MACC1和c-Met在同期多发肺癌中的表达及临床意义
|
摘要
肺癌是发病率和死亡率增长最快，对人群健康和生命威胁最大的恶性肿瘤之一。伴随着人们体检意识的日益提高，以及高端螺旋CT在基层医院的普及，越来越多的早期肺癌患者被从无症状的健康人群中筛查出来，尤其是一些双肺多发肺结节（≥2个）的病人越来越多的出现在临床医师的视野内。对于这类病人，一旦其中一个结节被诊断为恶性病变，那么剩余的结节性病变多数会被诊断为肺内转移癌，而其中一部分同期多发肺癌的患者会因此丧失临床治愈的机会。因此，对于肺内多发恶性结节的病人，能否在诊断早期明确其是否为肺内转移癌，对其后续治疗就显得尤为重要。
肿瘤的转移是一个复杂的，多因素参与调控的过程。多种基因参与其中，结肠癌转移相关基因1（MACC1）是这其中备受关注的一个。MACC1于2009年由stein第一次报道出来，它通过对HGF/c-Met信号通路的调控引起肿瘤的转移和侵袭。MACC1和c-Met高表达与多种肿瘤侵润转移有关，这点已在结肠癌、肝癌、胃癌、肾盂癌、肺癌等多种肿瘤中均有报道。但在肺部转移癌组织中是否存在高表达，其表达程度是否和肺原发癌组织中的表达程度存在明显差异，国内外尚无此类报道。通过此项研究我们可以明确肺部转移癌组织中的MACC1和c-Met的表达程度；并反向通过MACC1和c-Met的高表达鉴别肺部结节是否为转移癌，从而指导同期肺多发恶性肿瘤的具体临床治疗方法。目的：
探讨结肠癌转移相关基因1（MACC1）及肝细胞生长因子受体（c-Met）在同期多发肺癌、原发肺癌、肺内转移癌中的表达及其临床意义。方法：
采用免疫组织化学染色法和Western印迹检测法检测8例同期双原发肺癌（其中4例有新鲜冰冻标本）、20例原发肺癌及20例肺内转移癌组织中MACC1和c-Met的表达情况，并结合临床情况进行分析。结果：
在所有标本中MACC1的高表达和c-Met的高表达呈正相关（P＜0.01），免疫组化法：在所有标本中MACC1的高表达和c-Met的高表达呈正相关（P＜0.01），免疫组化染色后，MACC１蛋白的表达主要位于组织细胞的胞质及包膜，在肺部转移癌的强阳性表达率为60%（12/20）；在多原发肺癌强阳性表达率为12.5%（2/16）；在原发肺癌的强阳性表达率为15.5%（3/20）；在癌旁组织中强阳性表达率为10.0%（2/20）。进行统计学检验，MACC1在肺部转移癌的强阳性表达与在癌旁组织中的表达上的差异有统计学意义（P＝0.031），在多原发肺癌及原发肺癌中的强阳性表达与癌旁组织中的表达无统计学差异。C-Met蛋白主要定位于组织的包膜。在肺部转移癌的强阳性表达率为55.0%（11/20）；在多原发肺癌的强阳性表达率为12.5%（2/16）；在原发肺癌的强阳性表达率为15.0%（3/20）；在癌旁组织中强阳性表达率为15.0%（3/20）。进行统计学检验，C-Met在肺部转移癌的强阳性表达与在癌旁组织中的表达上的差异有统计学意义（P＝0.033），在多原发肺癌及原发肺癌中的强阳性表达与癌旁组织中的表达无统计学差异。在所有肺内转移癌标本中MACC1和C-Met均强阳性表达率为50%（10/20）。蛋白印迹法检测：肺部转移癌组织、同期多原发肺癌组织、原发肺癌组织MACC１蛋白的相对表达量分别为（1.03±0.97）、（0.59±0.57）、（0.47±0.41），其中肺部转移癌MACC１蛋白表达量显著高于多原发肺癌和原发肺癌组织（P＝0.031、P＝0.042），多原发肺癌组织MACC１蛋白的表达量与原发肺癌组织之间差异没有统计学意义（P＝0.452）。结论：
MACC1和c-Met的高表达与肺内转移癌密切相关，联合检测可作为判断肺内可疑结节是否为转移癌的重要指标。
Objective：
To investigate the expressions of metastasis-associated in colon cancer1(MACC1) and hepatocyte growth factor receptor(c-Met) in synchronous multipleprimary lung carcinoma, and to demonstrate their relationship with the metastasis oflung.Methods:
The expression of MACC1and c–Met in8cases of the same period (4caseswith fresh frozen specimen) of double primary lung cancer,20cases of primary lungcancer and20cases of pulmonary metastatic carcinoma were detected byimmunohistochemical staining and Western imprinting method, and based on whichclinical situations are analyzed.Results:
High expression of MACC1was positively correlated with high expression of c–Met in all specimens(P <0.01).Immunohistochemical method: The expression ofMACC1protein is mainly located in cytoplasm and capsular tissue cells, the strongpositive expression rate of pulmonary metastatic carcinoma was60.0%(12/20), theexpression rate of multiple primary lung cancer is12.5%(2/16), the expression rate ofprimary lung cancer is15.5%(3/20)，the expression rate of pericarcinoma tissues is10.0%(2/20). The strong positive expression rate of pulmonary metastatic carcinomawas significantly higher than that of pericarcinoma tissues (P=0.031). The strongpositive expression rate of multiple primary lung cancer and primary lung cancer werenot significantly higher than that of pericarcinoma tissues. C-Met protein mainlylocate in tissue of coating, the strong positive expression rate of pulmonary metastaticcarcinoma was55.0%(11/20), the expression rate of multiple primary lung cancer is12.5%(2/16), the expression rate of primary lung cancer is15.0%(3/20), the expression rate of pericarcinoma tissues is10.0%(2/20). The strong positiveexpression rate of pulmonary metastatic carcinoma was significantly higher than thatof pericarcinoma tissues (P=0.033). The strong positive expression rate of multipleprimary lung cancer and primary lung cancer were not significantly higher than that ofpericarcinoma tissues.Western imprinting method:
The relative gray value of MACC1protein was (1.03+0.97),(0.59-0.57),(0.47-0.41), in lung metastatic carcinoma tissues, and multiple primary lung cancertissues and primary lung cancer tissues. The relative gray value of MACC1protein inlung metastatic carcinoma tissues was significantly higher than that in multipleprimary lung cancer(P=0.031), and that in primary lung cancer tissues(P=0.042).The relative gray value of MACC1protein in multiple primary lung cancer was notsignificant difference with that in primary lung cancer tissues P=0.452).Conclusion:
The high expression of MACC1protein and c–Met protein may play animportant role in the metastasis of lung cancer. The combined detection will haveimportant clinical significance to diagnose whether the multiple lung node is themetastasis node of lung cancer.
肿瘤的转移是一个复杂的，多因素参与调控的过程。多种基因参与其中，结肠癌转移相关基因1（MACC1）是这其中备受关注的一个。MACC1于2009年由stein第一次报道出来，它通过对HGF/c-Met信号通路的调控引起肿瘤的转移和侵袭。MACC1和c-Met高表达与多种肿瘤侵润转移有关，这点已在结肠癌、肝癌、胃癌、肾盂癌、肺癌等多种肿瘤中均有报道。但在肺部转移癌组织中是否存在高表达，其表达程度是否和肺原发癌组织中的表达程度存在明显差异，国内外尚无此类报道。通过此项研究我们可以明确肺部转移癌组织中的MACC1和c-Met的表达程度；并反向通过MACC1和c-Met的高表达鉴别肺部结节是否为转移癌，从而指导同期肺多发恶性肿瘤的具体临床治疗方法。目的：
探讨结肠癌转移相关基因1（MACC1）及肝细胞生长因子受体（c-Met）在同期多发肺癌、原发肺癌、肺内转移癌中的表达及其临床意义。方法：
采用免疫组织化学染色法和Western印迹检测法检测8例同期双原发肺癌（其中4例有新鲜冰冻标本）、20例原发肺癌及20例肺内转移癌组织中MACC1和c-Met的表达情况，并结合临床情况进行分析。结果：
在所有标本中MACC1的高表达和c-Met的高表达呈正相关（P＜0.01），免疫组化法：在所有标本中MACC1的高表达和c-Met的高表达呈正相关（P＜0.01），免疫组化染色后，MACC１蛋白的表达主要位于组织细胞的胞质及包膜，在肺部转移癌的强阳性表达率为60%（12/20）；在多原发肺癌强阳性表达率为12.5%（2/16）；在原发肺癌的强阳性表达率为15.5%（3/20）；在癌旁组织中强阳性表达率为10.0%（2/20）。进行统计学检验，MACC1在肺部转移癌的强阳性表达与在癌旁组织中的表达上的差异有统计学意义（P＝0.031），在多原发肺癌及原发肺癌中的强阳性表达与癌旁组织中的表达无统计学差异。C-Met蛋白主要定位于组织的包膜。在肺部转移癌的强阳性表达率为55.0%（11/20）；在多原发肺癌的强阳性表达率为12.5%（2/16）；在原发肺癌的强阳性表达率为15.0%（3/20）；在癌旁组织中强阳性表达率为15.0%（3/20）。进行统计学检验，C-Met在肺部转移癌的强阳性表达与在癌旁组织中的表达上的差异有统计学意义（P＝0.033），在多原发肺癌及原发肺癌中的强阳性表达与癌旁组织中的表达无统计学差异。在所有肺内转移癌标本中MACC1和C-Met均强阳性表达率为50%（10/20）。蛋白印迹法检测：肺部转移癌组织、同期多原发肺癌组织、原发肺癌组织MACC１蛋白的相对表达量分别为（1.03±0.97）、（0.59±0.57）、（0.47±0.41），其中肺部转移癌MACC１蛋白表达量显著高于多原发肺癌和原发肺癌组织（P＝0.031、P＝0.042），多原发肺癌组织MACC１蛋白的表达量与原发肺癌组织之间差异没有统计学意义（P＝0.452）。结论：
MACC1和c-Met的高表达与肺内转移癌密切相关，联合检测可作为判断肺内可疑结节是否为转移癌的重要指标。
Objective：
To investigate the expressions of metastasis-associated in colon cancer1(MACC1) and hepatocyte growth factor receptor(c-Met) in synchronous multipleprimary lung carcinoma, and to demonstrate their relationship with the metastasis oflung.Methods:
The expression of MACC1and c–Met in8cases of the same period (4caseswith fresh frozen specimen) of double primary lung cancer,20cases of primary lungcancer and20cases of pulmonary metastatic carcinoma were detected byimmunohistochemical staining and Western imprinting method, and based on whichclinical situations are analyzed.Results:
High expression of MACC1was positively correlated with high expression of c–Met in all specimens(P <0.01).Immunohistochemical method: The expression ofMACC1protein is mainly located in cytoplasm and capsular tissue cells, the strongpositive expression rate of pulmonary metastatic carcinoma was60.0%(12/20), theexpression rate of multiple primary lung cancer is12.5%(2/16), the expression rate ofprimary lung cancer is15.5%(3/20)，the expression rate of pericarcinoma tissues is10.0%(2/20). The strong positive expression rate of pulmonary metastatic carcinomawas significantly higher than that of pericarcinoma tissues (P=0.031). The strongpositive expression rate of multiple primary lung cancer and primary lung cancer werenot significantly higher than that of pericarcinoma tissues. C-Met protein mainlylocate in tissue of coating, the strong positive expression rate of pulmonary metastaticcarcinoma was55.0%(11/20), the expression rate of multiple primary lung cancer is12.5%(2/16), the expression rate of primary lung cancer is15.0%(3/20), the expression rate of pericarcinoma tissues is10.0%(2/20). The strong positiveexpression rate of pulmonary metastatic carcinoma was significantly higher than thatof pericarcinoma tissues (P=0.033). The strong positive expression rate of multipleprimary lung cancer and primary lung cancer were not significantly higher than that ofpericarcinoma tissues.Western imprinting method:
The relative gray value of MACC1protein was (1.03+0.97),(0.59-0.57),(0.47-0.41), in lung metastatic carcinoma tissues, and multiple primary lung cancertissues and primary lung cancer tissues. The relative gray value of MACC1protein inlung metastatic carcinoma tissues was significantly higher than that in multipleprimary lung cancer(P=0.031), and that in primary lung cancer tissues(P=0.042).The relative gray value of MACC1protein in multiple primary lung cancer was notsignificant difference with that in primary lung cancer tissues P=0.452).Conclusion:
The high expression of MACC1protein and c–Met protein may play animportant role in the metastasis of lung cancer. The combined detection will haveimportant clinical significance to diagnose whether the multiple lung node is themetastasis node of lung cancer.
引文
[1] AMOS CI, XU W, SPITZ MR. Is there a genetic basis for lung cancersusceptibility?[J]. Recent results in cancer research Fortschritte derKrebsforschung,1999,151:3-12.
[2] JEMAL A, SIEGEL R, WARD E et al. Cancer statistics,2006[J]. CA: a cancerjournal for clinicians,2006,56(2):106-130.
[3] E VB, S K. Dtsch Med[J]. Wochenschr,1890,16:1113-1114.
[4] J H. Astronomical[J]. Science (New York, NY,1895,2(51):845-846.
[5] HIMMELWEIT F. Serological responses and clinical reactions to influenzavirus vaccines[J]. British medical journal,1960,2(5214):1690-1694.
[6] NADLER LM, STASHENKO P, HARDY R et al. Serotherapy of a patient witha monoclonal antibody directed against a human lymphoma-associatedantigen[J]. Cancer research,1980,40(9):3147-3154.
[7] MILLER RA, MALONEY DG, WARNKE R, LEVY R. Treatment of B-celllymphoma with monoclonal anti-idiotype antibody[J]. The New Englandjournal of medicine,1982,306(9):517-522.
[8] FOON KA, SCHROFF RW, BUNN PA et al. Effects of monoclonal antibodytherapy in patients with chronic lymphocytic leukemia[J]. Blood,1984,64(5):1085-1093.
[9] GOLDENBERG DM, DELAND F, KIM E et al. Use of radiolabeledantibodies to carcinoembryonic antigen for the detection and localization ofdiverse cancers by external photoscanning[J]. The New England journal ofmedicine,1978,298(25):1384-1386.
[10] GAFFAR SA, PANT KD, SHOCHAT D, BENNETT SJ, GOLDENBERG DM.Experimental studies of tumor radioimmunodetection using antibody mixturesagainst carcinoembryonic antigen (CEA) and colon-specific antigen-p(CSAp)[J]. International journal of cancer,1981,27(1):101-105.
[11] DENARDO SJ, DENARDO GL, O'GRADY LF et al. Treatment of B cellmalignancies with131I Lym-1monoclonal antibodies[J]. International journalof cancer Supplement=Journal international du cancer,1988,3:96-101.
[12] GOLDENBERG DM, HOROWITZ JA, SHARKEY RM et al. Targeting,dosimetry, and radioimmunotherapy of B-cell lymphomas withiodine-131-labeled LL2monoclonal antibody[J]. J Clin Oncol,1991,9(4):548-564.
[13] BUCHSBAUM DJ, WAHL RL, NORMOLLE DP, KAMINSKI MS. Therapywith unlabeled and131I-labeled pan-B-cell monoclonal antibodies in nudemice bearing Raji Burkitt's lymphoma xenografts[J]. Cancer research,1992,52(23):6476-6481.
[14] KAMINSKI MS, ZASADNY KR, FRANCIS IR et al. Radioimmunotherapy ofB-cell lymphoma with [131I]anti-B1(anti-CD20) antibody[J]. The NewEngland journal of medicine,1993,329(7):459-465.
[15] MALONEY DG, LILES TM, CZERWINSKI DK et al. Phase I clinical trialusing escalating single-dose infusion of chimeric anti-CD20monoclonalantibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma[J]. Blood,1994,84(8):2457-2466.
[16] JAZIREHI AR, BONAVIDA B. Cellular and molecular signal transductionpathways modulated by rituximab (rituxan, anti-CD20mAb) in non-Hodgkin'slymphoma: implications in chemosensitization and therapeutic intervention[J].Oncogene,2005,24(13):2121-2143.
[17] ZHANG N, KHAWLI LA, HU P, EPSTEIN AL. Generation of rituximabpolymer may cause hyper-cross-linking-induced apoptosis in non-Hodgkin'slymphomas[J]. Clin Cancer Res,2005,11(16):5971-5980.
[18] GHOBRIAL IM, WITZIG TE, ADJEI AA. Targeting apoptosis pathways incancer therapy[J]. CA: a cancer journal for clinicians,2005,55(3):178-194.
[19] BIANCO R, DANIELE G, CIARDIELLO F, TORTORA G. Monoclonalantibodies targeting the epidermal growth factor receptor[J]. Current drugtargets,2005,6(3):275-287.
[20] EMENS LA. Trastuzumab: targeted therapy for the management ofHER-2/neu-overexpressing metastatic breast cancer[J]. American journal oftherapeutics,2005,12(3):243-253.
[21] CZUCZMAN MS. CHOP plus rituximab chemoimmunotherapy of indolentB-cell lymphoma[J]. Seminars in oncology,1999,26(5Suppl14):88-96.
[22] MARTY M, COGNETTI F, MARANINCHI D et al. Randomized phase II trialof the efficacy and safety of trastuzumab combined with docetaxel in patientswith human epidermal growth factor receptor2-positive metastatic breastcancer administered as first-line treatment: the M77001study group[J]. J ClinOncol,2005,23(19):4265-4274.
[23] RABEN D, HELFRICH B, CHAN DC et al. The effects of cetuximab aloneand in combination with radiation and/or chemotherapy in lung cancer[J]. ClinCancer Res,2005,11(2Pt1):795-805.
