Ulyanovsk Medico-biological Journal

CLINICAL MEDICINE

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DOI 10.34014/2227-1848-2019-4-63-73

EXPRESSION LEVEL OF DRUG RESISTANCE GENES IN THE TUMOR OF OVARIAN CANCER PATIENTS AFTER NEOADJUVANT CHEMOTHERAPY

L.V. Poludnyakova, D.R. Dolgova, I.I. Antoneeva, T.V. Abakumova, I.O. Kolodiy

Ulyanovsk State University, Ulyanovsk, Russia

 

The purpose of the paper is to evaluate the relationship between the expression of drug resistance genes in the tumor tissue of patients with ovarian cancer after neoadjuvant chemotherapy (NAChT) with clinical and pathological disease parameters.

Materials and Methods. The study included 26 patients with ovarian cancer who had undergone NAChT according to the AP scheme. The authors used paired samples of normal and tumor ovatian tissue as material for their study. The expression level of ABCB1, ERCC1, and TOP2A genes was evaluated by real-time PCR.

Results. It was found out that in patients under 60 years of age, the level of ABCB1 expression is higher than in patients over 60. ERCC1 and TOP2A expression in different age groups was the same. The linkage between the studied genes, tumor size and metastasis was not discovered. TOP2A and ABCB1 expression levels in patients with and without relapses did not differ significantly. In patients with relapses, the level of ERCC1 expression is higher than in patients without relapses. In patients with a normal CA-125 value, the level of ERCC1 expression is lower than in patients with a high CA-125 value. An analysis of the linkage between the expression of the studied genes and the general and relapse-free patient survival did not give significant results.

Conclusion. The level of ABCB1expression is associated with the patients’ age, while the level of ERCC1expression is connected with disease recurrence and CA-125. In general, the expression of the studied genes weakly correlates with the main clinical and pathological disease parameters.

Keywords: ovarian cancer, neoadjuvant chemotherapy, expression, drug resistance genes ABCB1, ERCC1, TOP2A.

Conflict оf interest. The authors declare no conflict of interest.

 

References

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  20. Li D., Yuan Z., Chen S., Zhang C., Song L., Gao C., Chen Y., Tan C., Jiang Y. Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors. Bioorg. Med. Chem. 2017; 25 (13): 3437–3446.

  21. Konecny G.E., Pauletti C., Untch M., Wang H.-J., Modus V., Kulin W., Thomssen C., Harbeck N., Wang L., Apple S., Janicke F., Slamon D.J. Association between HER2, TOP2A, and response to antracycline-basedpreoperative chemotherapy in high-risk primary breast cancer. Breast Cancer Res. Treat. 2010; 120: 481–489.

  22. Ghisoni Е., Maggiorotto F., Borella F., eds. TOP2A as marker of response to pegylated lyposomal doxorubicin (PLD) in epithelial ovarian cancers. Journal of Ovarian Research. 2019; 12: 17.

  23. Chomczynski P., Sacchi N. The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: twenty-something years on. Nat. Protoc. 2006; 1 (2): 581–585.

  24. Pfaffl M.W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic acids research. 2001; 9 (9): 45.

  25. Moureau-Zabotto L., Ricci S., Lefranc J.P., Coulet F., Genestie C., Antoine M., Uzan S., Lotz J.P., Touboul E., Lacave R. Prognostic impact of multidrug resistance gene expression on the management of breast cancer in the context of adjuvant therapy based on a series of 171 patien. Br. J. Cancer. 2006; 94 (4): 473–480.

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Received 11 August 2019; Accepted 01 November 2019.

 

Information about the authors

Poludnyakova Lyudmila Viktorovna, Candidate of Sciences (Medicine), Associate Professor, Chair of Physiology and Pathophysiology, Ulyanovsk State University. 4321017, Russia, Ulyanovsk, L. Tolstoy St., 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0003-1320-9287

Dolgova Dinara Rishatovna, Candidate of Sciences (Biology), Associate Professor, Chair of Physiology and Pathophysiology, Ulyanovsk State University. 4321017, Russia, Ulyanovsk, L. Tolstoy St., 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0001-5475-7031

Antoneeva Inna Ivanovna, Doctor of Sciences (Medicine), Professor, Chair of Oncology and Radiation Diagnostics, Ulyanovsk State University. 4321017, Russia, Ulyanovsk, L. Tolstoy St., 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0002-1525-2070

Abakumova Tat'yana Vladimirovna, Candidate of Sciences (Biology), Associate Professor, Chair of Physiology and Pathophysiology, Ulyanovsk State University. 4321017, Russia, Ulyanovsk, L. Tolstoy St., 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0001-7559-5246

Kolodiy Irina Olegovna, 4th-year Student, Medical Department, Ulyanovsk State University. 4321017, Russia, Ulyanovsk, L. Tolstoy St., 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0002-8623-6027

 

For citation:

