Application of Molecular Targeted Drugs in Therapy of Hepatocellular Carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

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高军

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肝细胞癌; 分子靶向治疗; 索拉非尼; 血管内皮生长因子; 表皮生长因子

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Citation： 高军. Application of Molecular Targeted Drugs in Therapy of Hepatocellular Carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2011, 18(5): 560-563. doi: Copy

1.	Parkin DM. Global cancer statistics in the year 2000 [J]. Lancet Oncol， 2001， 2（9）: 533543.
2.	ElSerag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis [J]. Gastroenterology， 2007， 132（7）: 25572576.
3.	Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma [J]. Nat Genet， 2002， 31（4）: 339346.
4.	Villanueva A, Minguez B, Forner A, et al. Hepatocellular carcinoma: novel molecular approaches for diagnosis, prognosis, and therapy [J]. Annu Rev Med， 2010， 61: 317328.
5.	Tommasi S, Pinto R, Pilato B, et al. Molecular pathways and related target therapies in liver carcinoma [J]. Curr Pharm Des， 2007， 13（32）: 32793287.
6.	Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib improves survival advanced: Results of a phaseⅢ randomized placebocontrolled trial [C]. 2007 ASCO Annual Meeting Proceeding Part 1 vol 25. No18S.
7.	Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the AsiaPacific region with advanced hepatocellular carcinoma: a phase Ⅲrandomised, doubleblind, placebocontrolled trial [J]. Lancet Oncol， 2009， 10（1）: 2534.
8.	AbouAlfa GK, Schwartz L, Ricci S, et al. Phase Ⅱ study of sorafenib in patients with advanced hepatocellular carcinoma [J]. J Clin Oncol， 2006， 24（26): 42934300.
9.	Pinter M, Sieghart W, Graziadei I, et al. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis [J]. Oncologist， 2009， 14（1）: 7076.
10.	Miller AA, Murry DJ, Owzar K, et al. Phase Ⅰ and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301 [J]. J Clin Oncol， 2009， 27（11）: 18001805.
11.	Zhu AX, Sahani DV, Duda DG, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase Ⅱ study [J]. J Clin Oncol， 2009， 27（18）: 30273035.
12.	Faivre S, Raymond E, Boucher E, et al. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an openlabel, multicentre, phase Ⅱ study [J]. Lancet Oncol， 2009， 10（8）: 794800.
13.	Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGFspecific antibody bevacizumab has antivascular effects in human rectal cancer [J]. Nat Med， 2004， 10（2）:145147.
14.	Siegel AB, Cohen EI, Ocean A, et al. Phase Ⅱ trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma [J]. J Clin Oncol， 2008， 26（18）: 29922998.
15.	Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase Ⅱstudy of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma [J]. J Clin Oncol， 2006， 24（12）: 18981903.
16.	Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase Ⅱ study [J]. Cancer， 2007， 109（7）: 13841390.
17.	Altimari A, Fiorentino M, Gabusi E, et al. Investigation of ErbB1 and ErbB2 expression for therapeutic targeting in primary liver tumours [J]. Dig Liver Dis， 2003， 35（5）: 332338.
18.	Buckley AF, Burgart LJ, Sahai V, et al. Epidermal growth factor receptor expression and gene copy number in conventional hepatocellular carcinoma [J]. Am J Clin Pathol， 2008， 129（2）: 245251.
19.	Schiffer E, Housset C, Cacheux W, et al. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis [J]. Hepatology， 2005， 41（2）: 307314.
20.	Philip PA, Mahoney MR, Allmer C, et al. Phase Ⅱ study of Erlotinib (OSI774) in patients with advanced hepatocellular cancer [J]. J Clin Oncol， 2005， 23（27）: 66576663.
21.	Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma [J]. Cancer， 2007， 110（5）: 10591067.
22.	Thomas MB, Morris JS, Chadha R, et al. Phase Ⅱ trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma [J]. J Clin Oncol， 2009， 27（6）: 843850.
23.	Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma [J]. Cancer， 2007， 110（3）: 581589.
24.	Asnacios A, Fartoux L, Romano O, et al. Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: results of a multicenter phase 2 study [J]. Cancer， 2008， 112（12）: 27332739.
25.	Villanueva A, Chiang DY, Newell P, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma [J]. Gastroenterology， 2008， 135（6）: 19721983.
26.	Nocera A, Andorno E, Tagliamacco A, et al. Sirolimus therapy in liver transplant patients: an initial experience at a single center [J]. Transplant Proc， 2008， 40（6）: 19501952.
27.	Zhou J, Wang Z, Wu ZQ, et al. Sirolimusbased immunosuppression therapy in liver transplantation for patients with hepatocellular carcinoma exceeding the Milan criteria [J]. Transplant Proc， 2008， 40（10）: 35483553.
28.	Rizell M, Andersson M, Cahlin C, et al. Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer [J]. Int J Clin Oncol， 2008， 13（1）: 6670.
29.	Huynh H, Ngo VC, Koong HN, et al. Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma [J]. J Cell Mol Med， 2009， 13（8B）: 26732683.
30.	Arnault JP, Wechsler J, Escudier B, et al. Keratoacanthomas and squamous cell carcinomas in patients receiving sorafenib [J]. J Clin Oncol， 2009， 27（23）: e59e61.
31.	Sosman JA, Puzanov I, Atkins MB. Opportunities and obstacles to combination targeted therapy in renal cell cancer [J]. Clin Cancer Res， 2007， 13（2 Pt 2）: 764s769s.
32.	Camp ER, Summy J, Bauer TW, et al. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor [J]. Clin Cancer Res， 2005， 11（1）: 397405.
33.	Azad NS, Posadas EM, Kwitkowski VE, et al. Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity [J]. J Clin Oncol， 2008， 26（22）: 37093714.
34.	Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma [J]. J Natl Cancer Inst， 2008， 100（10）: 698711.