[24] FERRARA N, HILLAN KJ, NOVOTNY W. Bevacizumab (Avastin), ahumanized anti-VEGF monoclonal antibody for cancer therapy[J].Biochemical and biophysical research communications,2005,333(2):328-335.
[25] LEACH DR, KRUMMEL MF, ALLISON JP. Enhancement of antitumorimmunity by CTLA-4blockade[J]. Science (New York, NY,1996,271(5256):1734-1736.
[26] KAPADIA D, FONG L. CTLA-4blockade: autoimmunity as treatment[J]. JClin Oncol,2005,23(35):8926-8928.
[27] RUTGEERTS P, VAN ASSCHE G, VERMEIRE S. Review article: Infliximabtherapy for inflammatory bowel disease--seven years on[J]. Alimentarypharmacology&therapeutics,2006,23(4):451-463.
[28] CUPPOLETTI A, PEREZ-VILLA F, VALLEJOS I, ROIG E. Experience withsingle-dose daclizumab in the prevention of acute rejection in hearttransplantation[J]. Transplantation proceedings,2005,37(9):4036-4038.
[29] LIOSSIS SN, TSOKOS GC. Monoclonal antibodies and fusion proteins inmedicine[J]. The Journal of allergy and clinical immunology,2005,116(4):721-729; quiz730.
[30] CHATENOUD L. Monoclonal antibody-based strategies in autoimmunity andtransplantation[J]. Methods in molecular medicine,2005,109:297-328.
[31] CHAMBERS SA, ISENBERG D. Anti-B cell therapy (rituximab) in thetreatment of autoimmune diseases[J]. Lupus,2005,14(3):210-214.
[32] LOONEY RJ. B cell-targeted therapy in diseases other than rheumatoidarthritis[J]. The Journal of rheumatology,2005,73:25-28; discussion29-30.
[33] DEBAUN MR. Issues regarding study design for initial clinical trials usingdecitabine[J]. Seminars in hematology,2004,41(4Suppl6):23-27.
[34] ILANTZIS C, DEMARTE L, SCREATON RA, STANNERS CP. Deregulatedexpression of the human tumor marker CEA and CEA family memberCEACAM6disrupts tissue architecture and blocks colonocytedifferentiation[J]. Neoplasia (New York, NY,2002,4(2):151-163.
[35] BLUMENTHAL RD, OSORIO L, HAYES MK et al. Carcinoembryonicantigen antibody inhibits lung metastasis and augments chemotherapy in ahuman colonic carcinoma xenograft[J]. Cancer Immunol Immunother,2005,54(4):315-327.
[36] JAIN RK. Transport of molecules, particles, and cells in solid tumors[J].Annual review of biomedical engineering,1999,1:241-263.
[37] FUJIMORI K, COVELL DG, FLETCHER JE, WEINSTEIN JN. A modelinganalysis of monoclonal antibody percolation through tumors: a binding-sitebarrier[J]. J Nucl Med,1990,31(7):1191-1198.
[38] ADAMS GP, SCHIER R, MCCALL AM et al. High affinity restricts thelocalization and tumor penetration of single-chain fv antibody molecules[J].Cancer research,2001,61(12):4750-4755.
[39] BLUMENTHAL RD, FAND I, SHARKEY RM et al. The effect of antibodyprotein dose on the uniformity of tumor distribution of radioantibodies: anautoradiographic study[J]. Cancer Immunol Immunother,1991,33(6):351-358.
[40] KOHLER G, MILSTEIN C. Continuous cultures of fused cells secretingantibody of predefined specificity[J]. Nature,1975,256(5517):495-497.
[41] SEARS HF, HERLYN D, STEPLEWSKI Z, KOPROWSKI H. Phase II clinicaltrial of a murine monoclonal antibody cytotoxic for gastrointestinaladenocarcinoma[J]. Cancer research,1985,45(11Pt2):5910-5913.
[42] HOUGHTON AN, MINTZER D, CORDON-CARDO C et al. Mousemonoclonal IgG3antibody detecting GD3ganglioside: a phase I trial inpatients with malignant melanoma[J]. Proceedings of the National Academy ofSciences of the United States of America,1985,82(4):1242-1246.
[43] GOODMAN GE, BEAUMIER P, HELLSTROM I, FERNYHOUGH B,HELLSTROM KE. Pilot trial of murine monoclonal antibodies in patientswith advanced melanoma[J]. J Clin Oncol,1985,3(3):340-352.
[44] WALDMANN H, HALE G. CAMPATH: from concept to clinic[J].Philosophical transactions of the Royal Society of London,2005,360(1461):1707-1711.
[45] MORRISON SL, JOHNSON MJ, HERZENBERG LA, OI VT. Chimerichuman antibody molecules: mouse antigen-binding domains with humanconstant region domains[J]. Proceedings of the National Academy of Sciencesof the United States of America,1984,81(21):6851-6855.
[46] JONES PT, DEAR PH, FOOTE J, NEUBERGER MS, WINTER G. Replacingthe complementarity-determining regions in a human antibody with those froma mouse[J]. Nature,1986,321(6069):522-525.
[47] QU Z, GRIFFITHS GL, WEGENER WA et al. Development of humanizedantibodies as cancer therapeutics[J]. Methods (San Diego, Calif,2005,36(1):84-95.
[48] ANGENENDT P. Progress in protein and antibody microarray technology[J].Drug discovery today,2005,10(7):503-511.
[49] WENG WK, LEVY R. Two immunoglobulin G fragment C receptorpolymorphisms independently predict response to rituximab in patients withfollicular lymphoma[J]. J Clin Oncol,2003,21(21):3940-3947.
[50] MCLAUGHLIN P, GRILLO-LOPEZ AJ, LINK BK et al. Rituximab chimericanti-CD20monoclonal antibody therapy for relapsed indolent lymphoma: halfof patients respond to a four-dose treatment program[J]. J Clin Oncol,1998,16(8):2825-2833.
[51] DAVIS TA, GRILLO-LOPEZ AJ, WHITE CA et al. Rituximab anti-CD20monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacyof re-treatment[J]. J Clin Oncol,2000,18(17):3135-3143.
[52] HAINSWORTH JD, LITCHY S, SHAFFER DW et al. Maximizing therapeuticbenefit of rituximab: maintenance therapy versus re-treatment at progression inpatients with indolent non-Hodgkin's lymphoma--a randomized phase II trialof the Minnie Pearl Cancer Research Network[J]. J Clin Oncol,2005,23(6):1088-1095.
[53] COIFFIER B. First-line treatment of follicular lymphoma in the era ofmonoclonal antibodies[J]. Clin Adv Hematol Oncol,2005,3(6):484-491,505.
[54] COIFFIER B. Rituximab in diffuse large B-cell lymphoma[J]. Clin AdvHematol Oncol,2004,2(3):156-157.
[55] FEUGIER P, VIRION JM, TILLY H et al. Incidence and risk factors for centralnervous system occurrence in elderly patients with diffuse large-B-celllymphoma: influence of rituximab[J]. Ann Oncol,2004,15(1):129-133.
[56] BYRD JC, MURPHY T, HOWARD RS et al. Rituximab using a thrice weeklydosing schedule in B-cell chronic lymphocytic leukemia and smalllymphocytic lymphoma demonstrates clinical activity and acceptabletoxicity[J]. J Clin Oncol,2001,19(8):2153-2164.
[57] O'BRIEN SM, KANTARJIAN H, THOMAS DA et al. Rituximabdose-escalation trial in chronic lymphocytic leukemia[J]. J Clin Oncol,2001,19(8):2165-2170.
[58] LEONARD JP, COLEMAN M, KETAS JC et al. Epratuzumab, a humanizedanti-CD22antibody, in aggressive non-Hodgkin's lymphoma: phase I/IIclinical trial results[J]. Clin Cancer Res,2004,10(16):5327-5334.
[59] LEONARD JP, COLEMAN M, KETAS J et al. Combination antibody therapywith epratuzumab and rituximab in relapsed or refractory non-Hodgkin'slymphoma[J]. J Clin Oncol,2005,23(22):5044-5051.
[60] YOUNES A, HARIHARAN K, ALLEN RS, LEIGH BR. Initial trials ofanti-CD80monoclonal antibody (Galiximab) therapy for patients withrelapsed or refractory follicular lymphoma[J]. Clinical lymphoma,2003,3(4):257-259.
[61] CZUCZMAN MS, THALL A, WITZIG TE et al. Phase I/II study of galiximab,an anti-CD80antibody, for relapsed or refractory follicular lymphoma[J]. JClin Oncol,2005,23(19):4390-4398.
[62] REFF ME, CARNER K, CHAMBERS KS et al. Depletion of B cells in vivoby a chimeric mouse human monoclonal antibody to CD20[J]. Blood,1994,83(2):435-445.
[63] GOLAY J, LAZZARI M, FACCHINETTI V et al. CD20levels determine thein vitro susceptibility to rituximab and complement of B-cell chroniclymphocytic leukemia: further regulation by CD55and CD59[J]. Blood,2001,98(12):3383-3389.
[64] SHAN D, LEDBETTER JA, PRESS OW. Apoptosis of malignant human Bcells by ligation of CD20with monoclonal antibodies[J]. Blood,1998,91(5):1644-1652.
[65] GOLAY J, ZAFFARONI L, VACCARI T et al. Biologic response of Blymphoma cells to anti-CD20monoclonal antibody rituximab in vitro: CD55and CD59regulate complement-mediated cell lysis[J]. Blood,2000,95(12):3900-3908.
[66] TREON SP, MITSIADES C, MITSIADES N et al. Tumor Cell Expression ofCD59Is Associated With Resistance to CD20Serotherapy in Patients WithB-Cell Malignancies[J]. J Immunother (1991),2001,24(3):263-271.
[67] WENG WK, LEVY R. Expression of complement inhibitors CD46, CD55, andCD59on tumor cells does not predict clinical outcome after rituximabtreatment in follicular non-Hodgkin lymphoma[J]. Blood,2001,98(5):1352-1357.
[68] MANCHES O, LUI G, CHAPEROT L et al. In vitro mechanisms of action ofrituximab on primary non-Hodgkin lymphomas[J]. Blood,2003,101(3):949-954.
[69] UCHIDA J, HAMAGUCHI Y, OLIVER JA et al. The innate mononuclearphagocyte network depletes B lymphocytes through Fc receptor-dependentmechanisms during anti-CD20antibody immunotherapy[J]. The Journal ofexperimental medicine,2004,199(12):1659-1669.
[70] HERNANDEZ-ILIZALITURRI FJ, JUPUDY V, OSTBERG J et al.Neutrophils contribute to the biological antitumor activity of rituximab in anon-Hodgkin's lymphoma severe combined immunodeficiency mousemodel[J]. Clin Cancer Res,2003,9(16Pt1):5866-5873.
[71] PRESTA LG. Engineering antibodies for therapy[J]. Current pharmaceuticalbiotechnology,2002,3(3):237-256.
[72] SHIELDS RL, LAI J, KECK R et al. Lack of fucose on human IgG1N-linkedoligosaccharide improves binding to human Fcgamma RIII andantibody-dependent cellular toxicity[J]. The Journal of biological chemistry,2002,277(30):26733-26740.
[73] HODONICZKY J, ZHENG YZ, JAMES DC. Control of recombinantmonoclonal antibody effector functions by Fc N-glycan remodeling in vitro[J].Biotechnology progress,2005,21(6):1644-1652.
[74] CARTRON G, DACHEUX L, SALLES G et al. Therapeutic activity ofhumanized anti-CD20monoclonal antibody and polymorphism in IgG Fcreceptor FcgammaRIIIa gene[J]. Blood,2002,99(3):754-758.
[75] KAKINOKI Y, KUBOTA H, YAMAMOTO Y. CD64surface expression onneutrophils and monocytes is significantly up-regulated after stimulation withgranulocyte colony-stimulating factor during CHOP chemotherapy for patientswith non-Hodgkin's lymphoma[J]. International journal of hematology,2004,79(1):55-62.
[76] PARIHAR R, DIERKSHEIDE J, HU Y, CARSON WE. IL-12enhances thenatural killer cell cytokine response to Ab-coated tumor cells[J]. The Journalof clinical investigation,2002,110(7):983-992.
[77] ANSELL SM, WITZIG TE, KURTIN PJ et al. Phase1study of interleukin-12in combination with rituximab in patients with B-cell non-Hodgkinlymphoma[J]. Blood,2002,99(1):67-74.
[78] PRESTA LG, SHIELDS RL, NAMENUK AK, HONG K, MENG YG.Engineering therapeutic antibodies for improved function[J]. BiochemicalSociety transactions,2002,30(4):487-490.
[79] VACCARO C, ZHOU J, OBER RJ, WARD ES. Engineering the Fc region ofimmunoglobulin G to modulate in vivo antibody levels[J]. Naturebiotechnology,2005,23(10):1283-1288.
[80] IDUSOGIE EE, WONG PY, PRESTA LG et al. Engineered antibodies withincreased activity to recruit complement[J]. J Immunol,2001,166(4):2571-2575.
[81] STOCKMEYER B, ELSASSER D, DECHANT M et al. Mechanisms ofG-CSF-or GM-CSF-stimulated tumor cell killing by Fc receptor-directedbispecific antibodies[J]. Journal of immunological methods,2001,248(1-2):103-111.
[82] BEVAART L, JANSEN MJ, VAN VUGT MJ et al. The high-affinity IgGreceptor, FcgammaRI, plays a central role in antibody therapy of experimentalmelanoma[J]. Cancer research,2006,66(3):1261-1264.
[83] SLAMON DJ, LEYLAND-JONES B, SHAK S et al. Use of chemotherapyplus a monoclonal antibody against HER2for metastatic breast cancer thatoverexpresses HER2[J]. The New England journal of medicine,2001,344(11):783-792.
[84] PICCART-GEBHART MJ, PROCTER M, LEYLAND-JONES B et al.Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer[J].The New England journal of medicine,2005,353(16):1659-1672.
[85] ROMOND EH, PEREZ EA, BRYANT J et al. Trastuzumab plus adjuvantchemotherapy for operable HER2-positive breast cancer[J]. The New Englandjournal of medicine,2005,353(16):1673-1684.
[86] IZUMI Y, XU L, DI TOMASO E, FUKUMURA D, JAIN RK. Tumour biology:herceptin acts as an anti-angiogenic cocktail[J]. Nature,2002,416(6878):279-280.
[87] GENNARI R, MENARD S, FAGNONI F et al. Pilot study of the mechanismof action of preoperative trastuzumab in patients with primary operable breasttumors overexpressing HER2[J]. Clin Cancer Res,2004,10(17):5650-5655.
[88] WARBURTON C, DRAGOWSKA WH, GELMON K et al. Treatment ofHER-2/neu overexpressing breast cancer xenograft models with trastuzumab(Herceptin) and gefitinib (ZD1839): drug combination effects on tumor growth,HER-2/neu and epidermal growth factor receptor expression, and viablehypoxic cell fraction[J]. Clin Cancer Res,2004,10(7):2512-2524.
[89] NEGRO A, BRAR BK, LEE KF. Essential roles of Her2/erbB2in cardiacdevelopment and function[J]. Recent progress in hormone research,2004,59:1-12.
[90] GARRATT AN, OZCELIK C, BIRCHMEIER C. ErbB2pathways in heart andneural diseases[J]. Trends in cardiovascular medicine,2003,13(2):80-86.
[91] EWER MS, VOOLETICH MT, DURAND JB et al. Reversibility oftrastuzumab-related cardiotoxicity: new insights based on clinical course andresponse to medical treatment[J]. J Clin Oncol,2005,23(31):7820-7826.
[92] TAN-CHIU E, YOTHERS G, ROMOND E et al. Assessment of cardiacdysfunction in a randomized trial comparing doxorubicin andcyclophosphamide followed by paclitaxel, with or without trastuzumab asadjuvant therapy in node-positive, human epidermal growth factor receptor2-overexpressing breast cancer: NSABP B-31[J]. J Clin Oncol,2005,23(31):7811-7819.
[93] NORMANNO N, BIANCO C, DE LUCA A, MAIELLO MR, SALOMON DS.Target-based agents against ErbB receptors and their ligands: a novel approachto cancer treatment[J]. Endocrine-related cancer,2003,10(1):1-21.
[94] GUAN H, JIA SF, ZHOU Z, STEWART J, KLEINERMAN ES. Herceptindown-regulates HER-2/neu and vascular endothelial growth factor expressionand enhances taxol-induced cytotoxicity of human Ewing's sarcoma cells invitro and in vivo[J]. Clin Cancer Res,2005,11(5):2008-2017.
[95] BONNER JA, HARARI PM, GIRALT J et al. Radiotherapy plus cetuximab forsquamous-cell carcinoma of the head and neck[J]. The New England journalof medicine,2006,354(6):567-578.
[96] PEREZ-SOLER R, SALTZ L. Cutaneous adverse effects withHER1/EGFR-targeted agents: is there a silver lining?[J]. J Clin Oncol,2005,23(22):5235-5246.
[97] BASELGA J, NORTON L, ALBANELL J, KIM YM, MENDELSOHN J.Recombinant humanized anti-HER2antibody (Herceptin) enhances theantitumor activity of paclitaxel and doxorubicin against HER2/neuoverexpressing human breast cancer xenografts[J]. Cancer research,1998,58(13):2825-2831.
[98] GORSKI DH, BECKETT MA, JASKOWIAK NT et al. Blockage of thevascular endothelial growth factor stress response increases the antitumoreffects of ionizing radiation[J]. Cancer research,1999,59(14):3374-3378.
[99] DE GRAMONT A, VAN CUTSEM E. Investigating the potential ofbevacizumab in other indications: metastatic renal cell, non-small cell lung,pancreatic and breast cancer[J]. Oncology,2005,69Suppl3:46-56.
[100] D'ADAMO DR, ANDERSON SE, ALBRITTON K et al. Phase II study ofdoxorubicin and bevacizumab for patients with metastatic soft-tissuesarcomas[J]. J Clin Oncol,2005,23(28):7135-7142.
