Ep-CAM和4D10在胃肠肿瘤血清中的表达及临床意义
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摘要
背景:胃癌和结直肠癌是我国常见的消化道恶性肿瘤,其发病率和死亡率均居前列,而且随着人们生活水平的提高和饮食结构的改变,其发病率和死亡率有上升趋势。大量临床资料表明胃癌和结直肠癌的预后有赖于早期发现、早期诊断以及选择合理的治疗方案。目前治疗胃癌和结直肠癌的主要手段是手术完整切除肿瘤,并辅以化疗、放疗、生物免疫及中医中药等综合治疗措施。因此早期诊断、早期治疗是降低死亡率、延长患者生存期的关键。
Ep-CAM(Epithelial Cell Adhesion Molecule)也称为KSA、KS1/4及17-1A等,是近年来发现的一种嗜同种非钙离子依赖性上皮细胞粘附分子。Ep-CAM在多种上皮源性癌细胞表面表达,包括胃癌、结直肠癌、乳腺癌、头颈部癌以及肝癌等。Ep-CAM的表达与肿瘤细胞的增殖、去分化、侵袭及转移相关。我们的前期研究结果表明,利用组织芯片技术,研究Ep-CAM在胃癌和结直肠癌组织以及癌旁组织中的表达情况,结果显示Ep-CAM在癌组织中的表达水平明显高于癌旁组织。
单克隆抗体4D10是以人结肠癌细胞株LOVO免疫Balb/c小鼠获得,免疫组化研究显示,4D10mAb能够与不同分期的结肠癌组织切片反应,并利用该单抗进行免疫亲和层析,可以从培养的结肠癌细胞株LOVO中纯化结肠癌相关抗原。从免疫组化的照片中可以发现,该抗原主要分布于胞膜和胞浆。纯化后的抗原进行SDS-PAGE和Western blot分析,结果显示其相对分子量约为65KDa。
目的:1.检测Ep-CAM和4D10在胃癌和结直肠癌血清中的表达水平;2.并与胃肠道良性疾病(包括结肠/直肠息肉、溃疡性结肠炎、胃炎等)及健康正常人血清表达水平之间进行比较;3.探讨胃癌和结直肠癌血清Ep-CAM和4D10表达水平与肿瘤临床病理参数之间的相关性及临床意义;4.初步研究Ep-CAM和4D10表达水平之间的相关性以及两者用于联合诊断的价值。旨在探讨其作为胃癌和结直肠癌肿瘤标志物的可行性,以期能够为胃肠肿瘤的早期诊断提供帮助。
方法:选取我院2005年9月至2006年6月手术切除并经病理证实的原发性胃癌患者血清标本53例和结直肠癌患者血清标本40例为实验组,同时选取胃肠道良性疾病患者血清标本30例和健康正常成人血清标本50例(安徽省红十字会中心血站提供)为对照组。利用双抗体夹心法ELISA分别检测实验组和对照组Ep-CAM和4D10的表达水平;实验组Ep-CAM和4D10表达水平与患者临床病理资料之间的关系;Ep-CAM和4D10表达水平之间的相关性。实验结果以光密度(OpticalDensity,OD值)表示。
结果:1.胃癌组Ep-CAM OD平均值为0.550±0.1109,阳性率66%(35/53);结直肠癌组血清Ep-CAM OD平均值为0.643±0.0573,阳性率67.5%(27/40);胃肠道良性疾病组血清Ep-CAM OD平均值为0.248±0.0411,阳性率13.3%(4/30);健康正常成人组血清Ep-CAM OD平均值为0.247±0.0152,均为阴性。实验组显著高于对照组(P＜0.01)。
2.胃癌组4D10 OD平均值为0.558±0.1197,阳性率54.7%(29/53);结直肠癌组血清4D10 OD平均值为0.741±0.1201,阳性率52.5%(21/40);胃肠道良性疾病组血清4D10 OD平均值为0.331±0.0151,阳性率23.3%(7/30);健康正常成人组血清4D10 OD平均值为0.262±0.0123,均为阴性。实验组显著高于对照组(P＜0.01)。
3.实验组Ep-CAM和4D10在胃癌TNMⅠ、Ⅱ期和结直肠癌Dukes A、B期;肿瘤直径小于5cm以及肿瘤侵及肌层时即有表达,并高于对照组。表明Ep-CAM和4D10在胃癌和结直肠癌早期即有高水平表达并可以在血清中被检测到。
4.Ep-CAM和4D10在胃肠肿瘤血清中的表达有相关性,在所有胃肠肿瘤标本中Ep-CAM单项阳性率为66.7%(62/93),4D10单项阳性率为53.8%(50/93),两者联合检测阳性率79.6%(74/93),联合检测可以提高阳性率。
5.Ep-CAM和4D10在胃肠肿瘤血清中的表达不受患者的年龄、性别、肿瘤的病理类型、分化程度、淋巴结转移等诸临床病理参数的影响。
结论:1.Ep-CAM和4D10在胃癌和结直肠癌血清中可以被检测到,而且表达水平高于对照组,可能由肿瘤细胞产生并参与了胃癌和结直肠癌的发生发展过程。
2.胃癌和结直肠癌早期即有Ep-CAM和4D10产生,并可以在血清中被检测到,表达水平高于对照组,有望被用于胃肠肿瘤的早期诊断。
3.Ep-CAM和4D10联合检测有望被用于提高胃肠肿瘤检出率。
4.Ep-CAM和4D10在胃肠肿瘤血清中的表达不受患者的年龄、性别、肿瘤的病理类型、分化程度、淋巴结转移等诸临床病理参数的影响,表明这两种指标可能是肿瘤发生发展过程中的独立影响因素。
Background: Gastric carcinoma (GC) and Colorectal carcinoma (CRC) are malignant tumors which frequently occurred in gastrointestinal system and their morbidity and mortality have been rising in resent years. It is important to detect and diagnose in nonage in order to prevent and cure GC and CRC in time. Resection remains the major treatment for GC and CRC at present, which assisted with combined therapy including chemotherapy, radiotherapy, immunotherapy, etc. Earlier diagnosis and surgery are key factors in decreasing morbidity and prolonging the life of patients with GC and CRC.
