胰腺癌的分子靶向治疗研究进展
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摘要
胰腺癌是一种恶性程度最高的恶性肿瘤之一,预后极差,患者5年生存率低于5%。胰腺癌常规治疗的效果非常有限,是一个需要多学科综合治疗的恶性肿瘤。随着分子生物学研究的不断深入,表皮生长因子受体抑制剂等分子靶向药物在胰腺癌的治疗中表现出了巨大的潜力。笔者就分子靶向药物治疗胰腺癌的研究现状及进展做一综述。
Pancreatic cancer is one of most malignant tumors with extremely poor prognosis, and the 5-year survival rate of the patients is below 5%. Conventional treatments produce very limited effects for pancreatic cancer, and it requires multidisciplinary approach and comprehensive management. With the deepening knowledge of molecular biology, molecular targeted drugs such as epidermal growth factor receptor inhibitors have shown impressive potential in treatment of pancreatic cancer. Here, the authors present the current status and progress in molecular targeted drug research for pancreatic cancer.
Pancreatic cancer is one of most malignant tumors with extremely poor prognosis, and the 5-year survival rate of the patients is below 5%. Conventional treatments produce very limited effects for pancreatic cancer, and it requires multidisciplinary approach and comprehensive management. With the deepening knowledge of molecular biology, molecular targeted drugs such as epidermal growth factor receptor inhibitors have shown impressive potential in treatment of pancreatic cancer. Here, the authors present the current status and progress in molecular targeted drug research for pancreatic cancer.
引文
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[18]Arya G,Vandana M,Acharya S,et al.Enhanced antiproliferative activity of He rceptin(HER2)-conjugated gemcitabineloaded chitosan nanoparticle in pancreatic cancer therapy[J].Nanomedicine,2011,7(6):859-870.
[19]Skrypek N,Vasseur R,Vincent A,et al.The oncogenic receptor Erb B2 modulates gemcitabine and irinotecan/SN-38chemoresistance of human pancreatic cancer cells via h CNT1transporter and multidrug-resistance associated protein MRP-2[J].Oncotarget,2015,6(13):10853-10867.
[20]Kan S,Koido S,Okamoto M,et al.Gemcitabine treatment enhances HER2 expression in low HER2-expressing breast cancer cells and enhances the antitumor effects of trastuzumab emtansine[J].Oncol Rep,2015,34(1):504-510.
[21]Safran H,Iannitti D,Ramana than R,et al.Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu[J].Cancer Invest,2004,22(5):706-712.
[22]孙维佳,肖军,谢虹.VEGF-C,FLt4在胰腺癌中的表达及临床意义[J].中国普通外科杂志,2005,14(6):465-467.Sun WJ,Xiao J,Xie H.Expressiion and clinical significance of VEGF-C,Flt4 in pancreatic carcinoma[J].Chinese Journal of General Surgery,2005,14(6):465-467.
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[25]Kindler HL,Friberg G,Singh DA,et al.Phase II trail of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer[J].J Clin Oncol,2005,23(31):8033-8040.
[26]Fogelman D,Jafari M,Varadhachary GR,et al.Bevacizumab plus gemcitabine and oxaliplatin as first-line therapy formetastatic or locally advanced pancreatic cancer:a phase II trial[J].Cancer Chemother Pharmacol,2011,68(6):1431-1438.
[27]Van Cutscm E,Ververnne WL,Bennouna J,et al.Phase III trail of bevacizumab in combination with gemictabine and erlontinib in patients with metastatic pancreatic cancer[J].J Clin Oncol,2009,27(13):2231-2237.
[28]Klein T,Bischoff R.Physiology and pathophysiology of matrix metalloproteases[J].Amino Acids,2011,41(2):271-290.
[29]Yang H,Liang J,Zhou J,et al.Knockdown of RHOC by sh RNAsuppresses invasion and migration of cholangiocellular carcinoma cells via inhibition of MMP2,MMP3,MMP9 and epithelialmesenchymal transition[J].Mol Med Rep,2016,13(6):5255-5261.