[101] BRUNS I, FOX F, REINECKE P et al. Complete remission in a patient withrelapsed angioimmunoblastic T-cell lymphoma following treatment withbevacizumab[J]. Leukemia,2005,19(11):1993-1995.
[102] GORDON MS, CUNNINGHAM D. Managing patients treated withbevacizumab combination therapy[J]. Oncology,2005,69Suppl3:25-33.
[103] WITZIG TE, GORDON LI, CABANILLAS F et al. Randomized controlledtrial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versusrituximab immunotherapy for patients with relapsed or refractory low-grade,follicular, or transformed B-cell non-Hodgkin's lymphoma[J]. J Clin Oncol,2002,20(10):2453-2463.
[104] DAVIS TA, KAMINSKI MS, LEONARD JP et al. The radioisotopecontributes significantly to the activity of radioimmunotherapy[J]. Clin CancerRes,2004,10(23):7792-7798.
[105] SILVERSTEIN AM. Labeled antigens and antibodies: the evolution of magicmarkers and magic bullets[J]. Nature immunology,2004,5(12):1211-1217.
[106] GOLDENBERG DM. Perspectives on oncologic imaging with radiolabeledantibodies[J]. Cancer,1997,80(12Suppl):2431-2435.
[107] LARSON SM, PENTLOW KS, VOLKOW ND et al. PET scanning ofiodine-124-3F9as an approach to tumor dosimetry during treatment planningfor radioimmunotherapy in a child with neuroblastoma[J]. J Nucl Med,1992,33(11):2020-2023.
[108] WONG JY, CHU DZ, WILLIAMS LE et al. Pilot trial evaluating an123I-labeled80-kilodalton engineered anticarcinoembryonic antigen antibodyfragment (cT84.66minibody) in patients with colorectal cancer[J]. ClinCancer Res,2004,10(15):5014-5021.
[109] MCBRIDE WJ, ZANZONICO P, SHARKEY RM et al. Bispecific antibodypretargeting PET (immunoPET) with an124I-labeled hapten-peptide[J]. JNucl Med,2006,47(10):1678-1688.
[110] SHARKEY RM, GOLDENBERG DM. Perspectives on cancer therapy withradiolabeled monoclonal antibodies[J]. J Nucl Med,2005,46Suppl1:115S-127S.
[111] ROBERSON PL, BUCHSBAUM DJ. Reconciliation of tumor dose responseto external beam radiotherapy versus radioimmunotherapy with131iodine-labeled antibody for a colon cancer model[J]. Cancer research,1995,55(23Suppl):5811s-5816s.
[112] HERNANDEZ MC, KNOX SJ. Radiobiology of radioimmunotherapy with90Y ibritumomab tiuxetan (Zevalin)[J]. Seminars in oncology,2003,30(6Suppl17):6-10.
[113] KASSIS AI, ADELSTEIN SJ. Radiobiologic principles in radionuclidetherapy[J]. J Nucl Med,2005,46Suppl1:4S-12S.
[114] OTZERKE J, BUNJES D, SCHEINBERG DA. Radioimmunoconjugates inacute leukemia treatment: the future is radiant[J]. Bone marrow transplantation,2005,36(12):1021-1026.
[115] MICHEL RB, BRECHBIEL MW, MATTES MJ. A comparison of4radionuclides conjugated to antibodies for single-cell kill[J]. J Nucl Med,2003,44(4):632-640.
[116] OLAFSEN T, KENANOVA VE, SUNDARESAN G et al. Optimizingradiolabeled engineered anti-p185HER2antibody fragments for in vivoimaging[J]. Cancer research,2005,65(13):5907-5916.
[117] KENANOVA V, OLAFSEN T, CROW DM et al. Tailoring thepharmacokinetics and positron emission tomography imaging properties ofanti-carcinoembryonic antigen single-chain Fv-Fc antibody fragments[J].Cancer research,2005,65(2):622-631.
[118] BEHR TM, GOLDENBERG DM, BECKER W. Reducing the renal uptake ofradiolabeled antibody fragments and peptides for diagnosis and therapy:present status, future prospects and limitations[J]. European journal of nuclearmedicine,1998,25(2):201-212.
[119] SHARKEY RM, KARACAY H, CARDILLO TM et al. Improving thedelivery of radionuclides for imaging and therapy of cancer using pretargetingmethods[J]. Clin Cancer Res,2005,11(19Pt2):7109s-7121s.
[120] SHARKEY RM, CARDILLO TM, ROSSI EA et al. Signal amplification inmolecular imaging by pretargeting a multivalent, bispecific antibody[J].Nature medicine,2005,11(11):1250-1255.
[121] KARACAY H, BRARD PY, SHARKEY RM et al. Therapeutic advantage ofpretargeted radioimmunotherapy using a recombinant bispecific antibody in ahuman colon cancer xenograft[J]. Clin Cancer Res,2005,11(21):7879-7885.
[122] ROSSI EA, GOLDENBERG DM, CARDILLO TM et al. Stably tetheredmultifunctional structures of defined composition made by the dock and lockmethod for use in cancer targeting[J]. Proceedings of the National Academy ofSciences of the United States of America,2006,103(18):6841-6846.
[123] LIN Y, PAGEL JM, AXWORTHY D et al. A genetically engineered anti-CD45single-chain antibody-streptavidin fusion protein for pretargetedradioimmunotherapy of hematologic malignancies[J]. Cancer research,2006,66(7):3884-3892.
[124] GOLDENBERG DM, SHARKEY RM, PAGANELLI G, BARBET J,CHATAL JF. Antibody pretargeting advances cancer radioimmunodetectionand radioimmunotherapy[J]. J Clin Oncol,2006,24(5):823-834.
[125] SHEN S, FORERO A, LOBUGLIO AF et al. Patient-specific dosimetry ofpretargeted radioimmunotherapy using CC49fusion protein in patients withgastrointestinal malignancies[J]. J Nucl Med,2005,46(4):642-651.
[126] CHATAL JF, CAMPION L, KRAEBER-BODERE F et al. Survivalimprovement in patients with medullary thyroid carcinoma who undergopretargeted anti-carcinoembryonic-antigen radioimmunotherapy: acollaborative study with the French Endocrine Tumor Group[J]. J Clin Oncol,2006,24(11):1705-1711.
[127] CHESON BD. The role of radioimmunotherapy with yttrium-90ibritumomabtiuxetan in the treatment of non-Hodgkin lymphoma[J]. BioDrugs,2005,19(5):309-322.
[128] GORDON LI, MOLINA A, WITZIG T et al. Durable responses afteribritumomab tiuxetan radioimmunotherapy for CD20+B-cell lymphoma:long-term follow-up of a phase1/2study[J]. Blood,2004,103(12):4429-4431.
[129] WISEMAN GA, WITZIG TE. Yttrium-90(90Y) ibritumomab tiuxetan(Zevalin) induces long-term durable responses in patients with relapsed orrefractory B-Cell non-Hodgkin's lymphoma[J]. Cancer biotherapy&radiopharmaceuticals,2005,20(2):185-188.
[130] FISHER RI, KAMINSKI MS, WAHL RL et al. Tositumomab and iodine-131tositumomab produces durable complete remissions in a subset of heavilypretreated patients with low-grade and transformed non-Hodgkin'slymphomas[J]. J Clin Oncol,2005,23(30):7565-7573.
[131] KAMINSKI MS, TUCK M, ESTES J et al.131I-tositumomab therapy asinitial treatment for follicular lymphoma[J]. The New England journal ofmedicine,2005,352(5):441-449.
[132] HACKSHAW A, SWEETENHAM J, KNIGHT A. Are prophylactichaematopoietic growth factors of value in the management of patients withaggressive non-Hodgkin's lymphoma?[J]. British journal of cancer,2004,90(7):1302-1305.
[133] BENNETT JM, KAMINSKI MS, LEONARD JP et al. Assessment oftreatment-related myelodysplastic syndromes and acute myeloid leukemia inpatients with non-Hodgkin lymphoma treated with tositumomab and iodineI131tositumomab[J]. Blood,2005,105(12):4576-4582.
[134] ANSELL SM, RISTOW KM, HABERMANN TM, WISEMAN GA, WITZIGTE. Subsequent chemotherapy regimens are well tolerated afterradioimmunotherapy with yttrium-90ibritumomab tiuxetan for non-Hodgkin'slymphoma[J]. J Clin Oncol,2002,20(18):3885-3890.
[135] CONNORS JM. Radioimmunotherapy--hot new treatment for lymphoma[J].The New England journal of medicine,2005,352(5):496-498.
[136] GOPAL AK, GOOLEY TA, MALONEY DG et al. High-doseradioimmunotherapy versus conventional high-dose therapy and autologoushematopoietic stem cell transplantation for relapsed follicular non-Hodgkinlymphoma: a multivariable cohort analysis[J]. Blood,2003,102(7):2351-2357.
[137] NADEMANEE A, FORMAN S, MOLINA A et al. A phase1/2trial ofhigh-dose yttrium-90-ibritumomab tiuxetan in combination with high-doseetoposide and cyclophosphamide followed by autologous stem celltransplantation in patients with poor-risk or relapsed non-Hodgkinlymphoma[J]. Blood,2005,106(8):2896-2902.
[138] LEONARD JP, COLEMAN M, KOSTAKOGLU L et al. Abbreviatedchemotherapy with fludarabine followed by tositumomab and iodine I131tositumomab for untreated follicular lymphoma[J]. J Clin Oncol,2005,23(24):5696-5704.
[139] CHESON BD. Radioimmunotherapy of non-Hodgkin lymphomas[J]. Blood,2003,101(2):391-398.
[140] LINDEN O, HINDORF C, CAVALLIN-STAHL E et al. Dose-fractionatedradioimmunotherapy in non-Hodgkin's lymphoma using DOTA-conjugated,90Y-radiolabeled, humanized anti-CD22monoclonal antibody, epratuzumab[J].Clin Cancer Res,2005,11(14):5215-5222.
[141] CHEN S, YU L, JIANG C et al. Pivotal study of iodine-131-labeled chimerictumor necrosis treatment radioimmunotherapy in patients with advanced lungcancer[J]. J Clin Oncol,2005,23(7):1538-1547.
[142] SHARKEY RM, PYKETT MJ, SIEGEL JA et al. Radioimmunotherapy of theGW-39human colonic tumor xenograft with131I-labeled murine monoclonalantibody to carcinoembryonic antigen[J]. Cancer research,1987,47(21):5672-5677.
[143] BLUMENTHAL RD, SHARKEY RM, HAYWOOD L et al. Targeted therapyof athymic mice bearing GW-39human colonic cancer micrometastases with131I-labeled monoclonal antibodies[J]. Cancer research,1992,52(21):6036-6044.
[144] LIERSCH T, MELLER J, KULLE B et al. Phase II trial of carcinoembryonicantigen radioimmunotherapy with131I-labetuzumab after salvage resection ofcolorectal metastases in the liver: five-year safety and efficacy results[J]. JClin Oncol,2005,23(27):6763-6770.
[145] REARDON DA, AKABANI G, COLEMAN RE et al. Salvageradioimmunotherapy with murine iodine-131-labeled antitenascin monoclonalantibody81C6for patients with recurrent primary and metastatic malignantbrain tumors: phase II study results[J]. J Clin Oncol,2006,24(1):115-122.
[146] ALVAREZ RD, HUH WK, KHAZAELI MB et al. A Phase I study ofcombined modality (90)Yttrium-CC49intraperitoneal radioimmunotherapy forovarian cancer[J]. Clin Cancer Res,2002,8(9):2806-2811.
[147] MAHE MA, FUMOLEAU P, FABBRO M et al. A phase II study ofintraperitoneal radioimmunotherapy with iodine-131-labeled monoclonalantibody OC-125in patients with residual ovarian carcinoma[J]. Clin CancerRes,1999,5(10Suppl):3249s-3253s.
[148] DENARDO SJ, KUKIS DL, KROGER LA et al. Synergy of Taxol andradioimmunotherapy with yttrium-90-labeled chimeric L6antibody: efficacyand toxicity in breast cancer xenografts[J]. Proceedings of the NationalAcademy of Sciences of the United States of America,1997,94(8):4000-4004.
[149] TSCHMELITSCH J, BARENDSWAARD E, WILLIAMS C, JR. et al.Enhanced antitumor activity of combination radioimmunotherapy(131I-labeled monoclonal antibody A33) with chemotherapy (fluorouracil)[J].Cancer research,1997,57(11):2181-2186.
[150] CLARKE K, LEE FT, BRECHBIEL MW et al. Therapeutic efficacy ofanti-Lewis(y) humanized3S193radioimmunotherapy in a breast cancer model:enhanced activity when combined with taxol chemotherapy[J]. Clin CancerRes,2000,6(9):3621-3628.
[151] BURKE PA, DENARDO SJ, MIERS LA, KUKIS DL, DENARDO GL.Combined modality radioimmunotherapy. Promise and peril[J]. Cancer,2002,94(4Suppl):1320-1331.
[152] GOLD DV, MODRAK DE, SCHUTSKY K, CARDILLO TM. Combined90Yttrium-DOTA-labeled PAM4antibody radioimmunotherapy andgemcitabine radiosensitization for the treatment of a human pancreatic cancerxenograft[J]. International journal of cancer,2004,109(4):618-626.
[153] GOLD DV, SCHUTSKY K, MODRAK D, CARDILLO TM. Low-doseradioimmunotherapy ((90)Y-PAM4) combined with gemcitabine for thetreatment of experimental pancreatic cancer[J]. Clin Cancer Res,2003,9(10Pt2):3929S-3937S.
[154] GRAVES SS, DEARSTYNE E, LIN Y et al. Combination therapy withPretarget CC49radioimmunotherapy and gemcitabine prolongs tumordoubling time in a murine xenograft model of colon cancer more effectivelythan either monotherapy[J]. Clin Cancer Res,2003,9(10Pt1):3712-3721.
[155] KRAEBER-BODERE F, SAI-MAUREL C, CAMPION L et al. Enhancedantitumor activity of combined pretargeted radioimmunotherapy and paclitaxelin medullary thyroid cancer xenograft[J]. Molecular cancer therapeutics,2002,1(4):267-274.
[156] BAUMANN M, KRAUSE M. Targeting the epidermal growth factor receptorin radiotherapy: radiobiological mechanisms, preclinical and clinical results[J].Radiother Oncol,2004,72(3):257-266.
[157] MATHE G, LOC T, BERNARD J. Effet sur la leucemie1210de la sourisd′une combinaison par diazotation d′A-methopterine et de γ-globulines dehamsters porteurs de cette leucemie par heterogreffe[J]. C R Acad Sci,1958,246:1626-1628.
[158] BROSS PF, BEITZ J, CHEN G et al. Approval summary: gemtuzumabozogamicin in relapsed acute myeloid leukemia[J]. Clin Cancer Res,2001,7(6):1490-1496.
[159] LARSON RA, SIEVERS EL, STADTMAUER EA et al. Final report of theefficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients withCD33-positive acute myeloid leukemia in first recurrence[J]. Cancer,2005,104(7):1442-1452.
[160] CHEVALLIER P, ROLAND V, MAHE B et al. Administration of mylotarg4days after beginning of a chemotherapy including intermediate-dose aracytinand mitoxantrone (MIDAM regimen) produces a high rate of completehematologic remission in patients with CD33+primary resistant or relapsedacute myeloid leukemia[J]. Leukemia research,2005,29(9):1003-1007.
[161] AMADORI S, SUCIU S, STASI R et al. Gemtuzumab ozogamicin (Mylotarg)as single-agent treatment for frail patients61years of age and older with acutemyeloid leukemia: final results of AML-15B, a phase2study of the EuropeanOrganisation for Research and Treatment of Cancer and Gruppo ItalianoMalattie Ematologiche dell'Adulto Leukemia Groups[J]. Leukemia,2005,19(10):1768-1773.
[162] ARCECI RJ, SANDE J, LANGE B et al. Safety and efficacy of gemtuzumabozogamicin in pediatric patients with advanced CD33+acute myeloidleukemia[J]. Blood,2005,106(4):1183-1188.
[163] WU AM, SENTER PD. Arming antibodies: prospects and challenges forimmunoconjugates[J]. Nature biotechnology,2005,23(9):1137-1146.
[164] CHEN J, JARACZ S, ZHAO X, CHEN S, OJIMA I. Antibody-cytotoxic agentconjugates for cancer therapy[J]. Expert opinion on drug delivery,2005,2(5):873-890.
[165] GOVINDAN SV, GRIFFITHS GL, HANSEN HJ, HORAK ID,GOLDENBERG DM. Cancer therapy with radiolabeled anddrug/toxin-conjugated antibodies[J]. Technology in cancer research&treatment,2005,4(4):375-391.
[166] SMITH SV. Technology evaluation: cantuzumab mertansine, ImmunoGen[J].Current opinion in molecular therapeutics,2004,6(6):666-674.
[167] LAW CL, CERVENY CG, GORDON KA et al. Efficient elimination ofB-lineage lymphomas by anti-CD20-auristatin conjugates[J]. Clin Cancer Res,2004,10(23):7842-7851.
[168] TORGOV MY, ALLEY SC, CERVENY CG, FARQUHAR D, SENTER PD.Generation of an intensely potent anthracycline by a monoclonalantibody-beta-galactosidase conjugate[J]. Bioconjugate chemistry,2005,16(3):717-721.
[169] HAMANN PR, HINMAN LM, BEYER CF et al. A calicheamicin conjugatewith a fully humanized anti-MUC1antibody shows potent antitumor effects inbreast and ovarian tumor xenografts[J]. Bioconjugate chemistry,2005,16(2):354-360.