Epithelial cell adhesion molecule (Ep-CAM) is a kind of transmembrane glycoprotein which was negatively or weakly expressed in normal epithelial cells and frequently overexpressed in epithelial carcinomas such as gastric carcinoma, colorectal carcinoma, breast cancer, head and neck carcinoma and hepatoma,etc. It was reported that Ep-CAM mediates calcium-independent homophilic adhesion and correlates with cellular proliferation, invasion, de-differentiation as well as migration. We have studied the expression of Ep-CAM in GC and CRC tissues and adjacent paracancerous tissues and the results showed that the expression of Ep-CAM in GC and CRC tissues were higher than that of the latter (p<0.01). At present, there are few studies about the Ep-CAM quantitive expression in cancer sera and its clinical significance was reported.
4D10 was a tumor associated antigen obtained from cultured colon cancer cell line LOVO, which can react to the colon cancer but very little or not to normal tissue and other caner tissues. The purified antigen was identified by SDS-PAGE and Western blot analyse. The antigen 4D10 was a heterodimer composed of two subunits with relative molecular mass (Mr) of 3×10~3 and 35×10~3 respectively.
Objective: 1.To investigate the expression of Ep-CAM and 4D10 in sera of GC and CRC, 2. Expression of Ep-CAM and 4D10 in sera of gastrointestinal benign disease and health adults were also detected and compraed with that of GC and CRC. 3. To study the correlation of the expression of Ep-CAM and 4D10 in sera of GC and CRC with clinicopatholgic characteristics of tumors. 4. The values of combined detection of Ep-CAM and 4D10 in GC and CRC and to explore the feasibility of Ep-CAM and 4D10 as tumor markers for GC and CRC.
Methods: 53 primary gastric carcinoma sera specimens and 40 colorectal carcinoma sera specimens which obtained from patients underwent surgery and confirmed by pathology were included in the study group. 30 sera specimens of gastrointestinal benign disease and 50 sera specimens from health adults which offered by Central Blood Bank of Red Cross of Anhui province were included in control group. Double antibody sandwich ELISA was used to examine the expression of Ep-CAM and 4D10 in all sera specimens, and the relation of expression of Ep-CAM and 4D10 between study group and control group was analyzed. Furthermore, the expression of Ep-CAM and 4D10 in study group was also analyzed with regard to clinicopathologic characteristics. The results demonstrated as optical density (Ep-CAM OD). Relation between the expression of Ep-CAM and that of 4D10 was also analyzed.
Results: 1. The Ep-CAM OD of GC group was 0.550±0.1109, the Ep-CAM OD of CRC group was 0.643±0.0573, the Ep-CAM OD of gastrointestinal benign disease group was 0.248±0.0411 and the Ep-CAM OD of health adults group was 0.247±0.0152. The Ep-CAM OD in study group was significantly higher than control group (P<0.01).
2. The 4D10 OD of GC group was 0.558±0.1197, the 4D10 OD of CRC group was 0.741±0.1201, the 4D10 OD of gastrointestinal benign disease group was 0.331±0.0151 and the OD of health adults group was 0.247±0.0152. The 4D10 OD in study group was significantly higher than control group (P<0.01).
3. High-level expression of Ep-CAM and 4D10 were observed in gastric carcinoma in TNMⅠ,Ⅱstage and in colorectal carcinoma in Dukes A,B stage. High-level expression of Ep-CAM and 4D10 were also observed in tumor size less than 5cm and tumor infiltrate in muscular layer .The expression of Ep-CAM and 4D10 in study group increased in early period of GC and CRC and could be detected.
4. Expression of Ep-CAM correlates with that of 4D10 in GC and CRC, and the early diagnosis rate of GC and CRC could be raised by combined detection with Ep-CAM and 4D10.
5. Expression of Ep-CAM and 4D10 were not influenced by clinicopathological characteristic such as age, gender, pathologic type, differention and lymphoid node metastasis etc.
Conclusion: 1. High-level expression of Ep-CAM and 4D10 were observed in gastric carcinoma and colorectal carcinoma, and they were involved in GC and CRC genesis and development.
2. Ep-CAM and 4D10 play important roles in gastric and colorectal carcinogenesis and can be detected in early stage. They may serve as markers in the early diagnosis of gastric carcinoma and colorectal carcinoma.
3. The early diagnosis rate of GC and CRC could be raised by combined detection with Ep-CAM and 4D10.
4. Expression of Ep-CAM and 4D10 were not influenced by clinicopathological characteristic such as age, gender, pathologic type, differention and lymphoid node metastasis, etc. Ep-CAM and 4D10 may be independent inflence factors in the GC and CRC carcinogenesis and development.
