pharmjournalРазработка и регистрация лекарственных средствDrug development & registration2305-20662658-5049LLC «CPHA»10.33380/2305-2066-2022-11-4-253-260pharmjournal-1384Research ArticleДОКЛИНИЧЕСКИЕ И КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯPRECLINICAL AND CLINICAL STUDIESПрогностическая и предиктивная значимость экспрессии мРНК генов ABC-транспортеров у пациентов с немелкоклеточным раком легкогоPrognostic and Predictive Significance of mRNA Expression of ABC-transporter Genes in Patients with Non-small Cell Lung Cancerhttps://orcid.org/0000-0001-7419-4512ЦыгановМ. М.TsyganovM. M.

634009, г. Томск, пер. Кооперативный, д. 5; 634050, г. Томск, Московский тракт, д. 2

5, Kooperativny lane, Tomsk, 634009;2, Moscow tract, Tomsk, 634050

https://orcid.org/0000-0001-8815-2786ИбрагимоваМ. К.IbragimovaM. K.

634009, г. Томск, пер. Кооперативный, д. 5; 634050, г. Томск, пр. Ленина, д. 36; 634050, г. Томск, Московский тракт, д. 2

5, Kooperativny lane, Tomsk, 634009; 36, Lenina av., Tomsk, 634050;2, Moscow tract, Tomsk, 634050

imk1805@yandex.ruhttps://orcid.org/0000-0003-4980-8986РодионовЕ. О.RodionovE. O.

634009, г. Томск, пер. Кооперативный, д. 5

5, Kooperativny lane, Tomsk, 634009

https://orcid.org/0000-0003-3297-1680ФроловаА. А.FrolovaA. A.

634009, г. Томск, пер. Кооперативный, д. 5

5, Kooperativny lane, Tomsk, 634009

https://orcid.org/0000-0002-5365-9840МиллерС. В.MillerS. V.

634009, г. Томск, пер. Кооперативный, д. 5

5, Kooperativny lane, Tomsk, 634009

https://orcid.org/0000-0001-7234-4708ЧеремисинаО. В.CheremisinaO. V.

634009, г. Томск, пер. Кооперативный, д. 5

5, Kooperativny lane, Tomsk, 634009

https://orcid.org/0000-0002-0884-1838ТузиковС. А.TuzikovS. A.

634009, г. Томск, пер. Кооперативный, д. 5

5, Kooperativny lane, Tomsk, 634009

https://orcid.org/0000-0002-0714-8927ЛитвяковН. В.LitvyakovN. V.

634009, г. Томск, пер. Кооперативный, д. 5

5, Kooperativny lane, Tomsk, 634009

НИИ онкологии, ФГБНУ «Томский национальный исследовательский медицинский центр Российской академии наук» (Томский НИМЦ РАН); ФГБОУ ВО «Сибирский государственный медицинский университет» Министерства здравоохранения Российской Федерации (ФГБОУ ВО СибГМУ Минздрава России)Research Institute of Oncology, Federal State Budgetary Scientific Institution «Tomsk National Research Center for Medicine by the Russian Academy of Sciences»; Siberian State Medical University, SSMUНИИ онкологии, ФГБНУ «Томский национальный исследовательский медицинский центр Российской академии наук» (Томский НИМЦ РАН); ФГАОУ ВО «Национальный исследовательский Томский государственный университет» (ТГУ); ФГБОУ ВО «Сибирский государственный медицинский университет» Министерства здравоохранения Российской Федерации (ФГБОУ ВО СибГМУ Минздрава России)Research Institute of Oncology, Federal State Budgetary Scientific Institution «Tomsk National Research Center for Medicine by the Russian Academy of Sciences»; The National Research Tomsk State University, TSU; Siberian State Medical University, SSMUНИИ онкологии, ФГБНУ «Томский национальный исследовательский медицинский центр Российской академии наук» (Томский НИМЦ РАН)Research Institute of Oncology, Federal State Budgetary Scientific Institution «Tomsk National Research Center for Medicine by the Russian Academy of Sciences»202227112022114253260Copyright © Цыганов М.М., Ибрагимова М.К., Родионов Е.О., Фролова А.А., Миллер С.В., Черемисина О.В., Тузиков С.А., Литвяков Н.В., 20222022Цыганов М.М., Ибрагимова М.К., Родионов Е.О., Фролова А.А., Миллер С.В., Черемисина О.В., Тузиков С.А., Литвяков Н.В.Tsyganov M.M., Ibragimova M.K., Rodionov E.O., Frolova A.A., Miller S.V., Cheremisina O.V., Tuzikov S.A., Litvyakov N.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmjournal.ru/jour/article/view/1384Введение