[170] BURTON JD, ELY S, REDDY PK et al. CD74is expressed by multiplemyeloma and is a promising target for therapy[J]. Clin Cancer Res,2004,10(19):6606-6611.
[171] GRIFFITHS GL, MATTES MJ, STEIN R et al. Cure of SCID mice bearinghuman B-lymphoma xenografts by an anti-CD74antibody-anthracycline drugconjugate[J]. Clin Cancer Res,2003,9(17):6567-6571.
[172] SAPRA P, STEIN R, PICKETT J et al. Anti-CD74antibody-doxorubicinconjugate, IMMU-110, in a human multiple myeloma xenograft and inmonkeys[J]. Clin Cancer Res,2005,11(14):5257-5264.
[173] CHANG CH, SAPRA P, VANAMA SS et al. Effective therapy of humanlymphoma xenografts with a novel recombinant ribonuclease/anti-CD74humanized IgG4antibody immunotoxin[J]. Blood,2005,106(13):4308-4314.
[174] JEDEMA I, BARGE RM, VAN DER VELDEN VH et al. Internalization andcell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin:rationale for efficacy in CD33-negative malignancies with endocyticcapacity[J]. Leukemia,2004,18(2):316-325.
[175] LESLIE EM, DEELEY RG, COLE SP. Multidrug resistance proteins: role ofP-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense[J].Toxicology and applied pharmacology,2005,204(3):216-237.
[176] NAITO K, TAKESHITA A, SHIGENO K et al. Calicheamicin-conjugatedhumanized anti-CD33monoclonal antibody (gemtuzumab zogamicin,CMA-676) shows cytocidal effect on CD33-positive leukemia cell lines, but isinactive on P-glycoprotein-expressing sublines[J]. Leukemia,2000,14(8):1436-1443.
[177] HAMANN PR, HINMAN LM, BEYER CF et al. An anti-MUC1antibody-calicheamicin conjugate for treatment of solid tumors. Choice oflinker and overcoming drug resistance[J]. Bioconjugate chemistry,2005,16(2):346-353.
[178] HAMANN PR, HINMAN LM, BEYER CF et al. An anti-CD33antibody-calicheamicin conjugate for treatment of acute myeloid leukemia.Choice of linker[J]. Bioconjugate chemistry,2002,13(1):40-46.
[179] SHARMA SK, BAGSHAWE KD, BEGENT RH. Advances inantibody-directed enzyme prodrug therapy[J]. Curr Opin Investig Drugs,2005,6(6):611-615.
[180] FRANCIS RJ, SHARMA SK, SPRINGER C et al. A phase I trial of antibodydirected enzyme prodrug therapy (ADEPT) in patients with advancedcolorectal carcinoma or other CEA producing tumours[J]. British journal ofcancer,2002,87(6):600-607.
[181] MAYER A, SHARMA SK, TOLNER B et al. Modifying an immunogenicepitope on a therapeutic protein: a step towards an improved system forantibody-directed enzyme prodrug therapy (ADEPT)[J]. British journal ofcancer,2004,90(12):2402-2410.
[182] CORTEZ-RETAMOZO V, BACKMANN N, SENTER PD et al. Efficientcancer therapy with a nanobody-based conjugate[J]. Cancer research,2004,64(8):2853-2857.
[183] EKLUND JW, KUZEL TM. Denileukin diftitox: a concise clinical review[J].Expert review of anticancer therapy,2005,5(1):33-38.
[184] FRANKEL AE, KREITMAN RJ, SAUSVILLE EA. Targeted toxins[J]. ClinCancer Res,2000,6(2):326-334.
[185] PASTAN I. Immunotoxins containing Pseudomonas exotoxin A: a shorthistory[J]. Cancer Immunol Immunother,2003,52(5):338-341.
[186] NEWTON DL, HANSEN HJ, MIKULSKI SM, GOLDENBERG DM,RYBAK SM. Potent and specific antitumor effects of an anti-CD22-targetedcytotoxic ribonuclease: potential for the treatment of non-Hodgkinlymphoma[J]. Blood,2001,97(2):528-535.
[187] VITETTA ES, FULTON RJ, MAY RD, TILL M, UHR JW. Redesigningnature's poisons to create anti-tumor reagents[J]. Science (New York, NY,1987,238(4830):1098-1104.
[188] GADINA M, NEWTON DL, RYBAK SM, WU YN, YOULE RJ. Humanizedimmunotoxins[J]. Therapeutic immunology,1994,1(1):59-64.
[189] AMLOT PL, STONE MJ, CUNNINGHAM D et al. A phase I study of ananti-CD22-deglycosylated ricin A chain immunotoxin in the treatment ofB-cell lymphomas resistant to conventional therapy[J]. Blood,1993,82(9):2624-2633.
[190] SAUSVILLE EA, HEADLEE D, STETLER-STEVENSON M et al.Continuous infusion of the anti-CD22immunotoxin IgG-RFB4-SMPT-dgA inpatients with B-cell lymphoma: a phase I study[J]. Blood,1995,85(12):3457-3465.
[191] STONE MJ, SAUSVILLE EA, FAY JW et al. A phase I study of bolus versuscontinuous infusion of the anti-CD19immunotoxin, IgG-HD37-dgA, inpatients with B-cell lymphoma[J]. Blood,1996,88(4):1188-1197.
[192] SMALLSHAW JE, GHETIE V, RIZO J et al. Genetic engineering of animmunotoxin to eliminate pulmonary vascular leak in mice[J]. Naturebiotechnology,2003,21(4):387-391.
[193] KREITMAN RJ, SQUIRES DR, STETLER-STEVENSON M et al. Phase Itrial of recombinant immunotoxin RFB4(dsFv)-PE38(BL22) in patients withB-cell malignancies[J]. J Clin Oncol,2005,23(27):6719-6729.
[194] POSEY JA, KHAZAELI MB, BOOKMAN MA et al. A phase I trial of thesingle-chain immunotoxin SGN-10(BR96sFv-PE40) in patients withadvanced solid tumors[J]. Clin Cancer Res,2002,8(10):3092-3099.
[195] HELLSTROM I, GARRIGUES HJ, GARRIGUES U, HELLSTROM KE.Highly tumor-reactive, internalizing, mouse monoclonal antibodies toLe(y)-related cell surface antigens[J]. Cancer research,1990,50(7):2183-2190.
[196] NAKAMURA Y, SODA H, OKA M et al. Randomized phase II trial ofirinotecan with paclitaxel or gemcitabine for non-small cell lung cancer:association of UGT1A1*6and UGT1A1*27with severe neutropenia[J]. JThorac Oncol,6(1):121-127.
[197] KODERA Y, IMANO M, YOSHIKAWA T et al. A randomized phase II trial totest the efficacy of intra-peritoneal paclitaxel for gastric cancer with high riskfor the peritoneal metastasis (INPACT trial)[J]. Japanese journal of clinicaloncology,41(2):283-286.
[198] JEMAL A, SIEGEL R, WARD E et al. Cancer statistics,2006[J]. CA: a cancerjournal for clinicians,2006,56(2):106-130.
[199] SUN S, SCHILLER JH, GAZDAR AF. Lung cancer in never smokers--adifferent disease[J]. Nature reviews,2007,7(10):778-790.
[200] BACH PB, KELLEY MJ, TATE RC, MCCRORY DC. Screening for lungcancer: a review of the current literature[J]. Chest,2003,123(1Suppl):72S-82S.
[201] HENSCHKE CI, YANKELEVITZ DF, LIBBY DM et al. Survival of patientswith stage I lung cancer detected on CT screening[J]. The New Englandjournal of medicine,2006,355(17):1763-1771.
[202] DING L, GETZ G, WHEELER DA et al. Somatic mutations affect keypathways in lung adenocarcinoma[J]. Nature,2008,455(7216):1069-1075.
[203] WEIR BA, WOO MS, GETZ G et al. Characterizing the cancer genome inlung adenocarcinoma[J]. Nature,2007,450(7171):893-898.
[204] THOMAS RK, BAKER AC, DEBIASI RM et al. High-throughput oncogenemutation profiling in human cancer[J]. Nature genetics,2007,39(3):347-351.
[205] WISTUBA, II, BEHRENS C, VIRMANI AK et al. High resolutionchromosome3p allelotyping of human lung cancer andpreneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuoussites of3p allele loss and three regions of frequent breakpoints[J]. Cancerresearch,2000,60(7):1949-1960.
[206] Stein U, Walther W, Arlt F, et al. MACC1, a newly identified key regulator ofHGF-MET signaling, predicts colon cancer metastasis[J]. Nat Med,2009,15(1):59-67.
[207] Rygaard K, Nakamura T, Spang-Thomsen M, et al. Expression of theproto-oncegenes c-met and c-kit and their ligands, hepatocyte growthfactor/scatter factor and stem cell factor, in SCLC cell lines and xenografts [J].Br J Cancer,1993,67(1):37-46.
[208] Gautam Maulik, Takashi Kijima, Patrick C Ma, et al. Modulation of thec-Met/hepatocyte growth factor pathway in small cell lung cancer[J]. ClinCaner Res,2002,8(2):620-627.
[209] Jeffers M, Rong S, Vande Woude GF. Enhanced tumorigenicity and invasion–metastasis by hepatocyte growth factor/scatter factor-mer signalling in humancells concomitant with induction of the urokinase proteolysis network[J]. MolCell Biol,1996,16(3):1115-1125.
[210] Jeffers M, Rong S, Woude GF. Hepatocyte growth factor/scatter factor–Metsignaling in tumorigenicity and invasion/metastasis[J]. J Mol Med,1996,74(9):505-513.
[211] Shirahata A, Sakata M, Kitamura Y, et al. MACC1as a marker for advancedcolorectal cancinoma[J]. Anticancer Res,2010,30(9):3441-3444.
[212] Shirahata A, Sakata M, Kitamura Y, et al. MACC1as a marker for advancedcolorectal carcinoma[J]. Anticancer Res,2010,30(7)：2689-2692.
[213] Katarzyna K, Jacek Krynski, Leszek R, et al. Unexpected domain compositionof MACC1links MET signaling and apoptosis[J]. Acta Biochim Pol,2009,56(2):317-323.
[214] Stein U, Dahlmann M, Walther W, et al. MACC1-more than metastasis? Factsand predicitions about a novel gene[J]. J Mol Med,2010,88(1):11-18.
[215] Birchmeier C, Birchmeier W, Gherardi E, et al. Met, metastasis, motility andmore[J]. Nat Rev Mol Cell Biol,2003,4(12):915-925.
[216] Birchmeier W, Brinkmann V, Niemann C, et al. Role of HGF/SF and c-Met inmorphogenesis and metastasis of epithelial cells[J]. Ciba Found Symp,1997,212:230-240.
[217] Boccaccio C, Comoglio PM, Invasive growth: a MET-driven geneticprogramme for cancer and stem cells[J]. Nat Rev Cancer,2006,6(8):637-645.
[218] Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interferenceby double-stranded RNA in Cae–norhabditis elegans[J]. Nature,1998,19(2):806-811.
[219] Stein U, Burock S, Herrmann P, Circulating MACC1transcripts in colorectalcancer patient plasma predicts metastasis and prognosis[J]. Plos One,2012,7(11)
[220] Harpaz N, Taboada S, Mabel K, et al. Expression of MACC1and MET inInflammatory Bowel Disease-associated Colonic Neoplasia[J]. Inflamm BowelDis.2014.
[221] Chen Xiao-Ping,Ren Xin-Ping, Lan Jian-Yun, et al. Analysis of HGF, MACC1,C-met and apoptosis-related genes in cervical carcinoma mice[J]. Mol BiolRep.2014.
[222] Wang Yong, Hong Qiang, Wang Jian-Yun, et al. Downregulated expression ofmetastasis associated in colon cancer1(MACC1) reduces gallbladder cancercell proliferation and invasion[J]. Tumour Biol.2014.
[223] Wang Zhi-qiang, Li Zhi, Wu Chen, et al. MACC1overexpression predicts apoor prognosis for non-small cell lung cancer[J]. Med Oncol,2014.31(1):790.
[224] Cai Hong-xia, Yang Yong-xiu. Effects of MACC1siRNA on biologicalbehaviors of HeLa[J]. Arch Gynecol Obstet.2013.
[225] Guo Tian-kang, Yang Jing-yu, Yao Ji-bin, et al. Expression of MACC1andc-Met in human gastric cancer and its clinical significance[J]. Cancer Cell Int,2013,13(1):121.
[226] Hagemann C, Fuchs S, Stein U, et al. Impact of MACC1on human malignantglioma progression and patients' unfavorable prognosis[J]. Neuro Oncol,2013,15(12):1696-1709.
[227] Ren Bing, Zakharov V, Yang Qi, et al. MACC1Is Related to ColorectalCancer Initiation and Early-Stage Invasive Growth[J]. Am J Clin Pathol,2013,140(5):701-707.
[228] Zhang Kai, Tian Fang, Zhang Yong-gang, et al. MACC1is involved in theregulation of proliferation, colony formation, invasion ability, cell cycledistribution, apoptosis and tumorigenicity by altering Akt signaling pathway inhuman osteosarcoma[J]. Tumour Biol,2013.
[229] Juneja M, Ilm K, Schlag P, Stein U. Promoter identification and transcriptionalregulation of the metastasis gene MACC1in colorectal cancer[J].Mol Oncol,2013,7(5):929-943.
[230] Stein U. MACC1-a novel target for solid cancers[J]. Expert Opin TherTargets,2013,17(9):1039-1052.
[231] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancerstatistics. CA Cancer J Clin.2011,61(2):69-90.
[232] Huang Y, Zhang H, Cai J, Fang L, et al. Overexpression of MACC1and itssignificance in human Breast Cancer Progression. Cell Biosci.2013;3(1):16.
[233] Qiu J, Huang P, Liu Q, Hong J, Li B, et al. Identification of MACC1as a novelprognostic marker in hepatocellular carcinoma.[J] Transl Med.2011;9:166.
[234] Xie C, Wu J, Yun J, Lai J, Yuan Y, Gao Z, et al. MACC1as a prognosticbiomarker for early-stage and AFP-normal hepatocellular carcinoma.[J] PLOSONE.2013;8(5):e64235.
[235] Meng F, Li H, Shi H, Yang Q, et al. MACC1down-regulation inhibitsproliferation and tumourigenicity of nasopharyngeal carcinoma cells throughAkt/beta-catenim signaling pathway.[J] Plos One.2013;8(4):e60821.
[236] Wang G, Kang M, Lu W, Chen Y, Zhang B, Wu YL. MACC1: a potentialmolecule associated with pancreatic cancer metastasis and chemoresistance..[J]Oncol Lett.2012;4(4):783-791.
[237] Kawamura M, Saigusa S, Toiyama Y, Tanaka K, Okugawa Y, Hiro J, et al.Correlation of MACC1and MET expression in rectal cancer after neoadjuvantchemoradiotherapy.[J] Anticancer Res.2012;32(4):1527-1531.
[238] Hu X, Fu X, Wen S, Zou X, Liu Y. Prognostic value of MACC1and c-metexpressions in non-small cell lung cancer.[J] Chin J Lung Cancer.2012;15(7):399-403.
[239] Chundong G, Uramoto H, Onitsuka T, Shimokawa H, Iwanami T, NakagawaM, et al. Molecular diagnosis of MACC1status in lung adenocarcinoma byimmunohistochemical analysis.[J] Anticancer Res.2011;31(4):1141-1145.
[240] Shimokawa H, Uramoto H, Onitsuka T, Chundong G, Hanagiri T, Oyama T, etal.. Overexpression of MACC1mRNA in lung adenocarcinoma is associatedwith postoperative recurrence.[J] Thorac Cardiovasc Surg.2011;141(4):895-898.
[241] Xue X, Zhu YM, Woll PJ. Circulating DNA and lung cancer. Ann N Y AcadSci.2006;1075:154-164.
[242] An Q, Liu Y, Gao Y, et al. Detection of p16hypermethylation in circulatingplasma DNA of non-small cell lung cancer patients. CancerLett,2002;188(1-2):109-114.
[243] Bowman RV, Yang IA, Semmler AB, Fong KM. Epigenetics of lung cancer.Respirology,2006;11(4)：355-365.
[244] Mao L. Recent advances in the molecular diagnosis of lung cancer.Oncogene.2002;21(45):6960-6969.
[245] Ahrendt SA, Decker PA, Alawi EA, et al. Cigarette smoking is stronglyassociated with mutation of the K-ras gene in patients with primaryadenocarcinoma of the lung. Cancer.2001;92(6):1525-1530.
[246] Suecka E, Suecka N, Iwanaga K, et al. Detection of plasma hnRNP B1MRNA,a new cancer biomarker, in lung cancer patients by quantitative real-timepolymerase chain reaction. Lung Cancer.2005;48(1):77-83.
[247] Jeronimo C, Nomoto S, Caballero CL, et al. Mitochondrial mutations in earlystage prostate cancer and bodily fluids. Oncogene.2001;20(37):5195-5198.
[248] Howington JA, Blum MG, Chang AC, Balekian AA, Murthy SC. Treatment ofstage Ⅰ and Ⅱ non-small cell lung cancer: diagnosis and management of lungcancer,3rd edition: American College of Chest Physicians evidence-basedclinical pratice guidelines.[J] Chest.2013;143(5Suppl):e278S-313S.
[249] Matsuge S, Hosokawa Y, Sato K, et al. Surgical treatment for bilateral multiplelung cancers.[J] Kyobu Geka.2000,53:89-94.
[250] Niho S, Nishiwaki Y, Goto K, et al. Significance of serumpro-gastrin-releasing poptide as a predictor of relapse of small cell lung cancer:comparative evaluation with neuron-specific enolase and carcinoembryonicantigen.[J] Lung Cancer.2000,27:159-167.
[251] Shibayama T, Ueoka H, Nishii K, et al. Complementary roles of pro–gastrin-releasing peptide(ProGRP) and neuron specific enolase(NSE) indiagnosis and prognosis of small cell lung cancer(SCLC).[J] Lung Cancer.2001,32:61-69.