[30]Yang GY,Wagner TD,Fuss M,et al.Multimodality approaches for pancreatic cancer[J].CA Cancer J Clin,2005,55(6):352-367.
[31]Tao LY,Zhang LF,Xiu DR,et al.Prognostic significance of K-ras mutations in pancreatic cancer:a meta-analysis[J].World J Surg Oncol,2016,14(1):146-154.
[32]Subramani PA,Narala VR,Michael RD,et al.Molecular docking and simulation of Curcumin with Geranylgeranyl Transferase1(GGTase1)and Farnesyl Transferase(FTase)[J].Bioinformation,2015,11(5):248-253.
[33]Ding N,Cui XX,Gao Z,et al.A triple combination of atorvastatin,celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors[J].Int J Oncol,2014,44(6):2139-2145.
[34]Heestand GM,Kurzrock R.Molecular landscape of pancreatic cancer:implications for current clinical trials[J].Oncotarget,2015,6(7):4553-4561.
[35]Andreopoulou E,Vigoda IS,Valero V,et al.Phase I-II study of the farnesyl transferase inhibitor tipifarnib plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in HER2/neunegative inflammatory carcinoma and non-inflammatory estrogen receptor-positive breast carcinoma[J].Breast Cancer Res Treat,2013,141(3):429-435.
[36]Akasaka H,Ruan KH.Identification of the two-phase mechanism of arachidonic acid regulating inflammatory prostaglandin E2biosynthesis by targeting COX-2 and m PGES-1[J].Arch Biochem Biophys,2016,603(1):29-37.
[37]Jendrossek V.Targeting apoptosis pathways by Celecoxib in cancer[J].Cancer Lett,2013,332(2):313-324.
[38]Ferrari V,Valcamonico F,Amoroso V,et al.Gemcitabine plus celecoxib(GECO)in advanced pancreatic cancer:a phase II trail[J].Cancer Chemother Pharmacol,2006,57(2):185-190.
[39]H?rdtner C,Multhoff G,Falk W,et al.(-)-Epigallocatechin-3-gallate,a green tea-derived catechin,synergizes with celecoxib to inhibit IL-1-induced tumorigenic mediators by human pancreatic adenocarcinoma cells Colo357[J].Eur J Pharmacol,2012,684(1/3):36-43.
[40]El-Rayes BF,Zalupski MM,Shields AF,et al.A phase II study of celecoxib,gemcitabine,and cisplatinin advanced pancreatic cancer[J].Invest New Drags,2005,23(6):583-590.
[41]Al-Wadei HA,Al-Wadei MH,Ullah MF,et al.Celecoxib and GABA cooperatively prevent the progression of pancreatic cancer in vitro and in xenograft models of stress-free and stress-exposed mice[J].PLo S One,2012,7(8):e43376.doi:10.1371/journal.pone.0043376.
[42]Gao Y,Ma G,Liu S,et al.Thalidomide and multiple myeloma serum synergistically induce a hemostatic imbalance in endothelial cells in vitro[J].Thromb Res,2015,135(6):1154-1159.
[43]Eleutherakis-Papaiakovou V,Bamias A,Dimopoulos MA.Thalidomide in cancer medicine[J].Ann Oncol,2004,15(8):1151-1160.
[44]Qiao Z,Yuan J,Shen J,et al.Effect of thalidomide in combination with gemcitabine on human pancreatic carcinoma SW-1990 cell lines in vitro and in vivo[J].Oncol Lett,2015,9(5):2353-2360.
[45]时圣彬,马廷行,唐晓勇,等.卡培他滨联合沙利度胺二线治疗晚期胰腺癌的疗效观察[J].中华肿瘤杂志,2013,35(4):301-304.Shi SB,Ma TH,Tang XY,et al.Effect of second-line treatment with capecitabine and thalidomide in patients with advanced pancreatic cancer[J].Chinese Journal of Oncology,2013,35(4):301-304.
