• 1.雙流縣第二人民醫(yī)院外三科(四川雙流 610200);;
  • 2.瀘州醫(yī)學(xué)院附屬醫(yī)院普外科(四川瀘州 646000);;
  • 3.雙流縣第一人民醫(yī)院普外科(四川雙流610200);;
  • 4.四川大學(xué)華西醫(yī)院肝膽外科(成都 610041);;
  • 項(xiàng)目指導(dǎo)和合作者;

目的 通過觀察吉非替尼對(duì)肝內(nèi)病變膽管上皮細(xì)胞中表皮生長因子受體（EGFR）表達(dá)的影響，探討抑制膽管上皮細(xì)胞過度增殖的可行性。
方法 選擇雙流縣第一人民醫(yī)院2006年8月至 2008年8月期間住院需要手術(shù)的肝內(nèi)膽管結(jié)石患者共61例,年齡25～65歲(平均46.92歲)，隨機(jī)分為治療組和對(duì)照組。治療組30例，術(shù)中在病變膽管內(nèi)留置細(xì)導(dǎo)管，術(shù)后灌注吉非替尼溶液； 對(duì)照組31例只作T管引流。分別于術(shù)中、術(shù)后6周和12周行膽道鏡碎石及取石的同時(shí)，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(xué)變化和EGFR的表達(dá)。
結(jié)果 術(shù)中，2組膽管壁病理組織學(xué)改變及EGFR蛋白和mRNA表達(dá)無明顯差異。術(shù)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(duì)照組明顯減弱，EGFR蛋白表達(dá)較對(duì)照組明顯減弱，EGFR mRNA表達(dá)明顯低于對(duì)照組（P lt;0.05）。
結(jié)論 EGFR在慢性增生性膽管炎中呈過表達(dá)狀態(tài)，術(shù)后局部持續(xù)給予吉非替尼治療能夠特異性地阻斷EGFR的激活和表達(dá)，能有效地抑制術(shù)后膽管上皮細(xì)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(duì)表皮生長因子受體在膽管上皮細(xì)胞中表達(dá)的影響及意義. 中國普外基礎(chǔ)與臨床雜志, 2010, 17(5): 469-473. doi: 復(fù)制

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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(shù) [M]. 北京: 北京大學(xué)醫(yī)學(xué)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(xué), 等. 金雀異黃素與5-氟尿嘧啶對(duì)SGC-7901 細(xì)胞的抑制作用 [J]. 中國普外基礎(chǔ)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(yī)學(xué)呼吸系統(tǒng)分冊(cè), 2005; 25(5): 345-348.
25. 龍懷聰, 王曾禮. 表皮生長因子受體拮抗劑對(duì)氣道上皮細(xì)胞生長及修復(fù)的影響 [J]. 四川大學(xué)學(xué)報(bào)(醫(yī)學(xué)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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 12. 貨師鵬. 受體研究技術(shù) [M]. 北京: 北京大學(xué)醫(yī)學(xué)出版社, 2004: 275-277.
  13. 13. Schlessinger J. Cell signaling by receptor tyrosine kinases [J]. Cell, 2000; 103(2): 211-225.
  14. 14. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network [J]. Nat Rev Mol Cell Biol, 2001; 2(2): 127-137.
  15. 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. 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. 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. 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. 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. 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. 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. 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. 23. 正文, 朱明才, 湯為學(xué), 等. 金雀異黃素與5-氟尿嘧啶對(duì)SGC-7901 細(xì)胞的抑制作用 [J]. 中國普外基礎(chǔ)與臨床雜志, 2008； 15（1）： 17-22.
  24. 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(yī)學(xué)呼吸系統(tǒng)分冊(cè), 2005; 25(5): 345-348.
  25. 25. 龍懷聰, 王曾禮. 表皮生長因子受體拮抗劑對(duì)氣道上皮細(xì)胞生長及修復(fù)的影響 [J]. 四川大學(xué)學(xué)報(bào)(醫(yī)學(xué)版), 2003; 34(2): 254-256.
  26. 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. 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. 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. 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. 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. 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.