吉非替尼對表皮生長因子受體在膽管上皮細胞中表達的影響及意義_《中國普外基礎與臨床雜志》

作者：

吳興武 ¹ , 徐亮 ² , 秦昱 ³ , 侯昌映 ³ , 徐茂林 ³ , 李富宇 ⁴

1.雙流縣第二人民醫院外三科(四川雙流 610200);;
2.瀘州醫學院附屬醫院普外科(四川瀘州 646000);;
3.雙流縣第一人民醫院普外科(四川雙流610200);;
4.四川大學華西醫院肝膽外科(成都 610041);;
項目指導和合作者;

關鍵詞：

肝內膽管結石吉非替尼表皮生長因子受體膽管上皮細胞慢性增生性膽管炎免疫組化法實時聚合酶鏈式反應法

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目的通過觀察吉非替尼對肝內病變膽管上皮細胞中表皮生長因子受體（EGFR）表達的影響，探討抑制膽管上皮細胞過度增殖的可行性。
方法選擇雙流縣第一人民醫院2006年8月至 2008年8月期間住院需要手術的肝內膽管結石患者共61例,年齡25～65歲(平均46.92歲)，隨機分為治療組和對照組。治療組30例，術中在病變膽管內留置細導管，術后灌注吉非替尼溶液；對照組31例只作T管引流。分別于術中、術后6周和12周行膽道鏡碎石及取石的同時，活檢灌注處的病變膽管壁組織，行HE染色、免疫組化和RT-PCR檢測，觀察組織學變化和EGFR的表達。
結果術中，2組膽管壁病理組織學改變及EGFR蛋白和mRNA表達無明顯差異。術后6周和12周，治療組的膽管黏膜上皮和黏膜下腺體增殖程度均較對照組明顯減弱，EGFR蛋白表達較對照組明顯減弱，EGFR mRNA表達明顯低于對照組（P lt;0.05）。
結論 EGFR在慢性增生性膽管炎中呈過表達狀態，術后局部持續給予吉非替尼治療能夠特異性地阻斷EGFR的激活和表達，能有效地抑制術后膽管上皮細胞的過度增殖。

引用本文： 吳興武,徐亮,秦昱,侯昌映,徐茂林,李富宇. 吉非替尼對表皮生長因子受體在膽管上皮細胞中表達的影響及意義. 中國普外基礎與臨床雜志, 2010, 17(5): 469-473. doi: 復制