Poludnyakova L.V., Dolgova D.R., Antoneeva I.I., Abakumova T.V., Kolodiy I.O. Uroven' ekspressii genov lekarstvennoy ustoychivosti v opukholi bol'nykh rakom yaichnikov posle neoad"yuvantnoy khimioterapii [Expression level of drug resistance genes in the tumor of ovarian cancer patients after neoadjuvant chemotherapy]. Ulyanovsk Medico-Biological Journal. 2019; 4: 63–73. DOI: 10.34014/2227-1848-2019-4-63-73

 

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УДК 616-006.66:616-08-039.34

DOI 10.34014/2227-1848-2019-4-63-73

 

УРОВЕНЬ ЭКСПРЕССИИ ГЕНОВ ЛЕКАРСТВЕННОЙ УСТОЙЧИВОСТИ В ОПУХОЛИ БОЛЬНЫХ РАКОМ ЯИЧНИКОВ ПОСЛЕ НЕОАДЪЮВАНТНОЙ ХИМИОТЕРАПИИ

Л.В. Полуднякова, Д.Р. Долгова, И.И. Антонеева, Т.В. Абакумова, И.О. Колодий

ФГБОУ ВО «Ульяновский государственный университет», г. Ульяновск, Россия

 

Цель работы – оценка связи экспрессии генов лекарственной устойчивости в опухолевой ткани больных раком яичников после проведения неоадъювантной химиотерапии (НАХТ) с клинико-патологическими параметрами заболевания.

Материалы и методы. В исследование вошли 26 больных раком яичников после НАХТ по схеме АР. Материал для исследования – парные образцы нормальной и опухолевой ткани яичников. Уровень экспрессии генов ABCB1, ERCC1 и TOP2A оценивали при помощи ПЦР в реальном времени.

Результаты. Выявлено, что у больных до 60 лет уровень экспрессии гена ABCB1 выше, чем у больных старше 60 лет. Экспрессия ERCC1 и TOP2A в разных возрастных группах не отличалась. Не установлена связь изучаемых генов с размером опухоли и метастазированием. Уровень экспрессии генов TOP2A и ABCB1 у больных с рецидивами и без них достоверно не отличался. У больных с рецидивами уровень экспрессии ERCC1 выше, чем у больных без рецидивов. У больных с нормальным значением СА-125 уровень экспрессии ERCC1 ниже, чем у больных с высоким показателем. Анализ связи экспрессии исследуемых генов с общей и безрецидивной выживаемостью больных не дал значимых результатов.

Выводы. Уровень экспрессии гена ABCB1 связан с возрастом пациентов, а уровень экспрессии ERCC1 – с рецидивом заболевания и СА-125. В целом экспрессия изучаемых генов слабо коррелирует с основными клинико-патологическими параметрами заболевания.

Ключевые слова: рак яичников, неоадъювантная химиотерапия, экспрессия, гены лекарственной устойчивости ABCB1, ERCC1, ТОР2А.

Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.

 

Литература

  1. Momenimovahed Z., Tiznobaik А., Taheri S., Salehiniya H. Ovarian cancer in the world: epidemiology and risk factors. Int. J. Womens Health. 2019; 11: 287–299.

  2. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018; 68 (6): 394–424.

  3. Wenham R.M. Ovarian cancer: a bright future. Cancer Control. 2011; 18: 4–5.

  4. Morimoto A., Nagao S., Kogiku A. A preoperative low cancer antigen 125 level (<25.8 mg/dL) is useful criterion to determine the optimal timing of interval debulking surgery following neoadjuvant chemotherapy in epithelial ovarian cance. Jpn. J. Clin. Oncol. 2016; 46 (6): 517–521.

  5. Ledermann J.A., Raja F.A. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up 2013. Ann. Oncol. 2013; 24 (6): 24–32.

  6. Солопова А.Е., Чащин А.А., Солопова А.Г., Гуров С.Н., Макацария А.Д. Неоадъювантная химиотерапия рака яичников. Современные возможности и критерии отбора пациенток. Акушерство, гинекология и репродукция. 2016; 2: 44–54.

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  8. Schinkel A.H., Jonker J.W. Mammalian drug efflx transporters of the ATP binding cassette (ABC) family: an overview. Adv. Drug Deliv. Rev. 2003; 55 (1): 3–29.

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  10. Pan S.T., Li Z.L., He Z.X., Qiu J.X., Zhou S.F. Molecular mechanisms for tumour resistance to chemotherapy. Clin. Exp. Pharmacol. Physiol. 2016; 43 (8): 723–737.

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  13. Богуш Т.А., Стенина М.Б., Богуш Е.А., Заркуа В.Т., Калюжный С.А., Мамичев И.А., Тюляндина А.С., Тюляндин С.А. Количественные показатели экспрессии ERCC1 в ткани серозного рака яичников и эффективность I линии химиотерапии с включением препаратов платины. Антибиотики и химиотерапия. 2018; (1-2): 24–31.

  14. D’Incalci M., Galmarini C.M. Predicting cisplatin and trabectedin drug sensitivity in ovarian and colon cancers. Mol. Cancer Ther. 2008; 7 (1): 10–18.

  15. Хохлова С.В., Черкасова М.В., Орел Н.Ф., Лимарева С.В., Базаева И.Я., Горбунова В.А. Каким больным раком яичника показана комбинация трабектедина с пегилированным липосомальным доксорубицином. Вестник РАМН. 2013; 11: 115–121.