[252] Jorgensen LGM, Osterlind K, Genolla J, et al. Serum neuron-specific enolase(S-NSE) and the prognosis in small-cell lung cancer(SCLC): a combinedmultivariable analysis on data from nine centres.[J] Br J Cancer.1996,74:463-467.
[253] Goto K, Kodama T, Hojo F, et al. Clinicopathologic characteristics of patientswith nonsmall cell lung cancinoma with elevated serum progastrin-releasingpeptide levels.[J] Cancer,1998,82:1056-1061.
[254] Chang YL, Wu CT and Lee YC. Surgical treatment of synchronous multipleprimary lung cancers: experience of92patients.[J] Thorac CardiovascSurg.2007,134:630-637.
[255] Adebonojo SA, Moritz DM and Danby CA. The results of modern surgicaltherapy for multiple primary lung cancers.[J] Chest.1997,112:693-701.
[256] Tsunezuka Y, Matsumoto I, Tamura M, et al. The results of therapy forbilateral multiple primary lung cancers:30years experience in a singlecentre.[J] Eur J Surg Oncol.2004,30：781-785.
[257] Sethi N, Kang Y. Unravelling the complexity of metastasis-molecularunderstanding and targeted therapies.[J] Nat Rev Cancer.2011;11:735-748.
[258] Wanebo HJ, LeGolvan M, Paty PB, et al. Meeting the biologic chanllenge ofcolorectal metastases.[J] Clin Exp Metastasis.2012;29:821-839.
[259] Gherardi E, Birchmeier W, Birchmeier C, et al. Targeting MET in cancer:rationale and progess.[J] Nat Rev Cancer.2012;12:89-103.
[260] Luraghi P, Schelter F, Kruger A, et al. The MET oncogene as a therapeuticaltarget in cancer invasive growth.[J] Front Pharmacol.2012;3:164.
[261] Schmid F, Wang Q, Huska MR, et al. S100P, a target gene of MACC1,contributes to colorectal cancer metastasis.[J] Proc Am Ass Cancer Res.2012;54:416.
[262] Toiyama Y, Miki C, Inoue Y, et al. Serum hepatocyte growth factor as aprognostic marker for stage Ⅱor Ⅲ colorectal cancer patients.[J] Int JCancer.2009;125:1657-1662.
[263] Lang AH, Geller-Rhomberg S, Winder T, et al. A common variant of theMACC1gene is signitificantly in colorectal cancer patients.[J] BMCCancer.2012;12:20.
[264] Lang S, Geller-Rhomberg T, Winder BL, et al. Evaluation of the associationbetween tagging polymorphisms of the MACC1locus and overall survival inpatients with colorectal cancer. ACSO Meeting. J Clin Oncel.2011;29(suppl):abstracts3594.
[265] Ferguson MK, DeMeester TR, DesLauriers J, et al. Diagnosis andmanagement of synchronous lung cancer.[J] Thorac Cardiovasc Surg.1985,89:378-385.
[266] Martini N, Melamed MR. Multiple primary lung cancers.[J] ThoracCardiovasc Surg.1975,70:606-612.
[267] Ge SH, Wu XJ, Wang XH, Xing XF, Zhang LH, Zhu YB, et al.Over-expression of metastasis-associated in colon cancer-1(MACC1)associates with better prognosis of gastric cancer patients.[J] Chin J Cancer.2011;23(2):153-159.
[268] Boardman LA. Overexpression of MACC1leads to downstream activation ofHGF/MET and potentiates metastasis and recurrence of colorectal cancer.[J]Genome Med.2009;1(4):36.
[269] Isella C, Mellano A, Galimi F, Petti C, Capussotti L, De Simone M, et al.MACC1mRNA levels predict cancer recurrence after resection of colorectalcancer liver metastases.[J] Ann Surg.2013;257(6):1089-1095.
[270] Stein U, Smith J, Walther W, et al. MACC1controls Met: what a difference anSp1site makes.[J] Cell Cycle.2009;8:2467-2469.
[271] Shu C, Cheng H, Wang A, et al. Thymidylate synthase expression andmolecular alterations in adenosquamous carcinoma of the lung.[J] Mod Pathol.2013;26:239-246.
[272] Gallego MI, Bierie B, Hennighausen L. Targeted expression of HGF/SF inmouse mammary epithelium leads to metastatic adenosquamous carcinomasthrough the activation of multiple signal transduction pathways.[J] Oncogene.2003;22:8498-8508.
[273] Galimi F, Torti D, Sassi F, Isella C, et al. Genetic and expression analysis ofMET, MACC1, and HGF in metastatic colorectal cancer: response to Metinhibition in patient xenografts and pathologic correlations.[J] Clin CancerRes.2011;17:3146-3156.
[274] Stein U, Schlag PM. Clinical, biological, and molecular aspects of metastasisin colorectal cancer.[J] Recent Results Cancer Res.2007;176:61-80.
[275] Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in2008: globocan2008.[J] Int J Cancer,2010;127:2893-2917.
[276] Naishadham D, Jemal A. Cancer statistics,2013.[J] Cancer J Clin.2013;63:11-30.
[277] Wang X, Christiani DC, Mark EJ, et al. Carcinogen exposure, p53alteration,and K-ras mutation in synchronous multiple primary lung carcinoma.[J]Cancer.1999,85:1734-1739.
[278] Miura H, Nakajima N, Ikeda N, et al. Therapeutic strategy for secondary lungcancer.[J] Kyobu Geka,2010,63:956-961.
[279] Van Rens MTM, Zanen P, de la Ribiere AB, et al. Survival in synchronousversus single lung cancer: upstaging better reflects prognosis.[J] Chest.2000,118:952-958.
[280] Lam S, MacAulay C and Palcic B. Detection and localization of early lungcancer by imaging techniques.[J] Chest.1993,103:S12-S14.
[281] Woolner LB, Fontana RS, Cortese DA, et al. Roentgenographically occult lungcancer: pathologic findings and frequency of multicentricity during a10-yearperiod.[J] Mayo Clin Proc.1984,59:453-466.
[282] Morita T. Incidence, contents and change of autopsied multiple primarycancers of the lung based on the annual of the autopsy cases in Japan between1958and1992.[J] Haigan.1997,37:283-294.
[283] Saito Y, Fujimura S, Sato M, et al. Recent adbances in diagnosis and treatmentof multiple primary lung cancers.[J] Nippon Kyobu Rinsho.1993,52:95-101.
[2] JEMAL A, SIEGEL R, WARD E et al. Cancer statistics,2006[J]. CA: a cancerjournal for clinicians,2006,56(2):106-130.
[3] E VB, S K. Dtsch Med[J]. Wochenschr,1890,16:1113-1114.
[4] J H. Astronomical[J]. Science (New York, NY,1895,2(51):845-846.
[5] HIMMELWEIT F. Serological responses and clinical reactions to influenzavirus vaccines[J]. British medical journal,1960,2(5214):1690-1694.
[6] NADLER LM, STASHENKO P, HARDY R et al. Serotherapy of a patient witha monoclonal antibody directed against a human lymphoma-associatedantigen[J]. Cancer research,1980,40(9):3147-3154.
[7] MILLER RA, MALONEY DG, WARNKE R, LEVY R. Treatment of B-celllymphoma with monoclonal anti-idiotype antibody[J]. The New Englandjournal of medicine,1982,306(9):517-522.
[8] FOON KA, SCHROFF RW, BUNN PA et al. Effects of monoclonal antibodytherapy in patients with chronic lymphocytic leukemia[J]. Blood,1984,64(5):1085-1093.
[9] GOLDENBERG DM, DELAND F, KIM E et al. Use of radiolabeledantibodies to carcinoembryonic antigen for the detection and localization ofdiverse cancers by external photoscanning[J]. The New England journal ofmedicine,1978,298(25):1384-1386.
[10] GAFFAR SA, PANT KD, SHOCHAT D, BENNETT SJ, GOLDENBERG DM.Experimental studies of tumor radioimmunodetection using antibody mixturesagainst carcinoembryonic antigen (CEA) and colon-specific antigen-p(CSAp)[J]. International journal of cancer,1981,27(1):101-105.
[11] DENARDO SJ, DENARDO GL, O'GRADY LF et al. Treatment of B cellmalignancies with131I Lym-1monoclonal antibodies[J]. International journalof cancer Supplement=Journal international du cancer,1988,3:96-101.
[12] GOLDENBERG DM, HOROWITZ JA, SHARKEY RM et al. Targeting,dosimetry, and radioimmunotherapy of B-cell lymphomas withiodine-131-labeled LL2monoclonal antibody[J]. J Clin Oncol,1991,9(4):548-564.
[13] BUCHSBAUM DJ, WAHL RL, NORMOLLE DP, KAMINSKI MS. Therapywith unlabeled and131I-labeled pan-B-cell monoclonal antibodies in nudemice bearing Raji Burkitt's lymphoma xenografts[J]. Cancer research,1992,52(23):6476-6481.
[14] KAMINSKI MS, ZASADNY KR, FRANCIS IR et al. Radioimmunotherapy ofB-cell lymphoma with [131I]anti-B1(anti-CD20) antibody[J]. The NewEngland journal of medicine,1993,329(7):459-465.
[15] MALONEY DG, LILES TM, CZERWINSKI DK et al. Phase I clinical trialusing escalating single-dose infusion of chimeric anti-CD20monoclonalantibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma[J]. Blood,1994,84(8):2457-2466.
[16] JAZIREHI AR, BONAVIDA B. Cellular and molecular signal transductionpathways modulated by rituximab (rituxan, anti-CD20mAb) in non-Hodgkin'slymphoma: implications in chemosensitization and therapeutic intervention[J].Oncogene,2005,24(13):2121-2143.
[17] ZHANG N, KHAWLI LA, HU P, EPSTEIN AL. Generation of rituximabpolymer may cause hyper-cross-linking-induced apoptosis in non-Hodgkin'slymphomas[J]. Clin Cancer Res,2005,11(16):5971-5980.
[18] GHOBRIAL IM, WITZIG TE, ADJEI AA. Targeting apoptosis pathways incancer therapy[J]. CA: a cancer journal for clinicians,2005,55(3):178-194.
[19] BIANCO R, DANIELE G, CIARDIELLO F, TORTORA G. Monoclonalantibodies targeting the epidermal growth factor receptor[J]. Current drugtargets,2005,6(3):275-287.
[20] EMENS LA. Trastuzumab: targeted therapy for the management ofHER-2/neu-overexpressing metastatic breast cancer[J]. American journal oftherapeutics,2005,12(3):243-253.
[21] CZUCZMAN MS. CHOP plus rituximab chemoimmunotherapy of indolentB-cell lymphoma[J]. Seminars in oncology,1999,26(5Suppl14):88-96.
[22] MARTY M, COGNETTI F, MARANINCHI D et al. Randomized phase II trialof the efficacy and safety of trastuzumab combined with docetaxel in patientswith human epidermal growth factor receptor2-positive metastatic breastcancer administered as first-line treatment: the M77001study group[J]. J ClinOncol,2005,23(19):4265-4274.
[23] RABEN D, HELFRICH B, CHAN DC et al. The effects of cetuximab aloneand in combination with radiation and/or chemotherapy in lung cancer[J]. ClinCancer Res,2005,11(2Pt1):795-805.
[24] FERRARA N, HILLAN KJ, NOVOTNY W. Bevacizumab (Avastin), ahumanized anti-VEGF monoclonal antibody for cancer therapy[J].Biochemical and biophysical research communications,2005,333(2):328-335.
[25] LEACH DR, KRUMMEL MF, ALLISON JP. Enhancement of antitumorimmunity by CTLA-4blockade[J]. Science (New York, NY,1996,271(5256):1734-1736.
[26] KAPADIA D, FONG L. CTLA-4blockade: autoimmunity as treatment[J]. JClin Oncol,2005,23(35):8926-8928.
[27] RUTGEERTS P, VAN ASSCHE G, VERMEIRE S. Review article: Infliximabtherapy for inflammatory bowel disease--seven years on[J]. Alimentarypharmacology&therapeutics,2006,23(4):451-463.
[28] CUPPOLETTI A, PEREZ-VILLA F, VALLEJOS I, ROIG E. Experience withsingle-dose daclizumab in the prevention of acute rejection in hearttransplantation[J]. Transplantation proceedings,2005,37(9):4036-4038.
[29] LIOSSIS SN, TSOKOS GC. Monoclonal antibodies and fusion proteins inmedicine[J]. The Journal of allergy and clinical immunology,2005,116(4):721-729; quiz730.
[30] CHATENOUD L. Monoclonal antibody-based strategies in autoimmunity andtransplantation[J]. Methods in molecular medicine,2005,109:297-328.
[31] CHAMBERS SA, ISENBERG D. Anti-B cell therapy (rituximab) in thetreatment of autoimmune diseases[J]. Lupus,2005,14(3):210-214.
[32] LOONEY RJ. B cell-targeted therapy in diseases other than rheumatoidarthritis[J]. The Journal of rheumatology,2005,73:25-28; discussion29-30.
[33] DEBAUN MR. Issues regarding study design for initial clinical trials usingdecitabine[J]. Seminars in hematology,2004,41(4Suppl6):23-27.
[34] ILANTZIS C, DEMARTE L, SCREATON RA, STANNERS CP. Deregulatedexpression of the human tumor marker CEA and CEA family memberCEACAM6disrupts tissue architecture and blocks colonocytedifferentiation[J]. Neoplasia (New York, NY,2002,4(2):151-163.
[35] BLUMENTHAL RD, OSORIO L, HAYES MK et al. Carcinoembryonicantigen antibody inhibits lung metastasis and augments chemotherapy in ahuman colonic carcinoma xenograft[J]. Cancer Immunol Immunother,2005,54(4):315-327.
[36] JAIN RK. Transport of molecules, particles, and cells in solid tumors[J].Annual review of biomedical engineering,1999,1:241-263.
[37] FUJIMORI K, COVELL DG, FLETCHER JE, WEINSTEIN JN. A modelinganalysis of monoclonal antibody percolation through tumors: a binding-sitebarrier[J]. J Nucl Med,1990,31(7):1191-1198.
[38] ADAMS GP, SCHIER R, MCCALL AM et al. High affinity restricts thelocalization and tumor penetration of single-chain fv antibody molecules[J].Cancer research,2001,61(12):4750-4755.
[39] BLUMENTHAL RD, FAND I, SHARKEY RM et al. The effect of antibodyprotein dose on the uniformity of tumor distribution of radioantibodies: anautoradiographic study[J]. Cancer Immunol Immunother,1991,33(6):351-358.
[40] KOHLER G, MILSTEIN C. Continuous cultures of fused cells secretingantibody of predefined specificity[J]. Nature,1975,256(5517):495-497.
[41] SEARS HF, HERLYN D, STEPLEWSKI Z, KOPROWSKI H. Phase II clinicaltrial of a murine monoclonal antibody cytotoxic for gastrointestinaladenocarcinoma[J]. Cancer research,1985,45(11Pt2):5910-5913.
[42] HOUGHTON AN, MINTZER D, CORDON-CARDO C et al. Mousemonoclonal IgG3antibody detecting GD3ganglioside: a phase I trial inpatients with malignant melanoma[J]. Proceedings of the National Academy ofSciences of the United States of America,1985,82(4):1242-1246.
[43] GOODMAN GE, BEAUMIER P, HELLSTROM I, FERNYHOUGH B,HELLSTROM KE. Pilot trial of murine monoclonal antibodies in patientswith advanced melanoma[J]. J Clin Oncol,1985,3(3):340-352.
[44] WALDMANN H, HALE G. CAMPATH: from concept to clinic[J].Philosophical transactions of the Royal Society of London,2005,360(1461):1707-1711.
[45] MORRISON SL, JOHNSON MJ, HERZENBERG LA, OI VT. Chimerichuman antibody molecules: mouse antigen-binding domains with humanconstant region domains[J]. Proceedings of the National Academy of Sciencesof the United States of America,1984,81(21):6851-6855.
[46] JONES PT, DEAR PH, FOOTE J, NEUBERGER MS, WINTER G. Replacingthe complementarity-determining regions in a human antibody with those froma mouse[J]. Nature,1986,321(6069):522-525.
[47] QU Z, GRIFFITHS GL, WEGENER WA et al. Development of humanizedantibodies as cancer therapeutics[J]. Methods (San Diego, Calif,2005,36(1):84-95.
[48] ANGENENDT P. Progress in protein and antibody microarray technology[J].Drug discovery today,2005,10(7):503-511.
[49] WENG WK, LEVY R. Two immunoglobulin G fragment C receptorpolymorphisms independently predict response to rituximab in patients withfollicular lymphoma[J]. J Clin Oncol,2003,21(21):3940-3947.
[50] MCLAUGHLIN P, GRILLO-LOPEZ AJ, LINK BK et al. Rituximab chimericanti-CD20monoclonal antibody therapy for relapsed indolent lymphoma: halfof patients respond to a four-dose treatment program[J]. J Clin Oncol,1998,16(8):2825-2833.
[51] DAVIS TA, GRILLO-LOPEZ AJ, WHITE CA et al. Rituximab anti-CD20monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacyof re-treatment[J]. J Clin Oncol,2000,18(17):3135-3143.
[52] HAINSWORTH JD, LITCHY S, SHAFFER DW et al. Maximizing therapeuticbenefit of rituximab: maintenance therapy versus re-treatment at progression inpatients with indolent non-Hodgkin's lymphoma--a randomized phase II trialof the Minnie Pearl Cancer Research Network[J]. J Clin Oncol,2005,23(6):1088-1095.
[53] COIFFIER B. First-line treatment of follicular lymphoma in the era ofmonoclonal antibodies[J]. Clin Adv Hematol Oncol,2005,3(6):484-491,505.