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10.	Lu S, Yan L, Rao L, Xia T, et al. Down stream involvement of the bile duct in hepatolithiasis [J]. Chin Med J (Engl), 2002; 115(1): 62-64.
11.	Uchiyama K, Kawai M, Ueno M, et al. Reducing residual and recurrent stones by hepatectomy for hepatolithiasis [J]. J Gastrointest Surg, 2007; 11(5): 626-630.
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14.	Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network [J]. Nat Rev Mol Cell Biol, 2001; 2(2): 127-137.
15.	Hackel PO, Zwick E, Prenzel N, et al. Epidermal growth factor receptors: critical mediators of multiple receptor pathways [J]. Curr Opin Cell Biol, 1999; 11(2): 184-189.
16.	Moghal N, Sternberg PW. Multiple positive and negative regulators of signaling by the EGF-receptor [J]. Curr Opin Cell Biol, 1999; 11(2): 190-196.
17.	Ishii M, Vroman B, LaRusso NF. Morphologic demonstration of receptor-mediated endocytosis of epidermal growth factor by isolated bile duct epithelial cells [J]. Gastroenterology, 1990; 98(5 Pt 1): 1284-1291.
18.	Van Winkle LS, Isaac JM, Plopper CG. Distribution of epidermal growth factor receptor and ligands during bronchiolar epithelial repair from naphthalene-induced Clara cell injury in the mouse [J]. Am J Pathol, 1997; 151(2): 443-459.
19.	Giaccone G. HER1/EGFR-targeted agents: predicting the future for patients with unpredictable outcomes to therapy [J]. Ann Oncol, 2005; 16(4): 538-548.
20.	Hamdi MM, Mutungi GM. Dihydrotestosterone activates the mitogen activated protein kinase pathway and modulates maximum isometric force in isolated intact mouse skeletal muscle fibres through the epidermal growth factor receptor [J]. J Physiol [Epub ahead of print]. PMID: 20008468. doi: 10.1113/jphysiol.2009.182162.
21.	Kondratov KA, Chernorudskiy AL, Amosova AP, et al. Termination of tyrphostin AG1478 application results in different recovery of EGF receptor tyrosine residues 1 045 and 1 173 phosphorylation in A431 cells [J]. Cell Biol Int, 2010; 34(1): 81-87.
22.	Donnellan F, Keating N, Geoghegan P, et al. JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells [J]. Am J Physiol Gastrointest Liver Physiol, 2009 Oct 29[Epub ahead of print]. PMID: 19875701.
23.	正文, 朱明才, 湯為學, 等. 金雀異黃素與5-氟尿嘧啶對SGC-7901 細胞的抑制作用 [J]. 中國普外基礎與臨床雜志, 2008； 15（1）： 17-22.
24.	李龍, 岳紅梅, 余勤. 表皮生長因子受體抑制劑與肺纖維化 [J]. 國外醫學呼吸系統分冊, 2005; 25(5): 345-348.
25.	龍懷聰, 王曾禮. 表皮生長因子受體拮抗劑對氣道上皮細胞生長及修復的影響 [J]. 四川大學學報(醫學版), 2003; 34(2): 254-256.
26.	Fan ST, Choi TK, Lo CM, et al. Treatment of hepatolithiasis: improvement of result by a systematic approach [J]. Surgery, 1991; 109(4): 474-480.
27.	Douillard JY, Kim E, Hirsh V, et al. Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label Phase III study (INTEREST): PRS-02 [J]. J Thorac Oncol, 2007; 2(8): S305-S306.doi: 10.1097/01.JTO.0000283087.71346.19.
28.	Raymond E, Faivre S, Armand JP. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy [J]. Drugs, 2000; 60 Suppl 1: 15-23.
29.	Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer) [J]. Lancet, 2005; 366(9496): 1527-1537.
30.	Oguey D, Marti U, Reichen J. Epidermal growth factor receptor in chronic bile duct obstructed rats: implications for maintenance of hepatocellular mass [J]. Eur J Cell Biol, 1992; 59(1): 187-195.
31.	Matsumoto K, Fujii H, Michalopoulos G, et al. Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro [J]. Hepatology, 1994; 20(2): 376-368.