Введение. На сегодняшний день одной из причин неэффективности проводимой химиотерапии при разных злокачественных новообразованиях, в том числе и при раке легкого, считают формирование фенотипа множественной лекарственной устойчивости (МЛУ) у опухолевых клеток, которая обусловлена экспрессией генов ABC-транспортеров.

Цель

Цель. Целью работы явилась оценка экспрессии генов ABC-транспортеров в процессе химиотерапии и анализ связи с эффективностью химиотерапии и прогнозом заболевания.

Материалы и методы

Материалы и методы. В работе был использован биопсийный и операционный материал от 91 больного немелкоклеточным раком легкого (НМРЛ) IIВ–IIIА стадии. В схему лечения было включено 2 курса неоадъювантной химиотерапии (НХТ), операция и 3 курса адъювантной химиотерапии (АХТ) «платиновыми дуплетами». Из образцов выделяли РНК с последующей постановкой количественной ПЦР для оценки экспрессии генов ABCB1, ABCC1, ABCC2, ABCC5, ABCG1, ABCG2.

Результаты и обсуждение

Результаты и обсуждение. Показано, что уровень экспрессии исследуемых генов не связан с эффектом НХТ у больных раком легкого, кроме гена ABCC5, у которого показана связь на уровне выраженной тенденции (p = 0,07). Так же было показано, что в группе больных с объективным ответом на химиотерапию частота снижения экспрессии генов ABCC1 (p = 0,01) и ABCC5 (p = 0,004) статистически значимо выше по сравнению с группой пациентов со стабилизацией. Далее методом Каплана – Майера было установлено, что снижение экспрессии связано с высокими показателями безметастатической выживаемостью (БМВ). Наибольшие показатели 5-летней БМВ (более 85 %) отмечаются у пациентов со снижением экспрессии генов ABCB1 и ABCG2, log-rank test p = 0,0007 и p = 0,002 соответственно.

Заключение

Заключение. Таким образом, показано, что изменение экспрессии генов ABC-транспортеров связано с эффективностью химиотерапии и прогнозом заболевания. Полученные данные могут быть использованы в качестве основы для обнаружения потенциальных мишеней для лекарственных средств.  

Introduction

Introduction. To date, one of the reasons for the ineffectiveness of chemotherapy in various malignant neoplasms, including lung cancer, is the formation of the multidrug resistance (MDR) phenotype in tumor cells, which is caused by the expression of ABC transporter genes.

Aim

Aim. The aim of this work was to assess the expression of ABC-transporter genes during chemotherapy and to analyze the relationship with the effectiveness of chemotherapy and prognosis of the disease.

Materials and methods

Materials and methods. We used biopsy and surgical material from 91 patients with stage IIB–IIIA non-small cell lung cancer (NSCLC). The treatment regimen included: 2 courses of neoadjuvant chemotherapy (NAC), surgery and 3 courses of adjuvant chemotherapy (ACT) with platinum doublets. RNA was isolated from the samples, followed by quantitative PCR to assess the expression of genes ABCB1, ABCC1, ABCC2, ABCC5, ABCG1, ABCG2.