[54] COIFFIER B. Rituximab in diffuse large B-cell lymphoma[J]. Clin AdvHematol Oncol,2004,2(3):156-157.
[55] FEUGIER P, VIRION JM, TILLY H et al. Incidence and risk factors for centralnervous system occurrence in elderly patients with diffuse large-B-celllymphoma: influence of rituximab[J]. Ann Oncol,2004,15(1):129-133.
[56] BYRD JC, MURPHY T, HOWARD RS et al. Rituximab using a thrice weeklydosing schedule in B-cell chronic lymphocytic leukemia and smalllymphocytic lymphoma demonstrates clinical activity and acceptabletoxicity[J]. J Clin Oncol,2001,19(8):2153-2164.
[57] O'BRIEN SM, KANTARJIAN H, THOMAS DA et al. Rituximabdose-escalation trial in chronic lymphocytic leukemia[J]. J Clin Oncol,2001,19(8):2165-2170.
[58] LEONARD JP, COLEMAN M, KETAS JC et al. Epratuzumab, a humanizedanti-CD22antibody, in aggressive non-Hodgkin's lymphoma: phase I/IIclinical trial results[J]. Clin Cancer Res,2004,10(16):5327-5334.
[59] LEONARD JP, COLEMAN M, KETAS J et al. Combination antibody therapywith epratuzumab and rituximab in relapsed or refractory non-Hodgkin'slymphoma[J]. J Clin Oncol,2005,23(22):5044-5051.
[60] YOUNES A, HARIHARAN K, ALLEN RS, LEIGH BR. Initial trials ofanti-CD80monoclonal antibody (Galiximab) therapy for patients withrelapsed or refractory follicular lymphoma[J]. Clinical lymphoma,2003,3(4):257-259.
[61] CZUCZMAN MS, THALL A, WITZIG TE et al. Phase I/II study of galiximab,an anti-CD80antibody, for relapsed or refractory follicular lymphoma[J]. JClin Oncol,2005,23(19):4390-4398.
[62] REFF ME, CARNER K, CHAMBERS KS et al. Depletion of B cells in vivoby a chimeric mouse human monoclonal antibody to CD20[J]. Blood,1994,83(2):435-445.
[63] GOLAY J, LAZZARI M, FACCHINETTI V et al. CD20levels determine thein vitro susceptibility to rituximab and complement of B-cell chroniclymphocytic leukemia: further regulation by CD55and CD59[J]. Blood,2001,98(12):3383-3389.
[64] SHAN D, LEDBETTER JA, PRESS OW. Apoptosis of malignant human Bcells by ligation of CD20with monoclonal antibodies[J]. Blood,1998,91(5):1644-1652.
[65] GOLAY J, ZAFFARONI L, VACCARI T et al. Biologic response of Blymphoma cells to anti-CD20monoclonal antibody rituximab in vitro: CD55and CD59regulate complement-mediated cell lysis[J]. Blood,2000,95(12):3900-3908.
[66] TREON SP, MITSIADES C, MITSIADES N et al. Tumor Cell Expression ofCD59Is Associated With Resistance to CD20Serotherapy in Patients WithB-Cell Malignancies[J]. J Immunother (1991),2001,24(3):263-271.
[67] WENG WK, LEVY R. Expression of complement inhibitors CD46, CD55, andCD59on tumor cells does not predict clinical outcome after rituximabtreatment in follicular non-Hodgkin lymphoma[J]. Blood,2001,98(5):1352-1357.
[68] MANCHES O, LUI G, CHAPEROT L et al. In vitro mechanisms of action ofrituximab on primary non-Hodgkin lymphomas[J]. Blood,2003,101(3):949-954.
[69] UCHIDA J, HAMAGUCHI Y, OLIVER JA et al. The innate mononuclearphagocyte network depletes B lymphocytes through Fc receptor-dependentmechanisms during anti-CD20antibody immunotherapy[J]. The Journal ofexperimental medicine,2004,199(12):1659-1669.
[70] HERNANDEZ-ILIZALITURRI FJ, JUPUDY V, OSTBERG J et al.Neutrophils contribute to the biological antitumor activity of rituximab in anon-Hodgkin's lymphoma severe combined immunodeficiency mousemodel[J]. Clin Cancer Res,2003,9(16Pt1):5866-5873.
[71] PRESTA LG. Engineering antibodies for therapy[J]. Current pharmaceuticalbiotechnology,2002,3(3):237-256.
[72] SHIELDS RL, LAI J, KECK R et al. Lack of fucose on human IgG1N-linkedoligosaccharide improves binding to human Fcgamma RIII andantibody-dependent cellular toxicity[J]. The Journal of biological chemistry,2002,277(30):26733-26740.
[73] HODONICZKY J, ZHENG YZ, JAMES DC. Control of recombinantmonoclonal antibody effector functions by Fc N-glycan remodeling in vitro[J].Biotechnology progress,2005,21(6):1644-1652.
[74] CARTRON G, DACHEUX L, SALLES G et al. Therapeutic activity ofhumanized anti-CD20monoclonal antibody and polymorphism in IgG Fcreceptor FcgammaRIIIa gene[J]. Blood,2002,99(3):754-758.
[75] KAKINOKI Y, KUBOTA H, YAMAMOTO Y. CD64surface expression onneutrophils and monocytes is significantly up-regulated after stimulation withgranulocyte colony-stimulating factor during CHOP chemotherapy for patientswith non-Hodgkin's lymphoma[J]. International journal of hematology,2004,79(1):55-62.
[76] PARIHAR R, DIERKSHEIDE J, HU Y, CARSON WE. IL-12enhances thenatural killer cell cytokine response to Ab-coated tumor cells[J]. The Journalof clinical investigation,2002,110(7):983-992.
[77] ANSELL SM, WITZIG TE, KURTIN PJ et al. Phase1study of interleukin-12in combination with rituximab in patients with B-cell non-Hodgkinlymphoma[J]. Blood,2002,99(1):67-74.
[78] PRESTA LG, SHIELDS RL, NAMENUK AK, HONG K, MENG YG.Engineering therapeutic antibodies for improved function[J]. BiochemicalSociety transactions,2002,30(4):487-490.
[79] VACCARO C, ZHOU J, OBER RJ, WARD ES. Engineering the Fc region ofimmunoglobulin G to modulate in vivo antibody levels[J]. Naturebiotechnology,2005,23(10):1283-1288.
[80] IDUSOGIE EE, WONG PY, PRESTA LG et al. Engineered antibodies withincreased activity to recruit complement[J]. J Immunol,2001,166(4):2571-2575.
[81] STOCKMEYER B, ELSASSER D, DECHANT M et al. Mechanisms ofG-CSF-or GM-CSF-stimulated tumor cell killing by Fc receptor-directedbispecific antibodies[J]. Journal of immunological methods,2001,248(1-2):103-111.
[82] BEVAART L, JANSEN MJ, VAN VUGT MJ et al. The high-affinity IgGreceptor, FcgammaRI, plays a central role in antibody therapy of experimentalmelanoma[J]. Cancer research,2006,66(3):1261-1264.
[83] SLAMON DJ, LEYLAND-JONES B, SHAK S et al. Use of chemotherapyplus a monoclonal antibody against HER2for metastatic breast cancer thatoverexpresses HER2[J]. The New England journal of medicine,2001,344(11):783-792.
[84] PICCART-GEBHART MJ, PROCTER M, LEYLAND-JONES B et al.Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer[J].The New England journal of medicine,2005,353(16):1659-1672.
[85] ROMOND EH, PEREZ EA, BRYANT J et al. Trastuzumab plus adjuvantchemotherapy for operable HER2-positive breast cancer[J]. The New Englandjournal of medicine,2005,353(16):1673-1684.
[86] IZUMI Y, XU L, DI TOMASO E, FUKUMURA D, JAIN RK. Tumour biology:herceptin acts as an anti-angiogenic cocktail[J]. Nature,2002,416(6878):279-280.
[87] GENNARI R, MENARD S, FAGNONI F et al. Pilot study of the mechanismof action of preoperative trastuzumab in patients with primary operable breasttumors overexpressing HER2[J]. Clin Cancer Res,2004,10(17):5650-5655.
[88] WARBURTON C, DRAGOWSKA WH, GELMON K et al. Treatment ofHER-2/neu overexpressing breast cancer xenograft models with trastuzumab(Herceptin) and gefitinib (ZD1839): drug combination effects on tumor growth,HER-2/neu and epidermal growth factor receptor expression, and viablehypoxic cell fraction[J]. Clin Cancer Res,2004,10(7):2512-2524.
[89] NEGRO A, BRAR BK, LEE KF. Essential roles of Her2/erbB2in cardiacdevelopment and function[J]. Recent progress in hormone research,2004,59:1-12.
[90] GARRATT AN, OZCELIK C, BIRCHMEIER C. ErbB2pathways in heart andneural diseases[J]. Trends in cardiovascular medicine,2003,13(2):80-86.
[91] EWER MS, VOOLETICH MT, DURAND JB et al. Reversibility oftrastuzumab-related cardiotoxicity: new insights based on clinical course andresponse to medical treatment[J]. J Clin Oncol,2005,23(31):7820-7826.
[92] TAN-CHIU E, YOTHERS G, ROMOND E et al. Assessment of cardiacdysfunction in a randomized trial comparing doxorubicin andcyclophosphamide followed by paclitaxel, with or without trastuzumab asadjuvant therapy in node-positive, human epidermal growth factor receptor2-overexpressing breast cancer: NSABP B-31[J]. J Clin Oncol,2005,23(31):7811-7819.
[93] NORMANNO N, BIANCO C, DE LUCA A, MAIELLO MR, SALOMON DS.Target-based agents against ErbB receptors and their ligands: a novel approachto cancer treatment[J]. Endocrine-related cancer,2003,10(1):1-21.
[94] GUAN H, JIA SF, ZHOU Z, STEWART J, KLEINERMAN ES. Herceptindown-regulates HER-2/neu and vascular endothelial growth factor expressionand enhances taxol-induced cytotoxicity of human Ewing's sarcoma cells invitro and in vivo[J]. Clin Cancer Res,2005,11(5):2008-2017.
[95] BONNER JA, HARARI PM, GIRALT J et al. Radiotherapy plus cetuximab forsquamous-cell carcinoma of the head and neck[J]. The New England journalof medicine,2006,354(6):567-578.
[96] PEREZ-SOLER R, SALTZ L. Cutaneous adverse effects withHER1/EGFR-targeted agents: is there a silver lining?[J]. J Clin Oncol,2005,23(22):5235-5246.
[97] BASELGA J, NORTON L, ALBANELL J, KIM YM, MENDELSOHN J.Recombinant humanized anti-HER2antibody (Herceptin) enhances theantitumor activity of paclitaxel and doxorubicin against HER2/neuoverexpressing human breast cancer xenografts[J]. Cancer research,1998,58(13):2825-2831.
[98] GORSKI DH, BECKETT MA, JASKOWIAK NT et al. Blockage of thevascular endothelial growth factor stress response increases the antitumoreffects of ionizing radiation[J]. Cancer research,1999,59(14):3374-3378.
[99] DE GRAMONT A, VAN CUTSEM E. Investigating the potential ofbevacizumab in other indications: metastatic renal cell, non-small cell lung,pancreatic and breast cancer[J]. Oncology,2005,69Suppl3:46-56.
[100] D'ADAMO DR, ANDERSON SE, ALBRITTON K et al. Phase II study ofdoxorubicin and bevacizumab for patients with metastatic soft-tissuesarcomas[J]. J Clin Oncol,2005,23(28):7135-7142.
[101] BRUNS I, FOX F, REINECKE P et al. Complete remission in a patient withrelapsed angioimmunoblastic T-cell lymphoma following treatment withbevacizumab[J]. Leukemia,2005,19(11):1993-1995.
[102] GORDON MS, CUNNINGHAM D. Managing patients treated withbevacizumab combination therapy[J]. Oncology,2005,69Suppl3:25-33.
[103] WITZIG TE, GORDON LI, CABANILLAS F et al. Randomized controlledtrial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versusrituximab immunotherapy for patients with relapsed or refractory low-grade,follicular, or transformed B-cell non-Hodgkin's lymphoma[J]. J Clin Oncol,2002,20(10):2453-2463.
[104] DAVIS TA, KAMINSKI MS, LEONARD JP et al. The radioisotopecontributes significantly to the activity of radioimmunotherapy[J]. Clin CancerRes,2004,10(23):7792-7798.
[105] SILVERSTEIN AM. Labeled antigens and antibodies: the evolution of magicmarkers and magic bullets[J]. Nature immunology,2004,5(12):1211-1217.
[106] GOLDENBERG DM. Perspectives on oncologic imaging with radiolabeledantibodies[J]. Cancer,1997,80(12Suppl):2431-2435.
[107] LARSON SM, PENTLOW KS, VOLKOW ND et al. PET scanning ofiodine-124-3F9as an approach to tumor dosimetry during treatment planningfor radioimmunotherapy in a child with neuroblastoma[J]. J Nucl Med,1992,33(11):2020-2023.
[108] WONG JY, CHU DZ, WILLIAMS LE et al. Pilot trial evaluating an123I-labeled80-kilodalton engineered anticarcinoembryonic antigen antibodyfragment (cT84.66minibody) in patients with colorectal cancer[J]. ClinCancer Res,2004,10(15):5014-5021.
[109] MCBRIDE WJ, ZANZONICO P, SHARKEY RM et al. Bispecific antibodypretargeting PET (immunoPET) with an124I-labeled hapten-peptide[J]. JNucl Med,2006,47(10):1678-1688.
[110] SHARKEY RM, GOLDENBERG DM. Perspectives on cancer therapy withradiolabeled monoclonal antibodies[J]. J Nucl Med,2005,46Suppl1:115S-127S.
[111] ROBERSON PL, BUCHSBAUM DJ. Reconciliation of tumor dose responseto external beam radiotherapy versus radioimmunotherapy with131iodine-labeled antibody for a colon cancer model[J]. Cancer research,1995,55(23Suppl):5811s-5816s.
[112] HERNANDEZ MC, KNOX SJ. Radiobiology of radioimmunotherapy with90Y ibritumomab tiuxetan (Zevalin)[J]. Seminars in oncology,2003,30(6Suppl17):6-10.
[113] KASSIS AI, ADELSTEIN SJ. Radiobiologic principles in radionuclidetherapy[J]. J Nucl Med,2005,46Suppl1:4S-12S.
[114] OTZERKE J, BUNJES D, SCHEINBERG DA. Radioimmunoconjugates inacute leukemia treatment: the future is radiant[J]. Bone marrow transplantation,2005,36(12):1021-1026.
[115] MICHEL RB, BRECHBIEL MW, MATTES MJ. A comparison of4radionuclides conjugated to antibodies for single-cell kill[J]. J Nucl Med,2003,44(4):632-640.
[116] OLAFSEN T, KENANOVA VE, SUNDARESAN G et al. Optimizingradiolabeled engineered anti-p185HER2antibody fragments for in vivoimaging[J]. Cancer research,2005,65(13):5907-5916.
[117] KENANOVA V, OLAFSEN T, CROW DM et al. Tailoring thepharmacokinetics and positron emission tomography imaging properties ofanti-carcinoembryonic antigen single-chain Fv-Fc antibody fragments[J].Cancer research,2005,65(2):622-631.
[118] BEHR TM, GOLDENBERG DM, BECKER W. Reducing the renal uptake ofradiolabeled antibody fragments and peptides for diagnosis and therapy:present status, future prospects and limitations[J]. European journal of nuclearmedicine,1998,25(2):201-212.
[119] SHARKEY RM, KARACAY H, CARDILLO TM et al. Improving thedelivery of radionuclides for imaging and therapy of cancer using pretargetingmethods[J]. Clin Cancer Res,2005,11(19Pt2):7109s-7121s.
[120] SHARKEY RM, CARDILLO TM, ROSSI EA et al. Signal amplification inmolecular imaging by pretargeting a multivalent, bispecific antibody[J].Nature medicine,2005,11(11):1250-1255.
[121] KARACAY H, BRARD PY, SHARKEY RM et al. Therapeutic advantage ofpretargeted radioimmunotherapy using a recombinant bispecific antibody in ahuman colon cancer xenograft[J]. Clin Cancer Res,2005,11(21):7879-7885.
[122] ROSSI EA, GOLDENBERG DM, CARDILLO TM et al. Stably tetheredmultifunctional structures of defined composition made by the dock and lockmethod for use in cancer targeting[J]. Proceedings of the National Academy ofSciences of the United States of America,2006,103(18):6841-6846.
[123] LIN Y, PAGEL JM, AXWORTHY D et al. A genetically engineered anti-CD45single-chain antibody-streptavidin fusion protein for pretargetedradioimmunotherapy of hematologic malignancies[J]. Cancer research,2006,66(7):3884-3892.
[124] GOLDENBERG DM, SHARKEY RM, PAGANELLI G, BARBET J,CHATAL JF. Antibody pretargeting advances cancer radioimmunodetectionand radioimmunotherapy[J]. J Clin Oncol,2006,24(5):823-834.
[125] SHEN S, FORERO A, LOBUGLIO AF et al. Patient-specific dosimetry ofpretargeted radioimmunotherapy using CC49fusion protein in patients withgastrointestinal malignancies[J]. J Nucl Med,2005,46(4):642-651.
[126] CHATAL JF, CAMPION L, KRAEBER-BODERE F et al. Survivalimprovement in patients with medullary thyroid carcinoma who undergopretargeted anti-carcinoembryonic-antigen radioimmunotherapy: acollaborative study with the French Endocrine Tumor Group[J]. J Clin Oncol,2006,24(11):1705-1711.
[127] CHESON BD. The role of radioimmunotherapy with yttrium-90ibritumomabtiuxetan in the treatment of non-Hodgkin lymphoma[J]. BioDrugs,2005,19(5):309-322.