1. Mok T, Wu YL, Zhang L. A small step towards personalized medicine for non-small cell lung cancer [J]. Discov Med, 2009; 8(43): 227-231.
2. Chu Q, Amano O, Kanda Y, et al. Tumor-specific Cytotoxicity and Type of Cell Death Induced by Gefitinib in Oral Squamous Cell Carcinoma Cell Lines [J]. Anticancer Res, 2009; 29(12): 5023-5031.
3. Yang CT, Hung JY, Lai CL, et al. Gefitinib as first-line therapy for advanced or metastatic non-small cell lung cancer patients in Southern Taiwan [J]. Kaohsiung J Med Sci, 2010; 26(1): 1-7.
4. Herbst RS, Fukuoka M, Baselga J. Gefitinib－a novel targeted approach to treating cancer [J]. Nat Rev Cancer, 2004; 4(12): 956-965.
5. Yoon JH, Gwak GY, Lee HS, et al. Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells [J]. J Hepatol, 2004; 41(5): 808-814.
6. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase Ⅲ trial－INTACT 1 [J]. J Clin Oncol, 2004; 22(5): 777-784.
7. Hwang JH, Yoon YB, Kim YT, et al. Risk factors for recurrent cholangitis after initial hepatolithiasis treatment [J]. J Clin Gastroenterol, 2004; 38(4): 364-367.
8. Terada T, Nakanuma Y. Pathologic observations of intrahepatic peribiliary glands in 1 000 consecutive autopsy livers: Ⅳ. Hyperplasia of intramural and extramural glands [J]. Hum Pathol, 1992; 23(5): 483-490.
9. Terada T, Nakanuma Y. Innervation of intrahepatic bile ducts and peribiliary glands in normal human livers, extrahepatic biliary obstruction and hepatolithiasis. An immunohistochemical study [J]. J Hepatol, 1989; 9(2): 141-148.
10. Lu S, Yan L, Rao L, Xia T, et al. Down stream involvement of the bile duct in hepatolithiasis [J]. Chin Med J (Engl), 2002; 115(1): 62-64.
11. Uchiyama K, Kawai M, Ueno M, et al. Reducing residual and recurrent stones by hepatectomy for hepatolithiasis [J]. J Gastrointest Surg, 2007; 11(5): 626-630.
12. 貨師鵬. 受體研究技術 [M]. 北京: 北京大學醫學出版社, 2004: 275-277.
13. Schlessinger J. Cell signaling by receptor tyrosine kinases [J]. Cell, 2000; 103(2): 211-225.
14. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network [J]. Nat Rev Mol Cell Biol, 2001; 2(2): 127-137.
15. Hackel PO, Zwick E, Prenzel N, et al. Epidermal growth factor receptors: critical mediators of multiple receptor pathways [J]. Curr Opin Cell Biol, 1999; 11(2): 184-189.
16. Moghal N, Sternberg PW. Multiple positive and negative regulators of signaling by the EGF-receptor [J]. Curr Opin Cell Biol, 1999; 11(2): 190-196.
17. Ishii M, Vroman B, LaRusso NF. Morphologic demonstration of receptor-mediated endocytosis of epidermal growth factor by isolated bile duct epithelial cells [J]. Gastroenterology, 1990; 98(5 Pt 1): 1284-1291.
18. Van Winkle LS, Isaac JM, Plopper CG. Distribution of epidermal growth factor receptor and ligands during bronchiolar epithelial repair from naphthalene-induced Clara cell injury in the mouse [J]. Am J Pathol, 1997; 151(2): 443-459.
19. Giaccone G. HER1/EGFR-targeted agents: predicting the future for patients with unpredictable outcomes to therapy [J]. Ann Oncol, 2005; 16(4): 538-548.
20. Hamdi MM, Mutungi GM. Dihydrotestosterone activates the mitogen activated protein kinase pathway and modulates maximum isometric force in isolated intact mouse skeletal muscle fibres through the epidermal growth factor receptor [J]. J Physiol [Epub ahead of print]. PMID: 20008468. doi: 10.1113/jphysiol.2009.182162.
21. Kondratov KA, Chernorudskiy AL, Amosova AP, et al. Termination of tyrphostin AG1478 application results in different recovery of EGF receptor tyrosine residues 1 045 and 1 173 phosphorylation in A431 cells [J]. Cell Biol Int, 2010; 34(1): 81-87.
22. Donnellan F, Keating N, Geoghegan P, et al. JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells [J]. Am J Physiol Gastrointest Liver Physiol, 2009 Oct 29[Epub ahead of print]. PMID: 19875701.
23. 正文, 朱明才, 湯為學, 等. 金雀異黃素與5-氟尿嘧啶對SGC-7901 細胞的抑制作用 [J]. 中國普外基礎與臨床雜志, 2008； 15（1）： 17-22.
24. 李龍, 岳紅梅, 余勤. 表皮生長因子受體抑制劑與肺纖維化 [J]. 國外醫學呼吸系統分冊, 2005; 25(5): 345-348.
25. 龍懷聰, 王曾禮. 表皮生長因子受體拮抗劑對氣道上皮細胞生長及修復的影響 [J]. 四川大學學報(醫學版), 2003; 34(2): 254-256.
26. Fan ST, Choi TK, Lo CM, et al. Treatment of hepatolithiasis: improvement of result by a systematic approach [J]. Surgery, 1991; 109(4): 474-480.
27. Douillard JY, Kim E, Hirsh V, et al. Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label Phase III study (INTEREST): PRS-02 [J]. J Thorac Oncol, 2007; 2(8): S305-S306.doi: 10.1097/01.JTO.0000283087.71346.19.
28. Raymond E, Faivre S, Armand JP. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy [J]. Drugs, 2000; 60 Suppl 1: 15-23.
29. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer) [J]. Lancet, 2005; 366(9496): 1527-1537.
30. Oguey D, Marti U, Reichen J. Epidermal growth factor receptor in chronic bile duct obstructed rats: implications for maintenance of hepatocellular mass [J]. Eur J Cell Biol, 1992; 59(1): 187-195.
31. Matsumoto K, Fujii H, Michalopoulos G, et al. Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro [J]. Hepatology, 1994; 20(2): 376-368.

《中國普外基礎與臨床雜志》

吉非替尼對表皮生長因子受體在膽管上皮細胞中表達的影響及意義

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《中國普外基礎與臨床雜志》

吉非替尼對表皮生長因子受體在膽管上皮細胞中表達的影響及意義

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