[46]Ronga I,Gallucci F,Riccardi F,et al.Anorexia-cachexia syndrome in pancreatic cancer:recent advances and new pharmacological approach[J].Adv Med Sci,2014,59(1):1-6.
[2]Kindler HL.Front-line therapy of advanced pancreatic cancer[J].Semin Oncol,2005,32(6 Suppl 9):S33-36.
[3]Abrams RA.Evolving concepts regarding the use of radiotherapy in the adjuvant management of periampullary pancreatic adenocarcinoma[J].Cancer J,2012,18(6):624-632.
[4]曾复,葛春林.胰腺癌185例诊治回顾分析[J].中国普通外科杂志,2015,24(3):336-342.Zeng F,Ge CL.Diagnosis and treatment of pancreatic cancer:a retrospective analysis of 185 cases[J].Chinese Journal of General Surgery,2015,24(3):336-342.
[5]Stindt S,Cebula P,Albrecht U,et al.Hepatitis C Virus Activates a Neuregulin-Driven Circuitto Modify Surface Expression of Growth Factor Receptors of the Erb B Family[J].PLo S One,2016,11(2):e0148711.doi:10.1371/journal.pone.0148711.
[6]Francavilla C,Papetti M,Rigbolt KT,et al.Multilayered proteomics reveals molecular switches dictating ligand-dependent EGFRtrafficking[J].Nat Struct Mol Biol,2016,23(6):608-618.
[7]李洪涛,刘宏斌,赵青川,等.EGFR靶向药物西妥昔单抗在结直肠癌治疗中的应用进展[J].中华消化外科杂志,2013,12(7):556-560.Li HT,Liu HB,Zhao QC,et al.Prospect of cetuximab in the treatment of colorectal cancer[J].Chinese Journal of Digestive Surgery,2013,12(7):556-560.
[8]Fiore M,Trodella L,Valeri S,et al.Prospective study of cetuximab and gemcitabine in combination with radiation therapy:feasibility and efficacy in locally advanced pancreatic head cancer[J].Radiat Oncol,2015,10:255.doi:10.1186/s13014-015-0564-8.
[9]Bangard C,Gossmann A,Papyan A,et al.Magnetic resonance imaging in an orthotopic rat model:blockade of epidermal growth factor receptor with EMD72000 inhibits human pancreatic carcinoma growth[J].Int J Cancer,2005,114(1):131-138.
[10]Graeven U,Kremer B,Südhoff T,et al.Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab(EMD72000)combined with gemcitabine in advanced pancreatic cancer[J].Br J Cancer,2006,94(9):1293-1299.
[11]Moore MJ,Goldstein D,Hamm J,et al.Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer:a phase III trial of the National Cancer Institute of Canada Clinical Trials Group[J].J Clin Oncol,2007,25(15):1960-1966.
[12]Hammel P,Huguet F,van Laethem JL,et al.Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib:The LAP07 Randomized Clinical Trial[J].JAMA,2016,315(17):1844-1853.
[13]Baselga J,Mita AC,Sch?ffski P,et al.Using pharmacokinetic and pharmacodynamic data in early decision making regarding drug development:a phase I clinical trial evaluating tyrosine kinase inhibit-or,AEE788[J].Clin Cancer Res,2012,18(22):6364-6372.
[14]Lam ET,O'Bryant CL,Basche M,et al.A phase I study of gefitinib,capecitabine,and celecoxib in patients with advanced solid tumors[J].Mol Cancer Ther,2008,7(12):3685-3694.
[15]刑荣春,邓军.EGFR分子靶向治疗肝胆肿瘤的研究进展[J].中国普通外科杂志,2013,22(8):1069-1073.Xing RC,Deng J.EGFR-targeted therapy for hepatobiliary cancers:recent progress[J].Chinese Journal of General Surgery,2013,22(8):1069-1073.