  16. Lee S.M., Falzon M., Blackhall F. Randomized prospective biomarker trial of ercc1 for comparing platinum and nonplatinum therapy in advanced non-small-cell lung cancer: ERCC1 trial (ET). J. Clin. Oncol. 2017; 35 (4): 402–411.

  17. Kang C.H., Jang B.G., Kim D.W. The prognostic significance of ERCC1, BRCA1, XRCC1, and betaIII-tubulin expression in patientswith non-small cell lung cancer treated by platinum- and taxane-basedneoadjuvant chemotherapy and surgical resection. Lung Cancer. 2010; 68 (3): 478–483.

  18. Богуш Т.А., Попова А.С., Дудко Е.А., Богуш Е.А., Тюляндина А.С., Тюляндин С.А. ERCC1 как маркер резистентности рака яичников к препаратам платины. Антибиотики и химиотерапия. 2015; 60 (3–4): 42–50.

  19. Северин С.Е. Биологическая химия. Москва; 2011. 624.

  20. Li D., Yuan Z., Chen S., Zhang C., Song L., Gao C., Chen Y., Tan C., Jiang Y. Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors. Bioorg. Med. Chem. 2017; 25 (13): 3437–3446.

  21. Konecny G.E., Pauletti C., Untch M., Wang H.-J., Modus V., Kulin W., Thomssen C., Harbeck N., Wang L., Apple S., Janicke F., Slamon D.J. Association between HER2, TOP2A, and response to antracycline-basedpreoperative chemotherapy in high-risk primary breast cancer. Breast Cancer Res. Treat. 2010; 120: 481–489.

  22. Ghisoni Е., Maggiorotto F., Borella F., eds. TOP2A as marker of response to pegylated lyposomal doxorubicin (PLD) in epithelial ovarian cancers. Journal of Ovarian Research. 2019; 12: 17.

  23. Chomczynski P., Sacchi N. The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: twenty-something years on. Nat. Protoc. 2006; 1 (2): 581–585.

  24. Pfaffl M.W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic acids research. 2001; 9 (9): 45.

  25. Moureau-Zabotto L., Ricci S., Lefranc J.P., Coulet F., Genestie C., Antoine M., Uzan S.,Lotz J.P., Touboul E., Lacave R. Prognostic impact of multidrug resistance gene expression on the management of breast cancer in the context of adjuvant therapy based on a series of 171 patien. Br. J. Cancer. 2006; 94 (4): 473–480.

  26. Литвяков Н.В. Регуляция экспрессии генов множественной лекарственной устойчивости в опухоли молочной железы при проведении неоадъювантной химиотерапии: дис. … д-ра биол. наук. Томск; 2014. 237.

  27. Chebouti I., Kuhlmann J.D., Buderath P. ERCC1-expressing circulating tumor cells as a potential diagnostic tool for monitoring response to platinum-based chemotherapy and for predicting post-therapeutic outcome of ovarian cancer. Oncotarget. 2017; 8 (15): 24303–24313.

  28. Du P., Wang Y., Chen L., Gan Y., Wu Q. High ERCC1 expression is associated with platinum-resistance, but not survival in patients with epithelial ovarian cancer. Oncol Lett. 2016; 12 (2): 857–862.

Поступила в редакцию 11.08.2019; принята 01.11.2019.

 

Авторский коллектив

Полуднякова Людмила Викторовна – кандидат биологических наук, доцент кафедры физиологии и патофизиологии, ФГБОУ ВО «Ульяновский государственный университет». 4321017, Россия, г. Ульяновск, ул. Л. Толстого, 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0003-1320-9287

Долгова Динара Ришатовна – кандидат биологических наук, доцент кафедры физиологии и патофизиологии, ФГБОУ ВО «Ульяновский государственный университет». 4321017, Россия, г. Ульяновск, ул. Л. Толстого, 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0001-5475-7031

Антонеева Инна Ивановна – доктор медицинских наук, профессор кафедры онкологии и лучевой диагностики, ФГБОУ ВО «Ульяновский государственный университет». 4321017, Россия, г. Ульяновск, ул. Л. Толстого, 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0002-1525-2070

Абакумова Татьяна Владимировна – кандидат биологических наук, доцент кафедры физиологии и патофизиологии, ФГБОУ ВО «Ульяновский государственный университет». 4321017, Россия, г. Ульяновск, ул. Л. Толстого, 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0001-7559-5246

Колодий Ирина Олеговна – студентка 4 курса медицинского факультета, ФГБОУ ВО «Ульяновский государственный университет». 4321017, Россия, г. Ульяновск, ул. Л. Толстого, 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0002-8623-6027

 

Образец цитирования

Полуднякова Л.В., Долгова Д.Р., Антонеева И.И., Абакумова Т.В., Колодий И.О. Уровень экспрессии генов лекарственной устойчивости в опухоли больных раком яичников после неоадъювантной химиотерапии. Ульяновский медико-биологический журнал. 2019; 4: 63–73. DOI: 10.34014/2227-1848-2019-4-63-73