Ep-CAM(Epithelial Cell Adhesion Molecule)也称为KSA、KS1/4及17-1A等,是近年来发现的一种嗜同种非钙离子依赖性上皮细胞粘附分子。Ep-CAM在多种上皮源性癌细胞表面表达,包括胃癌、结直肠癌、乳腺癌、头颈部癌以及肝癌等。Ep-CAM的表达与肿瘤细胞的增殖、去分化、侵袭及转移相关。我们的前期研究结果表明,利用组织芯片技术,研究Ep-CAM在胃癌和结直肠癌组织以及癌旁组织中的表达情况,结果显示Ep-CAM在癌组织中的表达水平明显高于癌旁组织。
单克隆抗体4D10是以人结肠癌细胞株LOVO免疫Balb/c小鼠获得,免疫组化研究显示,4D10mAb能够与不同分期的结肠癌组织切片反应,并利用该单抗进行免疫亲和层析,可以从培养的结肠癌细胞株LOVO中纯化结肠癌相关抗原。从免疫组化的照片中可以发现,该抗原主要分布于胞膜和胞浆。纯化后的抗原进行SDS-PAGE和Western blot分析,结果显示其相对分子量约为65KDa。
目的:1.检测Ep-CAM和4D10在胃癌和结直肠癌血清中的表达水平;2.并与胃肠道良性疾病(包括结肠/直肠息肉、溃疡性结肠炎、胃炎等)及健康正常人血清表达水平之间进行比较;3.探讨胃癌和结直肠癌血清Ep-CAM和4D10表达水平与肿瘤临床病理参数之间的相关性及临床意义;4.初步研究Ep-CAM和4D10表达水平之间的相关性以及两者用于联合诊断的价值。旨在探讨其作为胃癌和结直肠癌肿瘤标志物的可行性,以期能够为胃肠肿瘤的早期诊断提供帮助。
方法:选取我院2005年9月至2006年6月手术切除并经病理证实的原发性胃癌患者血清标本53例和结直肠癌患者血清标本40例为实验组,同时选取胃肠道良性疾病患者血清标本30例和健康正常成人血清标本50例(安徽省红十字会中心血站提供)为对照组。利用双抗体夹心法ELISA分别检测实验组和对照组Ep-CAM和4D10的表达水平;实验组Ep-CAM和4D10表达水平与患者临床病理资料之间的关系;Ep-CAM和4D10表达水平之间的相关性。实验结果以光密度(OpticalDensity,OD值)表示。
结果:1.胃癌组Ep-CAM OD平均值为0.550±0.1109,阳性率66%(35/53);结直肠癌组血清Ep-CAM OD平均值为0.643±0.0573,阳性率67.5%(27/40);胃肠道良性疾病组血清Ep-CAM OD平均值为0.248±0.0411,阳性率13.3%(4/30);健康正常成人组血清Ep-CAM OD平均值为0.247±0.0152,均为阴性。实验组显著高于对照组(P＜0.01)。
2.胃癌组4D10 OD平均值为0.558±0.1197,阳性率54.7%(29/53);结直肠癌组血清4D10 OD平均值为0.741±0.1201,阳性率52.5%(21/40);胃肠道良性疾病组血清4D10 OD平均值为0.331±0.0151,阳性率23.3%(7/30);健康正常成人组血清4D10 OD平均值为0.262±0.0123,均为阴性。实验组显著高于对照组(P＜0.01)。
3.实验组Ep-CAM和4D10在胃癌TNMⅠ、Ⅱ期和结直肠癌Dukes A、B期;肿瘤直径小于5cm以及肿瘤侵及肌层时即有表达,并高于对照组。表明Ep-CAM和4D10在胃癌和结直肠癌早期即有高水平表达并可以在血清中被检测到。
4.Ep-CAM和4D10在胃肠肿瘤血清中的表达有相关性,在所有胃肠肿瘤标本中Ep-CAM单项阳性率为66.7%(62/93),4D10单项阳性率为53.8%(50/93),两者联合检测阳性率79.6%(74/93),联合检测可以提高阳性率。
5.Ep-CAM和4D10在胃肠肿瘤血清中的表达不受患者的年龄、性别、肿瘤的病理类型、分化程度、淋巴结转移等诸临床病理参数的影响。
结论:1.Ep-CAM和4D10在胃癌和结直肠癌血清中可以被检测到,而且表达水平高于对照组,可能由肿瘤细胞产生并参与了胃癌和结直肠癌的发生发展过程。
2.胃癌和结直肠癌早期即有Ep-CAM和4D10产生,并可以在血清中被检测到,表达水平高于对照组,有望被用于胃肠肿瘤的早期诊断。
3.Ep-CAM和4D10联合检测有望被用于提高胃肠肿瘤检出率。
4.Ep-CAM和4D10在胃肠肿瘤血清中的表达不受患者的年龄、性别、肿瘤的病理类型、分化程度、淋巴结转移等诸临床病理参数的影响,表明这两种指标可能是肿瘤发生发展过程中的独立影响因素。
Background: Gastric carcinoma (GC) and Colorectal carcinoma (CRC) are malignant tumors which frequently occurred in gastrointestinal system and their morbidity and mortality have been rising in resent years. It is important to detect and diagnose in nonage in order to prevent and cure GC and CRC in time. Resection remains the major treatment for GC and CRC at present, which assisted with combined therapy including chemotherapy, radiotherapy, immunotherapy, etc. Earlier diagnosis and surgery are key factors in decreasing morbidity and prolonging the life of patients with GC and CRC.
