.M., Weck K.E. et al. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study. J Clin Oncol 2011;29(24):3232–9.

47. Kiyotani K., Mushiroda T., Imamura C.K. at al. Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients. Breast Cancer Res Treat 2012;131(1):137–45.

48. Rolla R., Vidali M., Meola S. et al. Side effects associated with ultrarapid cytochrome P450 2D6 genotype among women with early stage breast cancer treated with tamoxifen. Clin Lab 2012;58(11–12): 1211–8.

49. Barginear M.F., Jaremko M., Peter I. et al. Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels: effect on active metabolite isomers and the antiestrogenic activity score. Clin Pharmacol Ther 2011;90(4):605–11.

50. Brauch H., Schroth W., Goetz M.P. et al. Tamoxifen use in postmenopausal breast cancer: CYP2D6 matters. J Clin Oncol 2013;31(2):176–80.

51. Fann J.R., Thomas-Rich A.M., Katon W.J. et al. Major depression after breast cancer: a review of epidemiology and treatment. Gen Hosp Psychiatry 2008;30(2):112–26.

52. Jeppesen U., Gram L.F., Vistisen K. et al. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol 1996;51(1):73–8.

53. Binkhorst L., Bannink M., de Bruijn P. et al. Augmentation of endoxifen exposure in tamoxifen-treated women following SSRI switch. Clin Pharmacokinet 2016;55(2):249–55.

54. Borges S., Desta Z., Jin Y. et al. Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients. J Clin Pharmacol 2010;50(4):450–8.

55. Jin Y., Desta Z., Stearns V. et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 2005;97(1):30–9.

56. Stearns V., Johnson M.D., Rae J.M. et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003;95(23):1758–64.

57. Chubak J., Buist D.S., Boudreau D.M. et al. Breast cancer recurrence risk in relation to antidepressant use after diagnosis. Breast Cancer Res Treat 2008;112(1):123–32.

58. Lehmann D., Nelsen J., Ramanath V. et al. Lack of attenuation in the antitumor effect of tamoxifen by chronic CYP isoform inhibition. J Clin Pharmacol 2004;44(8):861–5.

59. Stingl J.C., Parmar S., Huber-Wechselberger A. et al. Impact of CYP2D6*4 geno type on progression free survival in tamoxifen breast cancer treatment. Curr Med Res Opin 2010;26(11):2535–42.

60. Bijl M.J., van Schaik R.H., Lammers L.A. et al. The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users. Breast Cancer Res Treat 2009;118(1):125–30.

61. Schroth W., Antoniadou L., Fritz P. et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 2007;25(33):5187–93.

62. Martins D.M., Vidal F.C., Souza R.D. et al. Determination of CYP2D6 *3, *4, and *10 frequency in women with breast cancer in São Luís, Brazil, and its association with prognostic factors and diseasefree survival. Braz J Med Biol Res 2014;47(11):1008–15.

63. Nowell S., Ahn J., Rae J.M. et al. Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat 2005;91(3):249–58.

64. Wegman P., Elingarami S., Carstensen J. et al. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 2007;9(1):7.

65. Swen J.J., Nijenhuis M., de Boer A. Pharmacogenetics: from bench to byte – an update of guidelines. Clin Pharmacol Ther 2011;89(5):662–73.

66. Tamoxifen background summary Draft. Available at: www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4248b1-01-fdatamoxifenbackgroundsummaryfinal.pdf (Accessed September 15, 2006).


Для цитирования:


Любченко Л.Н., Филиппова М.Г., Шендрикова Т.А., Жукова Л.Г., Мехтиева Н.И., Крохина О.В., Портной С.М. Фармакогенетическое тестирование аллельных вариантов гена CYP2D6 при гормоноположительном раке молочной железы. Успехи молекулярной онкологии. 2017;4(3):57-66. https://doi.org/10.17650/2313-805X-2017-4-3-57-66

For citation:


Lyubchenko L.N., Filippova M.G., Shendrikova T.A., Zhukova L.G., Mekhtieva N.I., Krokhina O.V., Portnoy S.M. Pharmacogenetic testing of allelic variants of the CYP2D6 gene in hormone positive breast cancer. Advances in molecular oncology. 2017;4(3):57-66. (In Russ.) https://doi.org/10.17650/2313-805X-2017-4-3-57-66

Просмотров: 142


Creative Commons License
Контент доступен под лицензией Creative Commons Attribution 4.0 License.


ISSN 2313-805X (Print)
ISSN 2413-3787 (Online)