[128] GORDON LI, MOLINA A, WITZIG T et al. Durable responses afteribritumomab tiuxetan radioimmunotherapy for CD20+B-cell lymphoma:long-term follow-up of a phase1/2study[J]. Blood,2004,103(12):4429-4431.
[129] WISEMAN GA, WITZIG TE. Yttrium-90(90Y) ibritumomab tiuxetan(Zevalin) induces long-term durable responses in patients with relapsed orrefractory B-Cell non-Hodgkin's lymphoma[J]. Cancer biotherapy&radiopharmaceuticals,2005,20(2):185-188.
[130] FISHER RI, KAMINSKI MS, WAHL RL et al. Tositumomab and iodine-131tositumomab produces durable complete remissions in a subset of heavilypretreated patients with low-grade and transformed non-Hodgkin'slymphomas[J]. J Clin Oncol,2005,23(30):7565-7573.
[131] KAMINSKI MS, TUCK M, ESTES J et al.131I-tositumomab therapy asinitial treatment for follicular lymphoma[J]. The New England journal ofmedicine,2005,352(5):441-449.
[132] HACKSHAW A, SWEETENHAM J, KNIGHT A. Are prophylactichaematopoietic growth factors of value in the management of patients withaggressive non-Hodgkin's lymphoma?[J]. British journal of cancer,2004,90(7):1302-1305.
[133] BENNETT JM, KAMINSKI MS, LEONARD JP et al. Assessment oftreatment-related myelodysplastic syndromes and acute myeloid leukemia inpatients with non-Hodgkin lymphoma treated with tositumomab and iodineI131tositumomab[J]. Blood,2005,105(12):4576-4582.
[134] ANSELL SM, RISTOW KM, HABERMANN TM, WISEMAN GA, WITZIGTE. Subsequent chemotherapy regimens are well tolerated afterradioimmunotherapy with yttrium-90ibritumomab tiuxetan for non-Hodgkin'slymphoma[J]. J Clin Oncol,2002,20(18):3885-3890.
[135] CONNORS JM. Radioimmunotherapy--hot new treatment for lymphoma[J].The New England journal of medicine,2005,352(5):496-498.
[136] GOPAL AK, GOOLEY TA, MALONEY DG et al. High-doseradioimmunotherapy versus conventional high-dose therapy and autologoushematopoietic stem cell transplantation for relapsed follicular non-Hodgkinlymphoma: a multivariable cohort analysis[J]. Blood,2003,102(7):2351-2357.
[137] NADEMANEE A, FORMAN S, MOLINA A et al. A phase1/2trial ofhigh-dose yttrium-90-ibritumomab tiuxetan in combination with high-doseetoposide and cyclophosphamide followed by autologous stem celltransplantation in patients with poor-risk or relapsed non-Hodgkinlymphoma[J]. Blood,2005,106(8):2896-2902.
[138] LEONARD JP, COLEMAN M, KOSTAKOGLU L et al. Abbreviatedchemotherapy with fludarabine followed by tositumomab and iodine I131tositumomab for untreated follicular lymphoma[J]. J Clin Oncol,2005,23(24):5696-5704.
[139] CHESON BD. Radioimmunotherapy of non-Hodgkin lymphomas[J]. Blood,2003,101(2):391-398.
[140] LINDEN O, HINDORF C, CAVALLIN-STAHL E et al. Dose-fractionatedradioimmunotherapy in non-Hodgkin's lymphoma using DOTA-conjugated,90Y-radiolabeled, humanized anti-CD22monoclonal antibody, epratuzumab[J].Clin Cancer Res,2005,11(14):5215-5222.
[141] CHEN S, YU L, JIANG C et al. Pivotal study of iodine-131-labeled chimerictumor necrosis treatment radioimmunotherapy in patients with advanced lungcancer[J]. J Clin Oncol,2005,23(7):1538-1547.
[142] SHARKEY RM, PYKETT MJ, SIEGEL JA et al. Radioimmunotherapy of theGW-39human colonic tumor xenograft with131I-labeled murine monoclonalantibody to carcinoembryonic antigen[J]. Cancer research,1987,47(21):5672-5677.
[143] BLUMENTHAL RD, SHARKEY RM, HAYWOOD L et al. Targeted therapyof athymic mice bearing GW-39human colonic cancer micrometastases with131I-labeled monoclonal antibodies[J]. Cancer research,1992,52(21):6036-6044.
[144] LIERSCH T, MELLER J, KULLE B et al. Phase II trial of carcinoembryonicantigen radioimmunotherapy with131I-labetuzumab after salvage resection ofcolorectal metastases in the liver: five-year safety and efficacy results[J]. JClin Oncol,2005,23(27):6763-6770.
[145] REARDON DA, AKABANI G, COLEMAN RE et al. Salvageradioimmunotherapy with murine iodine-131-labeled antitenascin monoclonalantibody81C6for patients with recurrent primary and metastatic malignantbrain tumors: phase II study results[J]. J Clin Oncol,2006,24(1):115-122.
[146] ALVAREZ RD, HUH WK, KHAZAELI MB et al. A Phase I study ofcombined modality (90)Yttrium-CC49intraperitoneal radioimmunotherapy forovarian cancer[J]. Clin Cancer Res,2002,8(9):2806-2811.
[147] MAHE MA, FUMOLEAU P, FABBRO M et al. A phase II study ofintraperitoneal radioimmunotherapy with iodine-131-labeled monoclonalantibody OC-125in patients with residual ovarian carcinoma[J]. Clin CancerRes,1999,5(10Suppl):3249s-3253s.
[148] DENARDO SJ, KUKIS DL, KROGER LA et al. Synergy of Taxol andradioimmunotherapy with yttrium-90-labeled chimeric L6antibody: efficacyand toxicity in breast cancer xenografts[J]. Proceedings of the NationalAcademy of Sciences of the United States of America,1997,94(8):4000-4004.
[149] TSCHMELITSCH J, BARENDSWAARD E, WILLIAMS C, JR. et al.Enhanced antitumor activity of combination radioimmunotherapy(131I-labeled monoclonal antibody A33) with chemotherapy (fluorouracil)[J].Cancer research,1997,57(11):2181-2186.
[150] CLARKE K, LEE FT, BRECHBIEL MW et al. Therapeutic efficacy ofanti-Lewis(y) humanized3S193radioimmunotherapy in a breast cancer model:enhanced activity when combined with taxol chemotherapy[J]. Clin CancerRes,2000,6(9):3621-3628.
[151] BURKE PA, DENARDO SJ, MIERS LA, KUKIS DL, DENARDO GL.Combined modality radioimmunotherapy. Promise and peril[J]. Cancer,2002,94(4Suppl):1320-1331.
[152] GOLD DV, MODRAK DE, SCHUTSKY K, CARDILLO TM. Combined90Yttrium-DOTA-labeled PAM4antibody radioimmunotherapy andgemcitabine radiosensitization for the treatment of a human pancreatic cancerxenograft[J]. International journal of cancer,2004,109(4):618-626.
[153] GOLD DV, SCHUTSKY K, MODRAK D, CARDILLO TM. Low-doseradioimmunotherapy ((90)Y-PAM4) combined with gemcitabine for thetreatment of experimental pancreatic cancer[J]. Clin Cancer Res,2003,9(10Pt2):3929S-3937S.
[154] GRAVES SS, DEARSTYNE E, LIN Y et al. Combination therapy withPretarget CC49radioimmunotherapy and gemcitabine prolongs tumordoubling time in a murine xenograft model of colon cancer more effectivelythan either monotherapy[J]. Clin Cancer Res,2003,9(10Pt1):3712-3721.
[155] KRAEBER-BODERE F, SAI-MAUREL C, CAMPION L et al. Enhancedantitumor activity of combined pretargeted radioimmunotherapy and paclitaxelin medullary thyroid cancer xenograft[J]. Molecular cancer therapeutics,2002,1(4):267-274.
[156] BAUMANN M, KRAUSE M. Targeting the epidermal growth factor receptorin radiotherapy: radiobiological mechanisms, preclinical and clinical results[J].Radiother Oncol,2004,72(3):257-266.
[157] MATHE G, LOC T, BERNARD J. Effet sur la leucemie1210de la sourisd′une combinaison par diazotation d′A-methopterine et de γ-globulines dehamsters porteurs de cette leucemie par heterogreffe[J]. C R Acad Sci,1958,246:1626-1628.
[158] BROSS PF, BEITZ J, CHEN G et al. Approval summary: gemtuzumabozogamicin in relapsed acute myeloid leukemia[J]. Clin Cancer Res,2001,7(6):1490-1496.
[159] LARSON RA, SIEVERS EL, STADTMAUER EA et al. Final report of theefficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients withCD33-positive acute myeloid leukemia in first recurrence[J]. Cancer,2005,104(7):1442-1452.
[160] CHEVALLIER P, ROLAND V, MAHE B et al. Administration of mylotarg4days after beginning of a chemotherapy including intermediate-dose aracytinand mitoxantrone (MIDAM regimen) produces a high rate of completehematologic remission in patients with CD33+primary resistant or relapsedacute myeloid leukemia[J]. Leukemia research,2005,29(9):1003-1007.
[161] AMADORI S, SUCIU S, STASI R et al. Gemtuzumab ozogamicin (Mylotarg)as single-agent treatment for frail patients61years of age and older with acutemyeloid leukemia: final results of AML-15B, a phase2study of the EuropeanOrganisation for Research and Treatment of Cancer and Gruppo ItalianoMalattie Ematologiche dell'Adulto Leukemia Groups[J]. Leukemia,2005,19(10):1768-1773.
[162] ARCECI RJ, SANDE J, LANGE B et al. Safety and efficacy of gemtuzumabozogamicin in pediatric patients with advanced CD33+acute myeloidleukemia[J]. Blood,2005,106(4):1183-1188.
[163] WU AM, SENTER PD. Arming antibodies: prospects and challenges forimmunoconjugates[J]. Nature biotechnology,2005,23(9):1137-1146.
[164] CHEN J, JARACZ S, ZHAO X, CHEN S, OJIMA I. Antibody-cytotoxic agentconjugates for cancer therapy[J]. Expert opinion on drug delivery,2005,2(5):873-890.
[165] GOVINDAN SV, GRIFFITHS GL, HANSEN HJ, HORAK ID,GOLDENBERG DM. Cancer therapy with radiolabeled anddrug/toxin-conjugated antibodies[J]. Technology in cancer research&treatment,2005,4(4):375-391.
[166] SMITH SV. Technology evaluation: cantuzumab mertansine, ImmunoGen[J].Current opinion in molecular therapeutics,2004,6(6):666-674.
[167] LAW CL, CERVENY CG, GORDON KA et al. Efficient elimination ofB-lineage lymphomas by anti-CD20-auristatin conjugates[J]. Clin Cancer Res,2004,10(23):7842-7851.
[168] TORGOV MY, ALLEY SC, CERVENY CG, FARQUHAR D, SENTER PD.Generation of an intensely potent anthracycline by a monoclonalantibody-beta-galactosidase conjugate[J]. Bioconjugate chemistry,2005,16(3):717-721.
[169] HAMANN PR, HINMAN LM, BEYER CF et al. A calicheamicin conjugatewith a fully humanized anti-MUC1antibody shows potent antitumor effects inbreast and ovarian tumor xenografts[J]. Bioconjugate chemistry,2005,16(2):354-360.
[170] BURTON JD, ELY S, REDDY PK et al. CD74is expressed by multiplemyeloma and is a promising target for therapy[J]. Clin Cancer Res,2004,10(19):6606-6611.
[171] GRIFFITHS GL, MATTES MJ, STEIN R et al. Cure of SCID mice bearinghuman B-lymphoma xenografts by an anti-CD74antibody-anthracycline drugconjugate[J]. Clin Cancer Res,2003,9(17):6567-6571.
[172] SAPRA P, STEIN R, PICKETT J et al. Anti-CD74antibody-doxorubicinconjugate, IMMU-110, in a human multiple myeloma xenograft and inmonkeys[J]. Clin Cancer Res,2005,11(14):5257-5264.
[173] CHANG CH, SAPRA P, VANAMA SS et al. Effective therapy of humanlymphoma xenografts with a novel recombinant ribonuclease/anti-CD74humanized IgG4antibody immunotoxin[J]. Blood,2005,106(13):4308-4314.
[174] JEDEMA I, BARGE RM, VAN DER VELDEN VH et al. Internalization andcell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin:rationale for efficacy in CD33-negative malignancies with endocyticcapacity[J]. Leukemia,2004,18(2):316-325.
[175] LESLIE EM, DEELEY RG, COLE SP. Multidrug resistance proteins: role ofP-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense[J].Toxicology and applied pharmacology,2005,204(3):216-237.
[176] NAITO K, TAKESHITA A, SHIGENO K et al. Calicheamicin-conjugatedhumanized anti-CD33monoclonal antibody (gemtuzumab zogamicin,CMA-676) shows cytocidal effect on CD33-positive leukemia cell lines, but isinactive on P-glycoprotein-expressing sublines[J]. Leukemia,2000,14(8):1436-1443.
[177] HAMANN PR, HINMAN LM, BEYER CF et al. An anti-MUC1antibody-calicheamicin conjugate for treatment of solid tumors. Choice oflinker and overcoming drug resistance[J]. Bioconjugate chemistry,2005,16(2):346-353.
[178] HAMANN PR, HINMAN LM, BEYER CF et al. An anti-CD33antibody-calicheamicin conjugate for treatment of acute myeloid leukemia.Choice of linker[J]. Bioconjugate chemistry,2002,13(1):40-46.
[179] SHARMA SK, BAGSHAWE KD, BEGENT RH. Advances inantibody-directed enzyme prodrug therapy[J]. Curr Opin Investig Drugs,2005,6(6):611-615.
[180] FRANCIS RJ, SHARMA SK, SPRINGER C et al. A phase I trial of antibodydirected enzyme prodrug therapy (ADEPT) in patients with advancedcolorectal carcinoma or other CEA producing tumours[J]. British journal ofcancer,2002,87(6):600-607.
[181] MAYER A, SHARMA SK, TOLNER B et al. Modifying an immunogenicepitope on a therapeutic protein: a step towards an improved system forantibody-directed enzyme prodrug therapy (ADEPT)[J]. British journal ofcancer,2004,90(12):2402-2410.
[182] CORTEZ-RETAMOZO V, BACKMANN N, SENTER PD et al. Efficientcancer therapy with a nanobody-based conjugate[J]. Cancer research,2004,64(8):2853-2857.
[183] EKLUND JW, KUZEL TM. Denileukin diftitox: a concise clinical review[J].Expert review of anticancer therapy,2005,5(1):33-38.
[184] FRANKEL AE, KREITMAN RJ, SAUSVILLE EA. Targeted toxins[J]. ClinCancer Res,2000,6(2):326-334.
[185] PASTAN I. Immunotoxins containing Pseudomonas exotoxin A: a shorthistory[J]. Cancer Immunol Immunother,2003,52(5):338-341.
[186] NEWTON DL, HANSEN HJ, MIKULSKI SM, GOLDENBERG DM,RYBAK SM. Potent and specific antitumor effects of an anti-CD22-targetedcytotoxic ribonuclease: potential for the treatment of non-Hodgkinlymphoma[J]. Blood,2001,97(2):528-535.
[187] VITETTA ES, FULTON RJ, MAY RD, TILL M, UHR JW. Redesigningnature's poisons to create anti-tumor reagents[J]. Science (New York, NY,1987,238(4830):1098-1104.
[188] GADINA M, NEWTON DL, RYBAK SM, WU YN, YOULE RJ. Humanizedimmunotoxins[J]. Therapeutic immunology,1994,1(1):59-64.
[189] AMLOT PL, STONE MJ, CUNNINGHAM D et al. A phase I study of ananti-CD22-deglycosylated ricin A chain immunotoxin in the treatment ofB-cell lymphomas resistant to conventional therapy[J]. Blood,1993,82(9):2624-2633.
[190] SAUSVILLE EA, HEADLEE D, STETLER-STEVENSON M et al.Continuous infusion of the anti-CD22immunotoxin IgG-RFB4-SMPT-dgA inpatients with B-cell lymphoma: a phase I study[J]. Blood,1995,85(12):3457-3465.
[191] STONE MJ, SAUSVILLE EA, FAY JW et al. A phase I study of bolus versuscontinuous infusion of the anti-CD19immunotoxin, IgG-HD37-dgA, inpatients with B-cell lymphoma[J]. Blood,1996,88(4):1188-1197.
[192] SMALLSHAW JE, GHETIE V, RIZO J et al. Genetic engineering of animmunotoxin to eliminate pulmonary vascular leak in mice[J]. Naturebiotechnology,2003,21(4):387-391.
[193] KREITMAN RJ, SQUIRES DR, STETLER-STEVENSON M et al. Phase Itrial of recombinant immunotoxin RFB4(dsFv)-PE38(BL22) in patients withB-cell malignancies[J]. J Clin Oncol,2005,23(27):6719-6729.
[194] POSEY JA, KHAZAELI MB, BOOKMAN MA et al. A phase I trial of thesingle-chain immunotoxin SGN-10(BR96sFv-PE40) in patients withadvanced solid tumors[J]. Clin Cancer Res,2002,8(10):3092-3099.
[195] HELLSTROM I, GARRIGUES HJ, GARRIGUES U, HELLSTROM KE.Highly tumor-reactive, internalizing, mouse monoclonal antibodies toLe(y)-related cell surface antigens[J]. Cancer research,1990,50(7):2183-2190.
[196] NAKAMURA Y, SODA H, OKA M et al. Randomized phase II trial ofirinotecan with paclitaxel or gemcitabine for non-small cell lung cancer:association of UGT1A1*6and UGT1A1*27with severe neutropenia[J]. JThorac Oncol,6(1):121-127.