Epithelial cell adhesion molecule (Ep-CAM) is a kind of transmembrane glycoprotein which was negatively or weakly expressed in normal epithelial cells and frequently overexpressed in epithelial carcinomas such as gastric carcinoma, colorectal carcinoma, breast cancer, head and neck carcinoma and hepatoma,etc. It was reported that Ep-CAM mediates calcium-independent homophilic adhesion and correlates with cellular proliferation, invasion, de-differentiation as well as migration. We have studied the expression of Ep-CAM in GC and CRC tissues and adjacent paracancerous tissues and the results showed that the expression of Ep-CAM in GC and CRC tissues were higher than that of the latter (p<0.01). At present, there are few studies about the Ep-CAM quantitive expression in cancer sera and its clinical significance was reported.
4D10 was a tumor associated antigen obtained from cultured colon cancer cell line LOVO, which can react to the colon cancer but very little or not to normal tissue and other caner tissues. The purified antigen was identified by SDS-PAGE and Western blot analyse. The antigen 4D10 was a heterodimer composed of two subunits with relative molecular mass (Mr) of 3×10~3 and 35×10~3 respectively.
Objective: 1.To investigate the expression of Ep-CAM and 4D10 in sera of GC and CRC, 2. Expression of Ep-CAM and 4D10 in sera of gastrointestinal benign disease and health adults were also detected and compraed with that of GC and CRC. 3. To study the correlation of the expression of Ep-CAM and 4D10 in sera of GC and CRC with clinicopatholgic characteristics of tumors. 4. The values of combined detection of Ep-CAM and 4D10 in GC and CRC and to explore the feasibility of Ep-CAM and 4D10 as tumor markers for GC and CRC.
Methods: 53 primary gastric carcinoma sera specimens and 40 colorectal carcinoma sera specimens which obtained from patients underwent surgery and confirmed by pathology were included in the study group. 30 sera specimens of gastrointestinal benign disease and 50 sera specimens from health adults which offered by Central Blood Bank of Red Cross of Anhui province were included in control group. Double antibody sandwich ELISA was used to examine the expression of Ep-CAM and 4D10 in all sera specimens, and the relation of expression of Ep-CAM and 4D10 between study group and control group was analyzed. Furthermore, the expression of Ep-CAM and 4D10 in study group was also analyzed with regard to clinicopathologic characteristics. The results demonstrated as optical density (Ep-CAM OD). Relation between the expression of Ep-CAM and that of 4D10 was also analyzed.
Results: 1. The Ep-CAM OD of GC group was 0.550±0.1109, the Ep-CAM OD of CRC group was 0.643±0.0573, the Ep-CAM OD of gastrointestinal benign disease group was 0.248±0.0411 and the Ep-CAM OD of health adults group was 0.247±0.0152. The Ep-CAM OD in study group was significantly higher than control group (P<0.01).
2. The 4D10 OD of GC group was 0.558±0.1197, the 4D10 OD of CRC group was 0.741±0.1201, the 4D10 OD of gastrointestinal benign disease group was 0.331±0.0151 and the OD of health adults group was 0.247±0.0152. The 4D10 OD in study group was significantly higher than control group (P<0.01).
3. High-level expression of Ep-CAM and 4D10 were observed in gastric carcinoma in TNMⅠ,Ⅱstage and in colorectal carcinoma in Dukes A,B stage. High-level expression of Ep-CAM and 4D10 were also observed in tumor size less than 5cm and tumor infiltrate in muscular layer .The expression of Ep-CAM and 4D10 in study group increased in early period of GC and CRC and could be detected.
4. Expression of Ep-CAM correlates with that of 4D10 in GC and CRC, and the early diagnosis rate of GC and CRC could be raised by combined detection with Ep-CAM and 4D10.
5. Expression of Ep-CAM and 4D10 were not influenced by clinicopathological characteristic such as age, gender, pathologic type, differention and lymphoid node metastasis etc.
Conclusion: 1. High-level expression of Ep-CAM and 4D10 were observed in gastric carcinoma and colorectal carcinoma, and they were involved in GC and CRC genesis and development.
2. Ep-CAM and 4D10 play important roles in gastric and colorectal carcinogenesis and can be detected in early stage. They may serve as markers in the early diagnosis of gastric carcinoma and colorectal carcinoma.
3. The early diagnosis rate of GC and CRC could be raised by combined detection with Ep-CAM and 4D10.
4. Expression of Ep-CAM and 4D10 were not influenced by clinicopathological characteristic such as age, gender, pathologic type, differention and lymphoid node metastasis, etc. Ep-CAM and 4D10 may be independent inflence factors in the GC and CRC carcinogenesis and development.
引文
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18 Heideman DAM,Snijder PJF,Craanen ME,et al.Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors.Cancer Gene Ther.2001;8:342-351.
19 宋玉,刘晓燕,张萍,等.抗人结肠癌相关抗原单克隆抗体的制备及初步研究.中国免疫学杂志.2006:22:353-355,359.
20 柳晓燕,姚晓玲,徐振山,等.结肠癌相关抗原的制备及其临床意义.细胞与分子免疫学杂志.2007:23:335-337.