1. Parkin DM. Global cancer statistics in the year 2000 [J]. Lancet Oncol， 2001， 2（9）: 533543.
2. ElSerag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis [J]. Gastroenterology， 2007， 132（7）: 25572576.
3. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma [J]. Nat Genet， 2002， 31（4）: 339346.
4. Villanueva A, Minguez B, Forner A, et al. Hepatocellular carcinoma: novel molecular approaches for diagnosis, prognosis, and therapy [J]. Annu Rev Med， 2010， 61: 317328.
5. Tommasi S, Pinto R, Pilato B, et al. Molecular pathways and related target therapies in liver carcinoma [J]. Curr Pharm Des， 2007， 13（32）: 32793287.
6. Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib improves survival advanced: Results of a phaseⅢ randomized placebocontrolled trial [C]. 2007 ASCO Annual Meeting Proceeding Part 1 vol 25. No18S.
7. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the AsiaPacific region with advanced hepatocellular carcinoma: a phase Ⅲrandomised, doubleblind, placebocontrolled trial [J]. Lancet Oncol， 2009， 10（1）: 2534.
8. AbouAlfa GK, Schwartz L, Ricci S, et al. Phase Ⅱ study of sorafenib in patients with advanced hepatocellular carcinoma [J]. J Clin Oncol， 2006， 24（26): 42934300.
9. Pinter M, Sieghart W, Graziadei I, et al. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis [J]. Oncologist， 2009， 14（1）: 7076.
10. Miller AA, Murry DJ, Owzar K, et al. Phase Ⅰ and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301 [J]. J Clin Oncol， 2009， 27（11）: 18001805.
11. Zhu AX, Sahani DV, Duda DG, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase Ⅱ study [J]. J Clin Oncol， 2009， 27（18）: 30273035.
12. Faivre S, Raymond E, Boucher E, et al. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an openlabel, multicentre, phase Ⅱ study [J]. Lancet Oncol， 2009， 10（8）: 794800.
13. Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGFspecific antibody bevacizumab has antivascular effects in human rectal cancer [J]. Nat Med， 2004， 10（2）:145147.
14. Siegel AB, Cohen EI, Ocean A, et al. Phase Ⅱ trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma [J]. J Clin Oncol， 2008， 26（18）: 29922998.
15. Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase Ⅱstudy of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma [J]. J Clin Oncol， 2006， 24（12）: 18981903.
16. Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase Ⅱ study [J]. Cancer， 2007， 109（7）: 13841390.
17. Altimari A, Fiorentino M, Gabusi E, et al. Investigation of ErbB1 and ErbB2 expression for therapeutic targeting in primary liver tumours [J]. Dig Liver Dis， 2003， 35（5）: 332338.
18. Buckley AF, Burgart LJ, Sahai V, et al. Epidermal growth factor receptor expression and gene copy number in conventional hepatocellular carcinoma [J]. Am J Clin Pathol， 2008， 129（2）: 245251.
19. Schiffer E, Housset C, Cacheux W, et al. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis [J]. Hepatology， 2005， 41（2）: 307314.
20. Philip PA, Mahoney MR, Allmer C, et al. Phase Ⅱ study of Erlotinib (OSI774) in patients with advanced hepatocellular cancer [J]. J Clin Oncol， 2005， 23（27）: 66576663.
21. Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma [J]. Cancer， 2007， 110（5）: 10591067.
22. Thomas MB, Morris JS, Chadha R, et al. Phase Ⅱ trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma [J]. J Clin Oncol， 2009， 27（6）: 843850.
23. Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma [J]. Cancer， 2007， 110（3）: 581589.
24. Asnacios A, Fartoux L, Romano O, et al. Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: results of a multicenter phase 2 study [J]. Cancer， 2008， 112（12）: 27332739.
25. Villanueva A, Chiang DY, Newell P, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma [J]. Gastroenterology， 2008， 135（6）: 19721983.
26. Nocera A, Andorno E, Tagliamacco A, et al. Sirolimus therapy in liver transplant patients: an initial experience at a single center [J]. Transplant Proc， 2008， 40（6）: 19501952.
27. Zhou J, Wang Z, Wu ZQ, et al. Sirolimusbased immunosuppression therapy in liver transplantation for patients with hepatocellular carcinoma exceeding the Milan criteria [J]. Transplant Proc， 2008， 40（10）: 35483553.
28. Rizell M, Andersson M, Cahlin C, et al. Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer [J]. Int J Clin Oncol， 2008， 13（1）: 6670.
29. Huynh H, Ngo VC, Koong HN, et al. Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma [J]. J Cell Mol Med， 2009， 13（8B）: 26732683.
30. Arnault JP, Wechsler J, Escudier B, et al. Keratoacanthomas and squamous cell carcinomas in patients receiving sorafenib [J]. J Clin Oncol， 2009， 27（23）: e59e61.
31. Sosman JA, Puzanov I, Atkins MB. Opportunities and obstacles to combination targeted therapy in renal cell cancer [J]. Clin Cancer Res， 2007， 13（2 Pt 2）: 764s769s.
32. Camp ER, Summy J, Bauer TW, et al. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor [J]. Clin Cancer Res， 2005， 11（1）: 397405.
33. Azad NS, Posadas EM, Kwitkowski VE, et al. Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity [J]. J Clin Oncol， 2008， 26（22）: 37093714.
34. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma [J]. J Natl Cancer Inst， 2008， 100（10）: 698711.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Application of Molecular Targeted Drugs in Therapy of Hepatocellular Carcinoma

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