[16]Takata T,Tarutani M,Zouboulis CC,et al.Sebaceous glands as the primary target of EGFR-inhibitors in the development of papulopustular eruption[J].J Dermatol Sci,2012,66(2):165-168.
[17]Ho-Pun-Cheung A,Bazin H,Gaborit N,et al.Quantification of HER Expression and Dimerization in Patients’Tumor Samples Using Time-Resolved F?rster Resonance Energy Transfer[J].PLo SONE,2012,7(7):e37065.doi:10.1371/journal.pone.0037065.
[18]Arya G,Vandana M,Acharya S,et al.Enhanced antiproliferative activity of He rceptin(HER2)-conjugated gemcitabineloaded chitosan nanoparticle in pancreatic cancer therapy[J].Nanomedicine,2011,7(6):859-870.
[19]Skrypek N,Vasseur R,Vincent A,et al.The oncogenic receptor Erb B2 modulates gemcitabine and irinotecan/SN-38chemoresistance of human pancreatic cancer cells via h CNT1transporter and multidrug-resistance associated protein MRP-2[J].Oncotarget,2015,6(13):10853-10867.
[20]Kan S,Koido S,Okamoto M,et al.Gemcitabine treatment enhances HER2 expression in low HER2-expressing breast cancer cells and enhances the antitumor effects of trastuzumab emtansine[J].Oncol Rep,2015,34(1):504-510.
[21]Safran H,Iannitti D,Ramana than R,et al.Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu[J].Cancer Invest,2004,22(5):706-712.
[22]孙维佳,肖军,谢虹.VEGF-C,FLt4在胰腺癌中的表达及临床意义[J].中国普通外科杂志,2005,14(6):465-467.Sun WJ,Xiao J,Xie H.Expressiion and clinical significance of VEGF-C,Flt4 in pancreatic carcinoma[J].Chinese Journal of General Surgery,2005,14(6):465-467.
[23]Geiger-Gritsch S,Stollenwerk B,Miksad R,et al.Safety of Bevacizumab in patients with advanced cancer:a meta-analysis of randomized controlled trials[J].Oncologist,2010,15(11):1179-1191.
[24]Chappell NP,Miller C,Barnett J,et al.Is FDA Approved Bevacizumab Cost-Effective in the Setting of Platinum-Resistant Recurrent Ovarian Cancer?[18][J].Obstet Gynecol,2016,127(Suppl 1):6S-7S.
[25]Kindler HL,Friberg G,Singh DA,et al.Phase II trail of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer[J].J Clin Oncol,2005,23(31):8033-8040.
[26]Fogelman D,Jafari M,Varadhachary GR,et al.Bevacizumab plus gemcitabine and oxaliplatin as first-line therapy formetastatic or locally advanced pancreatic cancer:a phase II trial[J].Cancer Chemother Pharmacol,2011,68(6):1431-1438.
[27]Van Cutscm E,Ververnne WL,Bennouna J,et al.Phase III trail of bevacizumab in combination with gemictabine and erlontinib in patients with metastatic pancreatic cancer[J].J Clin Oncol,2009,27(13):2231-2237.
[28]Klein T,Bischoff R.Physiology and pathophysiology of matrix metalloproteases[J].Amino Acids,2011,41(2):271-290.
[29]Yang H,Liang J,Zhou J,et al.Knockdown of RHOC by sh RNAsuppresses invasion and migration of cholangiocellular carcinoma cells via inhibition of MMP2,MMP3,MMP9 and epithelialmesenchymal transition[J].Mol Med Rep,2016,13(6):5255-5261.
[30]Yang GY,Wagner TD,Fuss M,et al.Multimodality approaches for pancreatic cancer[J].CA Cancer J Clin,2005,55(6):352-367.