21 陈创,陈利琴,杨国梁等.肿瘤标志物在结直肠癌诊断和监测中的价值.武汉大学学报(医学版).2007:28:207-211.
22 王双双,范玉晶,关景明.大肠癌相关的肿瘤标志物.临床消化病杂志.2006; 18:115-116.
23 陶华林,李红霞.肿瘤标志物的研究及临床应用进展 国外医学临床生物化学与检验学分册.2005;1:54-57,59.
24 李岩.胃癌血清肿瘤标志物单项及联合检测的临床意义.临床内科杂志.2007:24:515-518.
25 刘云,李建刚.多项肿瘤标志物联检对胃恶性肿瘤诊断的临床价值放射免疫学杂志.2007;20:16-18.
26 Went PT,Lugli A,Meier S,et al.Frequent EpCAM protein expression in human carcinomas.Hum Pahtol.2004;35:122-128.
27 Trzpis M,McLaughlin PM,de Leij LM,et al.Epithelial cell adhesion molecule:more than a carcinoma marker and adhesion molecule.Am J Pathol.2007;171:386-395.
28 Yovchev MI,Grozdanov PN,Zhou H,et al.Identification of adult hepatic progenitor cells capable of repopulating injured rat liver.Hepatology.2008;47:636-647.
29 Joo M,Kim H,Kim HK,et al.Expression of Ep-CAM in intestinal metaplasia,gastric epithelia dysplasia and gastric adenocarcinoma.J Gastroenterol Hepatol.2005;20:1039-1045.
1 Winter MJ, Nagtegaal ID, Krieken JH, et al. The Epithelial Cell Adhesion Molecule (Ep-CAM) as a Morphoregulatory Molecule is a tool in Surgical Pathology. Am J Pathol. 2003;163:2139-2148.
2 Balzar M, Winter MJ, de Boer CJ, et al. The biology of the 17-1A antigen (Ep-CAM). J Mol Med. 1999;77:699-712.
3 Balzar M, Bakker HAM, Briaire-de Bruijn IH, et al. Cytoplasmic tail of the intercellular adhesion function of the epithelial adhesion molecule (Ep-CAM). Mol Cell Biol. 1998;18:4833-4843.
4 Strnad J, Hamilton AE, Beavers LS, et al. Molecular cloning and characterization of a human adenocarcinoma/epithelial cell surface antigen complementary DNA.Cancer Res. 1989;49:314-317.
5 Thampoe I, Ng J, Lloyd K. Biochemical analysis of a human epithelial surface antigen: differential cell expression and processing. Arch Biochem Biophys.1988;267.342-352.
6 Pauli C, Munz M, Kieu C, et al. Tumor-specific glycosylation of the carcinoma-associated epithelial cell adhesion molecule EpCAM in head and neck carcinomas. Cancer Lett. 2003; 193:25-32.
7 Schmelzer E, Reid LM. EpCAM expression in normal, non-pathological tissues. Front Biosci. 2008;13:3096-3100.
8 Shawler DL, Bartholonew RM, Garrett MA, et al. Antigenic and immunologic characterization of an allogeneic colon carcinoma vaccine. Clin Exp Immunol.2002;129:99-106.
9 Went P, Vassei M, Bubendorf L, et al. Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate, and lung cancers.Br J Cancer.2006;94:128-135.
10 Osta WA, Chen Y, Mikhitarian K, et al. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res.2004;64:5818-5824.
11 Went PT, Lugli A, Meier S, et al. Frequent EpCam protein expression in human carcinomas. Hum Pahtol. 2004;35:122-128.
12 Joo M , Kim H, Kim HK, et al. Expression of Ep-CAM in intestinal metaplasia ,gastric epithelia dysplasia and gastric adenocarcinoma. J Gastroenterol Hepatol.2005;20:1039-1045.
13 Kuhn S, Koch M, Nubel T, et al. A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression. Mol Cancer Res.2007;5:553-567.
14 Abe H, Kuroki M, Imakiire T, et al. Preparation of recombinant MK-1 Ep-CAM and establishment of an ELISA system for determining soluble MK-1 Ep-CAM levels in sera of cancer patients. J Immunol Methods. 2002;270:227-233.
15 Rao CG, Chianese D, Dolye GV, et al. Expression of epithelial cell adhesion molecule in carcinoma cells iin blood and primary and metastatic tumors. Int J Oncol. 2005;27:49-57.
16 Flieger D, Hoff AS, Sauerbruch T, et al. Influence of cytokines, monoclonal antibodies and chemotherapeutic drugs on epithelial cell adhesion molecule (EpCAM) and LewisY antigen expression. Clin Exp Immunol. 2001;123:9-14.
17 Molloy T J, Bosma A J, Laura J, et al. Towards an optimized platform for the detection, enrichment, and semi-quantitation circulating tumor cells. Breast Cancer Res Treat.2008;57:379-388.
18 Tveito S, Gunhild M, Maelandsmo, et al. Specific isolation of disseminated cancer cells: a new method permitting sensitive detection of target molecules of diagnostic and therapeutic value. Clin Exp Metastasis. 2007;24:317-327.
19 Spizzo G, Went P, Dirnhofer S, et al. Overexpression of epithelial cell adhesion molecule (Ep-CAM) is an independent prognostic marker for reduced survival of patients with epithelial ovarian cancer. Gynecol Oncol. 2006;103:483-488.