Results and discussion

Results and discussion. It was shown that the level of expression of the studied genes was not associated with the effect of NAC in patients with lung cancer, except for the ABCC5 gene, which showed a relationship at the level of a pronounced trend (p = 0.07). It was also shown that in the group of patients with an objective response to chemotherapy, the frequency of decreased expression of the ABCC1 (p = 0.01) and ABCC5 (p = 0.004) genes was statistically significantly higher than in the group of patients with stabilization. Further, using the Kaplan – Meier method, it was found that a decrease in expression is associated with high rates of metastatic-free survival (MFS). The highest rates of 5-year MFS (more than 85 %) are observed in patients with a decrease in the expression of the ABCB1 and ABCG2 genes, log-rank test p = 0.0007 and p = 0.002, respectively.

Conclusion

Conclusion. Thus, it has been shown that changes in the expression of ABC transporter genes are associated with the effectiveness of chemotherapy and the prognosis of the disease. The data obtained can be used as a basis for the detection of potential drug targets.

экспрессия геновнемелкоклеточный рак легкогоABC-транспортерыпрогноз заболеванияэффект химиотерапииgene expressionnon-small cell lung cancerABC transportersdisease prognosiseffect of chemotherapyРабота поддержана грантом РФФИ № 20-015-00023 «Исследование роли вируса папилломы человека (ВПЧ) в канцерогенезе немелкоклеточного рака легкого».This work was supported by grant number 20-015-00023 RFBR «Study of the role of human papillomavirus (HPV) in the carcinogenesis of non-small cell lung cancer».ReferencesDuma N., Santana-Davila R., Molina J. R. Non–small cell lung cancer: epidemiology, screening, diagnosis, and treatment. Mayo Clinic Proceedings. 2019;94(8):1623–1640. DOI: 10.1016/j.mayocp.2019.01.013.Duma N., Santana-Davila R., Molina J. R. Non–small cell lung cancer: epidemiology, screening, diagnosis, and treatment. Mayo Clinic Proceedings. 2019;94(8):1623–1640. DOI: 10.1016/j.mayocp.2019.01.013.Brandt W. S., Yan W., Zhou J., Tan K. S., Montecalvo J., Park B. J., Adusumilli P. S., Huang J., Bott M. J., Rusch V. W., Molena D., Travis W. D., Kris M. G., Chaft J. E., Jones D. R. Outcomes after neoadjuvant or adjuvant chemotherapy for cT2-4N0-1 non–small cell lung cancer: a propensity-matched analysis. The Journal of Thoracic and Cardiovascular Surgery. 2019;157(2):743–753. DOI: 10.1016/j.jtcvs.2018.09.098.Brandt W. S., Yan W., Zhou J., Tan K. S., Montecalvo J., Park B. J., Adusumilli P. S., Huang J., Bott M. J., Rusch V. W., Molena D., Travis W. D., Kris M. G., Chaft J. E., Jones D. R. Outcomes after neoadjuvant or adjuvant chemotherapy for cT2-4N0-1 non–small cell lung cancer: a propensity-matched analysis. The Journal of Thoracic and Cardiovascular Surgery. 2019;157(2):743–753. DOI: 10.1016/j.jtcvs.2018.09.098.Maclean M., Luo X., Wang S., Kernstine K., Gerber D. E., Xie Y. Outcomes of neoadjuvant and adjuvant chemotherapy in stage 2 and 3 non-small cell lung cancer: an analysis of the National Cancer Database. Oncotarget. 2018;9(36):24470–24479. DOI: 10.18632/oncotarget.25327.Maclean M., Luo X., Wang S., Kernstine K., Gerber D. E., Xie Y. Outcomes of neoadjuvant and adjuvant chemotherapy in stage 2 and 3 non-small cell lung cancer: an analysis of the National Cancer Database. Oncotarget. 