[31]Tao LY,Zhang LF,Xiu DR,et al.Prognostic significance of K-ras mutations in pancreatic cancer:a meta-analysis[J].World J Surg Oncol,2016,14(1):146-154.
[32]Subramani PA,Narala VR,Michael RD,et al.Molecular docking and simulation of Curcumin with Geranylgeranyl Transferase1(GGTase1)and Farnesyl Transferase(FTase)[J].Bioinformation,2015,11(5):248-253.
[33]Ding N,Cui XX,Gao Z,et al.A triple combination of atorvastatin,celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors[J].Int J Oncol,2014,44(6):2139-2145.
[34]Heestand GM,Kurzrock R.Molecular landscape of pancreatic cancer:implications for current clinical trials[J].Oncotarget,2015,6(7):4553-4561.
[35]Andreopoulou E,Vigoda IS,Valero V,et al.Phase I-II study of the farnesyl transferase inhibitor tipifarnib plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in HER2/neunegative inflammatory carcinoma and non-inflammatory estrogen receptor-positive breast carcinoma[J].Breast Cancer Res Treat,2013,141(3):429-435.
[36]Akasaka H,Ruan KH.Identification of the two-phase mechanism of arachidonic acid regulating inflammatory prostaglandin E2biosynthesis by targeting COX-2 and m PGES-1[J].Arch Biochem Biophys,2016,603(1):29-37.
[37]Jendrossek V.Targeting apoptosis pathways by Celecoxib in cancer[J].Cancer Lett,2013,332(2):313-324.
[38]Ferrari V,Valcamonico F,Amoroso V,et al.Gemcitabine plus celecoxib(GECO)in advanced pancreatic cancer:a phase II trail[J].Cancer Chemother Pharmacol,2006,57(2):185-190.
[39]H?rdtner C,Multhoff G,Falk W,et al.(-)-Epigallocatechin-3-gallate,a green tea-derived catechin,synergizes with celecoxib to inhibit IL-1-induced tumorigenic mediators by human pancreatic adenocarcinoma cells Colo357[J].Eur J Pharmacol,2012,684(1/3):36-43.
[40]El-Rayes BF,Zalupski MM,Shields AF,et al.A phase II study of celecoxib,gemcitabine,and cisplatinin advanced pancreatic cancer[J].Invest New Drags,2005,23(6):583-590.
[41]Al-Wadei HA,Al-Wadei MH,Ullah MF,et al.Celecoxib and GABA cooperatively prevent the progression of pancreatic cancer in vitro and in xenograft models of stress-free and stress-exposed mice[J].PLo S One,2012,7(8):e43376.doi:10.1371/journal.pone.0043376.
[42]Gao Y,Ma G,Liu S,et al.Thalidomide and multiple myeloma serum synergistically induce a hemostatic imbalance in endothelial cells in vitro[J].Thromb Res,2015,135(6):1154-1159.
[43]Eleutherakis-Papaiakovou V,Bamias A,Dimopoulos MA.Thalidomide in cancer medicine[J].Ann Oncol,2004,15(8):1151-1160.
[44]Qiao Z,Yuan J,Shen J,et al.Effect of thalidomide in combination with gemcitabine on human pancreatic carcinoma SW-1990 cell lines in vitro and in vivo[J].Oncol Lett,2015,9(5):2353-2360.
[45]时圣彬,马廷行,唐晓勇,等.卡培他滨联合沙利度胺二线治疗晚期胰腺癌的疗效观察[J].中华肿瘤杂志,2013,35(4):301-304.Shi SB,Ma TH,Tang XY,et al.Effect of second-line treatment with capecitabine and thalidomide in patients with advanced pancreatic cancer[J].Chinese Journal of Oncology,2013,35(4):301-304.
[46]Ronga I,Gallucci F,Riccardi F,et al.Anorexia-cachexia syndrome in pancreatic cancer:recent advances and new pharmacological approach[J].Adv Med Sci,2014,59(1):1-6.