20 Prince S, Zeidman A, Dekel Y et al . Expression of epithelial cell adhesion molecule in gallbladder carcinoma and its correlation with clinicopathologic variables. Am J Clin Pathol. 2008; 129:424-429.
21 Yovchev MI, Grozdanov PN, Zhou H, et al. Identification of adult hepatic progenitor cells capable of - repopulating injured rat liver. Hepatology.2008;47:636-647.
22 Trzpis M, McLaughlin PM, de Leij LM, et al. Epithelial cell adhesion molecule:more than a carcinoma marker and adhesion molecule. Am J Pathol.2007;171:386-395.
23 Munz M, Kieu C, Mack B, et al. The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene. 2004;23:5748-5758.
24 Litvinov SV, Balzar M, Winter MJ, et al. Epithelial Cell Adhesion Molecule (Ep-CAM) Modulates Cell- Cell Interaction Mediated by Classic Cadherins. J Cell Biol. 1997; 139:1337-1348.
25 Meyarrd L, van der Vuurst, de Vries, et al. The epithelial cell adhesion molecule (Ep-CAM) is a ligand for the leukocyte-associate immunoglobulin-like receptor (LAIR-l).J Exp Med.2001; 194:107-112.
26 Skiados M, Karina. The use of a novel chromatographic molecular method for the detection of the membrane cancer antigen Ep-cam (17-1 A) in peripheral blood and bone marrow of patients with metastatic colorectal cancer. Colorectal Cancer.Poster,2003.
27 Dalerba P, Dylla SJ, Park IK , et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci.2007; 104:158-163.
28 Zhang KH, Cao F, Fu QB, et al. Detection of mRNAs of GA733 genes by RT-PCR in exfoliated cells of pleural and peritoneal effusions and its clinical values. Intern Med.2007;46:1489-1494.
29 Muenz M, Hofmann T, Scheibe B, et al. The carcinoma-associat ed antigen EpCAM induces glyoxalase 1 resulting in enhanced methylglyoxal turnover. Cancer Genom Proteom. 2004;1:241-247.
30 Muenz M, Zeidler R, Gires O. The tumour-associated antigen EpCAM upregulates the fatty acid binding protein E-FABP. Cancer Lett. 2005;225:151-157.
31 Goel S, Bauer RJ, Desai K, et al. Pharmacokinetic and safety study of subcutaneously administered weekly ING-1, α human engineered monoclonal antibody targeting human EpCAM, in patients with advanced solid tumors. Ann Oncol. 2007; 18:1704-1707.
32 Hussain S, Pluckthun A, Allen TM, et al. Antitumor activity of an epithelial cell adhesion molecule targeted nanovesicular drug delivery system. Mol Cancer Ther.2007;6:3019-3027.
33 Haisma HJ, Pinedo HM, Rijswijk AV, et al. Tumor-specific gene transfer via an adenoviral vector targeted to pan-carcinoma antigen EpCAM. Gene Ther.1999;6:1469-1474.
34 Kirman I, Maydelman A, Asi Z, et al. Effect of surgical trauma on epithelial cell adhesion molecule (GA-733) vaccine-induced tumor resistance. Surg Endosc.2003;17:505-509.
35 Kirman I, Jenkins D, Fowler R, et al. Naturally Occurring Antibodies to Epithelial Cell Adhesion Molecule (EpCAM). Dig Dis Sci. 2003;48:2306-2309.
36 Kirman I, Whelan RL. Drug evaluation: adecatumumab, an engineered human anti-EpCAM antibody. Curr Opin Mol Ther. 2007;9:190-196.
37 Fogler W, Klinger M, Abraham K, et al. Enhanced cytotoxicity against colon carcinoma by combinations of non-competing monoclonal antibodies to 17-1A antigen. Cancer Res.l998;48:6303-6308.
38 Riethmuller G, Holz E, and Schiimok G, et al. Monoclonal antibody therapy for resected Dukes'C colorectal cancer: seven-year outcome of a multicenter randomized triad. J Clin Onco. 1998;16:1788-1794.
39 Gelderman KA, Kuppen PJ, Bruin W, et al. Enhancement of the complement activating capacity of 17-1A mAb to overcome the effect of membrane bound complement regulatory proteins on colorectal carcinoma. Eur J Immunol.2002;32:128-135.
40 Krusch M, Hermann T, Kanz L, et al. Induction of localized TNF activity against tumors using bispecific antibodies. Blood. 2005; 106: 624-625.
41 Amann M, Brischwein K, Lutterbuese P , et al. Therapeutic window of MuS110, a single-chain antibody construct bispecific for murine EpCAM and murine CD3.Cancer Res. 2008; 68:143-51.
42 Lutterbuese P, Brischwein K, Hofmeister R et al. Exchanging human Fc_1 with murine Fc_2a highly potentiates anti-tumor activity of anti-EpCAM antibody adecatumumab in a syngeneic mouse lung metastasis model. Cancer Immunol Immunother. 2007; 56:459-468.
43 Sebastian M, Passlick B, Jager M et al. Treatment of non-small cell lung cancer patients with the trifunctional monoclonal antibody catumaxomab (anti-EpCAM xanti-CD3): a phase I study. Cancer Immunol Immunother. 2007; 56:1637-1644.
44 Zeilder R, Mysliwietz J, Csanady M, et al. The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumor cells. Br J Cancer. 2000; 83:261-266.