2018;9(36):24470–24479. DOI: 10.18632/oncotarget.25327.Pisters K., Kris M. G., Gralla R. J., Zaman M. B., Heelan R. T., Martini N. Pathologic complete response in advanced non-small-cell lung cancer following preoperative chemotherapy: implications for the design of future non-small-cell lung cancer combined modality trials. Journal of Clinical Oncology. 1993;11(9):1757–1762. DOI: 10.1200/JCO.1993.11.9.1757.Pisters K., Kris M. G., Gralla R. J., Zaman M. B., Heelan R. T., Martini N. Pathologic complete response in advanced non-small-cell lung cancer following preoperative chemotherapy: implications for the design of future non-small-cell lung cancer combined modality trials. Journal of Clinical Oncology. 1993;11(9):1757–1762. DOI: 10.1200/JCO.1993.11.9.1757.Roth J. A., Fossella F., Komaki R., Ryan M. B., Putnam Jr. J., Lee J. S., Dhingra H., De Caro L., Chasen M., McGavran M., Atkinson E. N., Hong W. K. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. JNCI: Journal of the National Cancer Institute. 1994;86(9):673–680. DOI: 10.1093/jnci/86.9.673.Roth J. A., Fossella F., Komaki R., Ryan M. B., Putnam Jr. J., Lee J. S., Dhingra H., De Caro L., Chasen M., McGavran M., Atkinson E. N., Hong W. K. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. JNCI: Journal of the National Cancer Institute. 1994;86(9):673–680. DOI: 10.1093/jnci/86.9.673.Rosell R., Gomez-Codina J., Camps C., Maestre J., Padille J., Canto A., Mate J. L., Li S., Roig J., Olazabal A., Canela M., Ariza A., Skacel Z., Morera-Prat J., Abad A. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. New England Journal of Medicine. 1994;330(3):153–158. DOI: 10.1056/NEJM199401203300301.Rosell R., Gomez-Codina J., Camps C., Maestre J., Padille J., Canto A., Mate J. L., Li S., Roig J., Olazabal A., Canela M., Ariza A., Skacel Z., Morera-Prat J., Abad A. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. New England Journal of Medicine. 1994;330(3):153–158. DOI: 10.1056/NEJM199401203300301.Douillard J.-Y., Rosell R., De Lena M., Carpagnano F., Ramlau R., Gonzáles-Larriba J. L., Grodzki T., Pereira J. R., Le Groumellec A., Lorusso V., Clary C., Torres A. J., Dahabreh J., Souquet P.-J., Astudillo J., Fournel P., Artal-Cortes A., Jassem J., Koubkova L., His P., Riggi M., Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. The lancet oncology. 2006;7(9):719–727. DOI: 10.1016/S1470-2045(06)70804-X.Douillard J.-Y., Rosell R., De Lena M., Carpagnano F., Ramlau R., Gonzáles-Larriba J. L., Grodzki T., Pereira J. R., Le Groumellec A., Lorusso V., Clary C., Torres A. J., Dahabreh J., Souquet P.-J., Astudillo J., Fournel P., Artal-Cortes A., Jassem J., Koubkova L., His P., Riggi M., Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. The lancet oncology. 2006;7(9):719–727. DOI: 10.1016/S1470-2045(06)70804-X.Pirker R., Filipits M. Adjuvant therapy in patients with completely resected non–small-cell lung cancer: current status and perspectives. Clinical lung cancer. 2019;20(1):1–6. DOI: 10.1016/j.cllc.2018.09.016.Pirker R., Filipits M. Adjuvant therapy in patients with completely resected non–small-cell lung cancer: current status and perspectives. Clinical lung cancer. 2019;20(1):1–6. DOI: 10.1016/j.cllc.2018.09.016.Litviakov N. V., Cherdyntseva N. V., Tsyganov M. M., Denisov E. V., Garbukov E. Y., Merzliakova M. K., Volkomorov V. V., Vtorushin S. V., Zavyalova M. V., Slonimskaya E. M., Perelmuter V. M. Changing the expression vector of multidrug resistance genes is related to neoadjuvant chemotherapy response. Cancer chemotherapy and pharmacology. 