[197] KODERA Y, IMANO M, YOSHIKAWA T et al. A randomized phase II trial totest the efficacy of intra-peritoneal paclitaxel for gastric cancer with high riskfor the peritoneal metastasis (INPACT trial)[J]. Japanese journal of clinicaloncology,41(2):283-286.
[198] JEMAL A, SIEGEL R, WARD E et al. Cancer statistics,2006[J]. CA: a cancerjournal for clinicians,2006,56(2):106-130.
[199] SUN S, SCHILLER JH, GAZDAR AF. Lung cancer in never smokers--adifferent disease[J]. Nature reviews,2007,7(10):778-790.
[200] BACH PB, KELLEY MJ, TATE RC, MCCRORY DC. Screening for lungcancer: a review of the current literature[J]. Chest,2003,123(1Suppl):72S-82S.
[201] HENSCHKE CI, YANKELEVITZ DF, LIBBY DM et al. Survival of patientswith stage I lung cancer detected on CT screening[J]. The New Englandjournal of medicine,2006,355(17):1763-1771.
[202] DING L, GETZ G, WHEELER DA et al. Somatic mutations affect keypathways in lung adenocarcinoma[J]. Nature,2008,455(7216):1069-1075.
[203] WEIR BA, WOO MS, GETZ G et al. Characterizing the cancer genome inlung adenocarcinoma[J]. Nature,2007,450(7171):893-898.
[204] THOMAS RK, BAKER AC, DEBIASI RM et al. High-throughput oncogenemutation profiling in human cancer[J]. Nature genetics,2007,39(3):347-351.
[205] WISTUBA, II, BEHRENS C, VIRMANI AK et al. High resolutionchromosome3p allelotyping of human lung cancer andpreneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuoussites of3p allele loss and three regions of frequent breakpoints[J]. Cancerresearch,2000,60(7):1949-1960.
[206] Stein U, Walther W, Arlt F, et al. MACC1, a newly identified key regulator ofHGF-MET signaling, predicts colon cancer metastasis[J]. Nat Med,2009,15(1):59-67.
[207] Rygaard K, Nakamura T, Spang-Thomsen M, et al. Expression of theproto-oncegenes c-met and c-kit and their ligands, hepatocyte growthfactor/scatter factor and stem cell factor, in SCLC cell lines and xenografts [J].Br J Cancer,1993,67(1):37-46.
[208] Gautam Maulik, Takashi Kijima, Patrick C Ma, et al. Modulation of thec-Met/hepatocyte growth factor pathway in small cell lung cancer[J]. ClinCaner Res,2002,8(2):620-627.
[209] Jeffers M, Rong S, Vande Woude GF. Enhanced tumorigenicity and invasion–metastasis by hepatocyte growth factor/scatter factor-mer signalling in humancells concomitant with induction of the urokinase proteolysis network[J]. MolCell Biol,1996,16(3):1115-1125.
[210] Jeffers M, Rong S, Woude GF. Hepatocyte growth factor/scatter factor–Metsignaling in tumorigenicity and invasion/metastasis[J]. J Mol Med,1996,74(9):505-513.
[211] Shirahata A, Sakata M, Kitamura Y, et al. MACC1as a marker for advancedcolorectal cancinoma[J]. Anticancer Res,2010,30(9):3441-3444.
[212] Shirahata A, Sakata M, Kitamura Y, et al. MACC1as a marker for advancedcolorectal carcinoma[J]. Anticancer Res,2010,30(7)：2689-2692.
[213] Katarzyna K, Jacek Krynski, Leszek R, et al. Unexpected domain compositionof MACC1links MET signaling and apoptosis[J]. Acta Biochim Pol,2009,56(2):317-323.
[214] Stein U, Dahlmann M, Walther W, et al. MACC1-more than metastasis? Factsand predicitions about a novel gene[J]. J Mol Med,2010,88(1):11-18.
[215] Birchmeier C, Birchmeier W, Gherardi E, et al. Met, metastasis, motility andmore[J]. Nat Rev Mol Cell Biol,2003,4(12):915-925.
[216] Birchmeier W, Brinkmann V, Niemann C, et al. Role of HGF/SF and c-Met inmorphogenesis and metastasis of epithelial cells[J]. Ciba Found Symp,1997,212:230-240.
[217] Boccaccio C, Comoglio PM, Invasive growth: a MET-driven geneticprogramme for cancer and stem cells[J]. Nat Rev Cancer,2006,6(8):637-645.
[218] Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interferenceby double-stranded RNA in Cae–norhabditis elegans[J]. Nature,1998,19(2):806-811.
[219] Stein U, Burock S, Herrmann P, Circulating MACC1transcripts in colorectalcancer patient plasma predicts metastasis and prognosis[J]. Plos One,2012,7(11)
[220] Harpaz N, Taboada S, Mabel K, et al. Expression of MACC1and MET inInflammatory Bowel Disease-associated Colonic Neoplasia[J]. Inflamm BowelDis.2014.
[221] Chen Xiao-Ping,Ren Xin-Ping, Lan Jian-Yun, et al. Analysis of HGF, MACC1,C-met and apoptosis-related genes in cervical carcinoma mice[J]. Mol BiolRep.2014.
[222] Wang Yong, Hong Qiang, Wang Jian-Yun, et al. Downregulated expression ofmetastasis associated in colon cancer1(MACC1) reduces gallbladder cancercell proliferation and invasion[J]. Tumour Biol.2014.
[223] Wang Zhi-qiang, Li Zhi, Wu Chen, et al. MACC1overexpression predicts apoor prognosis for non-small cell lung cancer[J]. Med Oncol,2014.31(1):790.
[224] Cai Hong-xia, Yang Yong-xiu. Effects of MACC1siRNA on biologicalbehaviors of HeLa[J]. Arch Gynecol Obstet.2013.
[225] Guo Tian-kang, Yang Jing-yu, Yao Ji-bin, et al. Expression of MACC1andc-Met in human gastric cancer and its clinical significance[J]. Cancer Cell Int,2013,13(1):121.
[226] Hagemann C, Fuchs S, Stein U, et al. Impact of MACC1on human malignantglioma progression and patients' unfavorable prognosis[J]. Neuro Oncol,2013,15(12):1696-1709.
[227] Ren Bing, Zakharov V, Yang Qi, et al. MACC1Is Related to ColorectalCancer Initiation and Early-Stage Invasive Growth[J]. Am J Clin Pathol,2013,140(5):701-707.
[228] Zhang Kai, Tian Fang, Zhang Yong-gang, et al. MACC1is involved in theregulation of proliferation, colony formation, invasion ability, cell cycledistribution, apoptosis and tumorigenicity by altering Akt signaling pathway inhuman osteosarcoma[J]. Tumour Biol,2013.
[229] Juneja M, Ilm K, Schlag P, Stein U. Promoter identification and transcriptionalregulation of the metastasis gene MACC1in colorectal cancer[J].Mol Oncol,2013,7(5):929-943.
[230] Stein U. MACC1-a novel target for solid cancers[J]. Expert Opin TherTargets,2013,17(9):1039-1052.
[231] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancerstatistics. CA Cancer J Clin.2011,61(2):69-90.
[232] Huang Y, Zhang H, Cai J, Fang L, et al. Overexpression of MACC1and itssignificance in human Breast Cancer Progression. Cell Biosci.2013;3(1):16.
[233] Qiu J, Huang P, Liu Q, Hong J, Li B, et al. Identification of MACC1as a novelprognostic marker in hepatocellular carcinoma.[J] Transl Med.2011;9:166.
[234] Xie C, Wu J, Yun J, Lai J, Yuan Y, Gao Z, et al. MACC1as a prognosticbiomarker for early-stage and AFP-normal hepatocellular carcinoma.[J] PLOSONE.2013;8(5):e64235.
[235] Meng F, Li H, Shi H, Yang Q, et al. MACC1down-regulation inhibitsproliferation and tumourigenicity of nasopharyngeal carcinoma cells throughAkt/beta-catenim signaling pathway.[J] Plos One.2013;8(4):e60821.
[236] Wang G, Kang M, Lu W, Chen Y, Zhang B, Wu YL. MACC1: a potentialmolecule associated with pancreatic cancer metastasis and chemoresistance..[J]Oncol Lett.2012;4(4):783-791.
[237] Kawamura M, Saigusa S, Toiyama Y, Tanaka K, Okugawa Y, Hiro J, et al.Correlation of MACC1and MET expression in rectal cancer after neoadjuvantchemoradiotherapy.[J] Anticancer Res.2012;32(4):1527-1531.
[238] Hu X, Fu X, Wen S, Zou X, Liu Y. Prognostic value of MACC1and c-metexpressions in non-small cell lung cancer.[J] Chin J Lung Cancer.2012;15(7):399-403.
[239] Chundong G, Uramoto H, Onitsuka T, Shimokawa H, Iwanami T, NakagawaM, et al. Molecular diagnosis of MACC1status in lung adenocarcinoma byimmunohistochemical analysis.[J] Anticancer Res.2011;31(4):1141-1145.
[240] Shimokawa H, Uramoto H, Onitsuka T, Chundong G, Hanagiri T, Oyama T, etal.. Overexpression of MACC1mRNA in lung adenocarcinoma is associatedwith postoperative recurrence.[J] Thorac Cardiovasc Surg.2011;141(4):895-898.
[241] Xue X, Zhu YM, Woll PJ. Circulating DNA and lung cancer. Ann N Y AcadSci.2006;1075:154-164.
[242] An Q, Liu Y, Gao Y, et al. Detection of p16hypermethylation in circulatingplasma DNA of non-small cell lung cancer patients. CancerLett,2002;188(1-2):109-114.
[243] Bowman RV, Yang IA, Semmler AB, Fong KM. Epigenetics of lung cancer.Respirology,2006;11(4)：355-365.
[244] Mao L. Recent advances in the molecular diagnosis of lung cancer.Oncogene.2002;21(45):6960-6969.
[245] Ahrendt SA, Decker PA, Alawi EA, et al. Cigarette smoking is stronglyassociated with mutation of the K-ras gene in patients with primaryadenocarcinoma of the lung. Cancer.2001;92(6):1525-1530.
[246] Suecka E, Suecka N, Iwanaga K, et al. Detection of plasma hnRNP B1MRNA,a new cancer biomarker, in lung cancer patients by quantitative real-timepolymerase chain reaction. Lung Cancer.2005;48(1):77-83.
[247] Jeronimo C, Nomoto S, Caballero CL, et al. Mitochondrial mutations in earlystage prostate cancer and bodily fluids. Oncogene.2001;20(37):5195-5198.
[248] Howington JA, Blum MG, Chang AC, Balekian AA, Murthy SC. Treatment ofstage Ⅰ and Ⅱ non-small cell lung cancer: diagnosis and management of lungcancer,3rd edition: American College of Chest Physicians evidence-basedclinical pratice guidelines.[J] Chest.2013;143(5Suppl):e278S-313S.
[249] Matsuge S, Hosokawa Y, Sato K, et al. Surgical treatment for bilateral multiplelung cancers.[J] Kyobu Geka.2000,53:89-94.
[250] Niho S, Nishiwaki Y, Goto K, et al. Significance of serumpro-gastrin-releasing poptide as a predictor of relapse of small cell lung cancer:comparative evaluation with neuron-specific enolase and carcinoembryonicantigen.[J] Lung Cancer.2000,27:159-167.
[251] Shibayama T, Ueoka H, Nishii K, et al. Complementary roles of pro–gastrin-releasing peptide(ProGRP) and neuron specific enolase(NSE) indiagnosis and prognosis of small cell lung cancer(SCLC).[J] Lung Cancer.2001,32:61-69.
[252] Jorgensen LGM, Osterlind K, Genolla J, et al. Serum neuron-specific enolase(S-NSE) and the prognosis in small-cell lung cancer(SCLC): a combinedmultivariable analysis on data from nine centres.[J] Br J Cancer.1996,74:463-467.
[253] Goto K, Kodama T, Hojo F, et al. Clinicopathologic characteristics of patientswith nonsmall cell lung cancinoma with elevated serum progastrin-releasingpeptide levels.[J] Cancer,1998,82:1056-1061.
[254] Chang YL, Wu CT and Lee YC. Surgical treatment of synchronous multipleprimary lung cancers: experience of92patients.[J] Thorac CardiovascSurg.2007,134:630-637.
[255] Adebonojo SA, Moritz DM and Danby CA. The results of modern surgicaltherapy for multiple primary lung cancers.[J] Chest.1997,112:693-701.
[256] Tsunezuka Y, Matsumoto I, Tamura M, et al. The results of therapy forbilateral multiple primary lung cancers:30years experience in a singlecentre.[J] Eur J Surg Oncol.2004,30：781-785.
[257] Sethi N, Kang Y. Unravelling the complexity of metastasis-molecularunderstanding and targeted therapies.[J] Nat Rev Cancer.2011;11:735-748.
[258] Wanebo HJ, LeGolvan M, Paty PB, et al. Meeting the biologic chanllenge ofcolorectal metastases.[J] Clin Exp Metastasis.2012;29:821-839.
[259] Gherardi E, Birchmeier W, Birchmeier C, et al. Targeting MET in cancer:rationale and progess.[J] Nat Rev Cancer.2012;12:89-103.
[260] Luraghi P, Schelter F, Kruger A, et al. The MET oncogene as a therapeuticaltarget in cancer invasive growth.[J] Front Pharmacol.2012;3:164.
[261] Schmid F, Wang Q, Huska MR, et al. S100P, a target gene of MACC1,contributes to colorectal cancer metastasis.[J] Proc Am Ass Cancer Res.2012;54:416.
[262] Toiyama Y, Miki C, Inoue Y, et al. Serum hepatocyte growth factor as aprognostic marker for stage Ⅱor Ⅲ colorectal cancer patients.[J] Int JCancer.2009;125:1657-1662.
[263] Lang AH, Geller-Rhomberg S, Winder T, et al. A common variant of theMACC1gene is signitificantly in colorectal cancer patients.[J] BMCCancer.2012;12:20.
[264] Lang S, Geller-Rhomberg T, Winder BL, et al. Evaluation of the associationbetween tagging polymorphisms of the MACC1locus and overall survival inpatients with colorectal cancer. ACSO Meeting. J Clin Oncel.2011;29(suppl):abstracts3594.
[265] Ferguson MK, DeMeester TR, DesLauriers J, et al. Diagnosis andmanagement of synchronous lung cancer.[J] Thorac Cardiovasc Surg.1985,89:378-385.
[266] Martini N, Melamed MR. Multiple primary lung cancers.[J] ThoracCardiovasc Surg.1975,70:606-612.
[267] Ge SH, Wu XJ, Wang XH, Xing XF, Zhang LH, Zhu YB, et al.Over-expression of metastasis-associated in colon cancer-1(MACC1)associates with better prognosis of gastric cancer patients.[J] Chin J Cancer.2011;23(2):153-159.
[268] Boardman LA. Overexpression of MACC1leads to downstream activation ofHGF/MET and potentiates metastasis and recurrence of colorectal cancer.[J]Genome Med.2009;1(4):36.
[269] Isella C, Mellano A, Galimi F, Petti C, Capussotti L, De Simone M, et al.MACC1mRNA levels predict cancer recurrence after resection of colorectalcancer liver metastases.[J] Ann Surg.2013;257(6):1089-1095.
[270] Stein U, Smith J, Walther W, et al. MACC1controls Met: what a difference anSp1site makes.[J] Cell Cycle.2009;8:2467-2469.
[271] Shu C, Cheng H, Wang A, et al. Thymidylate synthase expression andmolecular alterations in adenosquamous carcinoma of the lung.[J] Mod Pathol.2013;26:239-246.
[272] Gallego MI, Bierie B, Hennighausen L. Targeted expression of HGF/SF inmouse mammary epithelium leads to metastatic adenosquamous carcinomasthrough the activation of multiple signal transduction pathways.[J] Oncogene.2003;22:8498-8508.
[273] Galimi F, Torti D, Sassi F, Isella C, et al. Genetic and expression analysis ofMET, MACC1, and HGF in metastatic colorectal cancer: response to Metinhibition in patient xenografts and pathologic correlations.[J] Clin CancerRes.2011;17:3146-3156.
[274] Stein U, Schlag PM. Clinical, biological, and molecular aspects of metastasisin colorectal cancer.[J] Recent Results Cancer Res.2007;176:61-80.
[275] Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in2008: globocan2008.[J] Int J Cancer,2010;127:2893-2917.
[276] Naishadham D, Jemal A. Cancer statistics,2013.[J] Cancer J Clin.2013;63:11-30.
[277] Wang X, Christiani DC, Mark EJ, et al. Carcinogen exposure, p53alteration,and K-ras mutation in synchronous multiple primary lung carcinoma.[J]Cancer.1999,85:1734-1739.
[278] Miura H, Nakajima N, Ikeda N, et al. Therapeutic strategy for secondary lungcancer.[J] Kyobu Geka,2010,63:956-961.
[279] Van Rens MTM, Zanen P, de la Ribiere AB, et al. Survival in synchronousversus single lung cancer: upstaging better reflects prognosis.[J] Chest.2000,118:952-958.
[280] Lam S, MacAulay C and Palcic B. Detection and localization of early lungcancer by imaging techniques.[J] Chest.1993,103:S12-S14.
[281] Woolner LB, Fontana RS, Cortese DA, et al. Roentgenographically occult lungcancer: pathologic findings and frequency of multicentricity during a10-yearperiod.[J] Mayo Clin Proc.1984,59:453-466.
[282] Morita T. Incidence, contents and change of autopsied multiple primarycancers of the lung based on the annual of the autopsy cases in Japan between1958and1992.[J] Haigan.1997,37:283-294.
[283] Saito Y, Fujimura S, Sato M, et al. Recent adbances in diagnosis and treatmentof multiple primary lung cancers.[J] Nippon Kyobu Rinsho.1993,52:95-101.