45 Gronau SS, Schmitt M, Thess B, et al. Trifunctional bispecific antibody-induced tumor cell lysis of squamous cell carcinoma of the upper aerodigestive tract. Head Neck. 2005; 27:376-382.
46 Kosterink JG, McLaughlin PM, Lub-de-Hooge MN,et al. Biodistribution Studies of Epithelial Cell Adhesion Molecule (EpCAM)-Directed Monoclonal Antibodies in the EpCAM-Transgenic Mouse Tumor Model. J Immuno. 2007; 79: 1362-1368.
47 Liljefors M, Ranhammar P, Nilsson B, et al. Anti- EpCAM monoclonal antibody (MAb17-1A) based treatment combined with alpha-interferon 5-fluorouracil and granulocyte-macrophage colony-stimulating factor in patients with metastatic colorectal carcinoma. Int J Oncol. 2004; 25:703-711.
48 Frodin JE, Fagerberg J, Hjelm S, et al. MAbl7-lA and cytokines for the treatment of patients with colorectal carcinoma. Hybrid Hybridom. 2002; 21:99-101.
49 Flieger D, Spengler U, Beier I, et al. Augment of 17-1A induced antibody-dependent cellular cytotoxity by the triple cytokine combination of interferon-alpha, interleukin-2, interleukin-12. J Immunother. 2000; 23:480-486.
50 Liljefors M, Nilsson B, Fagerberg J, et al. Clinical effects of a chimeric anti-EpCAM monoclonal antibody in combination with granulocyte-macrophage colony-stimulating factor in patients with metastatic colorectal carcinoma. Int J Oncol. 2005; 26:1581-1589.
51 Liljefors M, Nilsson B, Mellsted H, et al. Influence of varying doses of granulocyte-macrophage colony-stimulating factor on pharmacokinetics and antibody-dependent cellular cytotoxicity. Cancer Immunol Immunother .2008 ;57(3):379-388.
52 Xiang R, Lode HN, Dolman CS, et al. Elimination of established murine colon carcinoma metastases by antibody-interleukin 2 fusion protein therapy. Cancer Res.1997; 57:4948-4955.
53 Xiang R, Lode HN, Dreier T, et al. Induction of persistent tumor-protective immunity in mice cured of established colon carcinoma metastases. Cancer Res.1998; 58:3918-3925.
54 Birebent B, Somasundaram R, Purev E, et al. Anti-idiotypic antibody and recombinant antigen vaccines in colorectal cancer patients. Crit Rev Oncol Hematol. 2001;39:107-113.
55 Mellstdt H, Fagerberg J, Fordin JE, et al. Ga733/EpCAM as a target for passive and active specific immunotherapy in patients with colorectal carcinoma. Ann N Y Acad Sci. 2000; 910: 254-261.
56 Zaloudik J, Li W, Jacob L, et al. Inhibition of tumor recombinant vaccinia virus expressing GA733/CO17-lA/EpCAM/KSA/KSl-4 antigen in mice. Cancer Gene Ther. 2002; 9: 382-389.
57 Brodzik R, Spitsin S, Golovkin M, et al. Plant-derived EpCAM antigen induces protective anti-cancer response.Cancer Immunol Immunother.2008;57:317-323.
58 Heideman DAM,van Beusechem VW,Offerhaus GJ,et al.Selective gene transfer into primary human gastric tumors using epithelial cell adhesion molecule-targeted adenoviral vectors with ablated native tropism.Hum Gene Ther.2002;13:1677-1685.
59 Heideman DAM,Snijder PJF,Craanen ME,et al.Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targetd adenoviral vectors.Cancer Gene Ther.2001;8:342-351.
60 Haisma HJ,Pinedo HM,Rijswijk AV,et al.Tumor-specific gene transfer via an adenoviral vector targeted to pan-carcinoma antigen EpCAM.Gene Ther.1999;6:1469-1474.
61 Kokichi S,Hianao O,Setsuo H,et al.Detection of increased fecal carcinoembryonic antigen and its characterization as a membrane-bound form in colorectal carcinoma and other gastrointestinal disorders.Jpn J Cancer Res.1989;80:1156-1160.
62 Hussain S,Pl(u|¨)ckthun A,Allen TM et al.Antitumor activity of an epithelial cell adhesion molecule targeted nanovesicular drug delivery system.Mol Cancer Ther.2007;6:3019-3027.
63 Kirman I,Whelan RL.Drug evaluation:adecatumumab,an engineered human anti-EpCAM antibody.Curr Opin Mol Ther.2007;9:190-196.
64 宋玉 刘晓燕 徐振山等.抗人结肠癌相关抗原单克隆抗体的制备及初步研究.中国免疫学杂志.2006:22:353-356.
65 柳晓燕 姚晓玲 徐振山等.结肠癌相关抗原的制备及其临床意义.细胞与分子免疫学杂志.2007;23:335-337.
2 陈创,杨国梁,李雁,等.肿瘤标志物在胃癌诊断和监测中的价值和改进策略医学新知杂志.2007:17:15-19.
3 Winter MJ,Nagtegaal ID,Krieken JH,et al.The Epithelial Cell Adhesion Molecule(Ep-CAM) as a Morphoregulatory Molecule is a tool in Surgical Pathology.Am J Pathol.2003;163:2139-2148.