2013;71(1):153–163. DOI: 10.1007/s00280-012-1992-x.Litviakov N. V., Cherdyntseva N. V., Tsyganov M. M., Denisov E. V., Garbukov E. Y., Merzliakova M. K., Volkomorov V. V., Vtorushin S. V., Zavyalova M. V., Slonimskaya E. M., Perelmuter V. M. Changing the expression vector of multidrug resistance genes is related to neoadjuvant chemotherapy response. Cancer chemotherapy and pharmacology. 2013;71(1):153–163. DOI: 10.1007/s00280-012-1992-x.Slonimskaya E. M., Kazantseva P. V., Litviakov N. V., Tsyganov M. M., Ibragimova M. K., Doroshenko A. V., Vernadsky R. U., Vostrikova M. A., Lushnikova N. A. Experience of personalized appointment of neoadjuvant chemotherapy for patient with breast cancer: a prospective study. Farmateka. 2018;7:64–70. (In Russ.)Slonimskaya E. M., Kazantseva P. V., Litviakov N. V., Tsyganov M. M., Ibragimova M. K., Doroshenko A. V., Vernadsky R. U., Vostrikova M. A., Lushnikova N. A. Experience of personalized appointment of neoadjuvant chemotherapy for patient with breast cancer: a prospective study. Farmateka. 2018;7:64–70. (In Russ.)Đanić M., Mikov M. Biotransformation of Xenobiotics in Living Systems—Metabolism of Drugs: Partnership of Liver and Gut Microflora. Pharmaceutical Biocatalysis. 2020;1(1):129–166.Đanić M., Mikov M. Biotransformation of Xenobiotics in Living Systems—Metabolism of Drugs: Partnership of Liver and Gut Microflora. Pharmaceutical Biocatalysis. 2020;1(1):129–166.Vtorushin S., Khristenko K., Zavyalova M., Perelmuter V., Litviakov N., Denisov E., Dulesova A., Cherdyntseva N. The phenomenon of multi-drug resistance in the treatment of malignant tumors. Experimental Oncology. 2014;36(3):144–156.Vtorushin S., Khristenko K., Zavyalova M., Perelmuter V., Litviakov N., Denisov E., Dulesova A., Cherdyntseva N. The phenomenon of multi-drug resistance in the treatment of malignant tumors. Experimental Oncology. 2014;36(3):144–156.Schwartz G. F., Hortobagyi G. N. Proceedings of the consensus conference on neoadjuvant chemotherapy in carcinoma of the breast, April 26–28, 2003, Philadelphia, Pennsylvania. Cancer. 2004;100(4):2512–2532. DOI: 10.1002/cncr.20298.Schwartz G. F., Hortobagyi G. N. Proceedings of the consensus conference on neoadjuvant chemotherapy in carcinoma of the breast, April 26–28, 2003, Philadelphia, Pennsylvania. Cancer. 2004;100(4):2512–2532. DOI: 10.1002/cncr.20298.Pfaffl M. W. A new mathematical model for relative quantification in real-time RT–PCR. Nucleic acids research. 2001;29(9):e45. DOI: 10.1093/nar/29.9.e45.Pfaffl M. W. A new mathematical model for relative quantification in real-time RT–PCR. Nucleic acids research. 2001;29(9):e45. DOI: 10.1093/nar/29.9.e45.Robey R. W., Pluchino K. M., Hall M. D., Fojo A. T., Bates S. E., Gottesman M. M. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nature Reviews Cancer. 2018;18(7):452–464. DOI: 10.1038/s41568-018-0005-8.Robey R. W., Pluchino K. M., Hall M. D., Fojo A. T., Bates S. E., Gottesman M. M. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nature Reviews Cancer. 2018;18(7):452–464. DOI: 10.1038/s41568-018-0005-8.Fung S. W., Cheung P. F.-Y., Yip C. W., Ng L. W.-C., Cheung T. T., Chong C. C.-N., Lee C., Bo-San Lai P., Chan A. W.-H., Tsao G. S.-W., Wong C.-H., Chan S. L., Lo K. W., Cheung S. T. The ATP-binding cassette transporter ABCF1 is a hepatic oncofetal protein that promotes chemoresistance, EMT and cancer stemness in hepatocellular carcinoma. Cancer letters. 2019;457:98–109. DOI: 10.1016/j.canlet.2019.05.010.Fung S. W., Cheung P. F.-Y., Yip C. W., Ng L. W.-C., Cheung T. T., Chong C. C.-N., Lee C., Bo-San Lai P., Chan A. W.-H., Tsao G. S.-W., Wong C.-H., Chan S. L., Lo K. W., Cheung S. T. The ATP-binding cassette transporter ABCF1 is a hepatic oncofetal protein that promotes chemoresistance, EMT and cancer stemness in hepatocellular carcinoma. Cancer letters. 2019;457:98–109. DOI: 10.1016/j.canlet.2019.05.010.Bruckmueller H., Cascorbi I. ABCB1, ABCG2, ABCC1, ABCC2, and ABCC3 drug transporter polymorphisms and their impact on drug bioavailability: what is our current understanding? Expert opinion on drug metabolism & toxicology. 2021;17(4):369–396. DOI: 10.1080/17425255.2021.1876661.Bruckmueller H., Cascorbi I. ABCB1, ABCG2, ABCC1, ABCC2, and ABCC3 drug transporter polymorphisms and their impact on drug bioavailability: what is our current understanding? Expert opinion on drug metabolism & toxicology. 2021;17(4):369–396. DOI: 10.1080/17425255.2021.1876661.Zawadzka I., Jeleń A., Pietrzak J., Żebrowska-Nawrocka M., Michalska K., Szmajda-Krygier D., Mirowski M., Łochowski M., Kozak J., Balcerczak E. The impact of ABCB1 gene polymorphism and its expression on non-small-cell lung cancer development, progression and therapy – preliminary report. Scientific reports. 2020;10(1). DOI: 10.1038/s41598-020-63265-4.Zawadzka I., Jeleń A., Pietrzak J., Żebrowska-Nawrocka M., Michalska K., Szmajda-Krygier D., Mirowski M., Łochowski M., Kozak J., Balcerczak E. The impact of ABCB1 gene polymorphism and its expression on non-small-cell lung cancer development, progression and therapy – preliminary report. Scientific reports. 2020;10(1). DOI: 10.1038/s41598-020-63265-4.Yao S., Sucheston L. E., Zhao H., Barlow W. E., Zirpoli G., Liu S., Moore H. C. F., Budd G. T., Hershman D. L., Davis W. Ciupak G. L., Stewart J. A., Isaacs C., Hobday T. J., Salim M., Hortobagyi G. N., Gralow J. R., Livingston R. B., Albain K. S., Hayes D. F., Ambrosone C. B. Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer. The pharmacogenomics journal. 2014;14(3):241–247. DOI: 10.1038/tpj.2013.32.Yao S., Sucheston L. E., Zhao H., Barlow W. E., Zirpoli G., Liu S., Moore H. C. F., Budd G. T., Hershman D. L., Davis W. Ciupak G. L., Stewart J. A., Isaacs C., Hobday T. J., Salim M., Hortobagyi G. N., Gralow J. R., Livingston R. B., Albain K. S., Hayes D. F., Ambrosone C. B. Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer. The pharmacogenomics journal. 2014;14(3):241–247. DOI: 10.1038/tpj.2013.32.Vesel M., Rapp J., Feller D., Kiss E., Jaromi L., Meggyes M., Miskei G., Duga B., Smuk G., Laszlo T., Karner I., Pongracz J. E. ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling. Respiratory research. 2017;18(1). DOI: 10.1186/s12931-017-0537-6.Vesel M., Rapp J., Feller D., Kiss E., Jaromi L., Meggyes M., Miskei G., Duga B., Smuk G., Laszlo T., Karner I., Pongracz J. E. ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling. Respiratory research. 2017;18(1). DOI: 10.1186/s12931-017-0537-6.Han J.-Y., Lim H.-S., Yoo Y.-K., Shin E. S., Park Y. H., Lee S. Y., Lee J.-E., Lee D. H., Kim H. T., Lee J. S., Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. Cancer. 2007;110(1):138–147. DOI: 10.1002/cncr.22760.Han J.-Y., Lim H.-S., Yoo Y.-K., Shin E. S., Park Y. H., Lee S. Y., Lee J.-E., Lee D. H., Kim H. T., Lee J. S., Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. Cancer. 2007;110(1):138–147. DOI: 10.1002/cncr.22760.

The authors declare that there are no conflicts of interest present.