4 Balzar M,Winter MJ,de Boer CJ,et al.The biology of the 17-1A antigen (Ep-CAM).J Mol Med.1999;77:699-712.
5 Shawler DL,Bartholonew RM,Garrett MA,et al.Antigenic and immunologic characterization of an allogeneic colon carcinoma vaccine.Clin Exp Immunol.2002;129:99-106.
6 Went P,Vassei M,Bubendorf L,et al.Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon,stomach,prostate,and lung cancers.Br J Cancer.2006;94:128-135.
7 Osta WA,Chen Y,Mikhitarian K,et al.EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy.Cancer Res.2004;64:5818-5824.
8 Pauli C,Munz M,Kieu C,et al.Tumor-specific glycosylation of the carcinoma-associated epithelial cell adhesion molecule EpCAM in head and neck carcinomas.Cancer Lett.2003;193:25-32.
9 Munz M,Kieu C,Mack B,et al.The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation.Oncogene.2004;23:5748-5758.
10 Litvinov SV,Balzar M,Winter MJ,et al.Epithelial Cell Adhesion Molecule (Ep-CAM) Modulates Cell-Cell Interaction Mediated by Classic Cadherins.J Cell Biol.1997;139:1337-1348.
11 Haisma HJ,Pinedo HM,Rijswijk AV,et al.Tumor-specific gene transfer via an adenoviral vector targeted to pan-carcinoma antigen EpCAM.Gene Ther.1999; 6:1469-1474.
12 Kirman I,Maydelman A,Asi Z,et al.Effect of surgical trauma on epithelial cell adhesion molecule(GA-733) vaccine-induced tumor resistance.Surg Endosc.2003;17:505-509.
13 Kirman I,Jenkins D,Fowler R,et al.Naturally Occurring Antibodies to Epithelial Cell Adhesion Molecule(EpCAM).Dig Dis Sci.2003;48:2306-2309.
14 Amstrong A,Eck SL.EpCAM:A New Therapeutic Target for an Old Cancer Antigen.Cancer Biol Ther.2003;4:320-325.
15 Zaloudik J,Li W,Jacob L,et al.Inhibition of tumor growth by recombinant vaccinia virus expressing GA733/CO17-1A/EpCAM/KSA/KS1-4 antigen in mice.Cancer Gene Ther.2002;9:382-389.
16 Hussain S,Pl(u|¨)ckthun A,Allen TM,et al.Antitumor activity of an epithelial cell adhesion molecule targeted nanovesicular drug delivery system.Mol Cancer Ther.2007;6:3019-3027.
17 Goel S,Bauer RJ,Desai K,et al.Pharmacokinetic and safety study of subcutaneously administered weekly ING-1,a human engineered monoclonal antibody targeting human EpCAM,in patients with advanced solid tumors.Ann Oncol.2007;18:1704-1707.
18 Heideman DAM,Snijder PJF,Craanen ME,et al.Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors.Cancer Gene Ther.2001;8:342-351.
19 宋玉,刘晓燕,张萍,等.抗人结肠癌相关抗原单克隆抗体的制备及初步研究.中国免疫学杂志.2006:22:353-355,359.
20 柳晓燕,姚晓玲,徐振山,等.结肠癌相关抗原的制备及其临床意义.细胞与分子免疫学杂志.2007:23:335-337.
21 陈创,陈利琴,杨国梁等.肿瘤标志物在结直肠癌诊断和监测中的价值.武汉大学学报(医学版).2007:28:207-211.
22 王双双,范玉晶,关景明.大肠癌相关的肿瘤标志物.临床消化病杂志.2006; 18:115-116.
23 陶华林,李红霞.肿瘤标志物的研究及临床应用进展 国外医学临床生物化学与检验学分册.2005;1:54-57,59.
24 李岩.胃癌血清肿瘤标志物单项及联合检测的临床意义.临床内科杂志.2007:24:515-518.
25 刘云,李建刚.多项肿瘤标志物联检对胃恶性肿瘤诊断的临床价值放射免疫学杂志.2007;20:16-18.
26 Went PT,Lugli A,Meier S,et al.Frequent EpCAM protein expression in human carcinomas.Hum Pahtol.2004;35:122-128.
27 Trzpis M,McLaughlin PM,de Leij LM,et al.Epithelial cell adhesion molecule:more than a carcinoma marker and adhesion molecule.Am J Pathol.2007;171:386-395.
28 Yovchev MI,Grozdanov PN,Zhou H,et al.Identification of adult hepatic progenitor cells capable of repopulating injured rat liver.Hepatology.2008;47:636-647.
29 Joo M,Kim H,Kim HK,et al.Expression of Ep-CAM in intestinal metaplasia,gastric epithelia dysplasia and gastric adenocarcinoma.J Gastroenterol Hepatol.2005;20:1039-1045.
1 Winter MJ, Nagtegaal ID, Krieken JH, et al. The Epithelial Cell Adhesion Molecule (Ep-CAM) as a Morphoregulatory Molecule is a tool in Surgical Pathology. Am J Pathol. 2003;163:2139-2148.
2 Balzar M, Winter MJ, de Boer CJ, et al. The biology of the 17-1A antigen (Ep-CAM). J Mol Med. 1999;77:699-712.
3 Balzar M, Bakker HAM, Briaire-de Bruijn IH, et al. Cytoplasmic tail of the intercellular adhesion function of the epithelial adhesion molecule (Ep-CAM). Mol Cell Biol. 1998;18:4833-4843.
4 Strnad J, Hamilton AE, Beavers LS, et al. Molecular cloning and characterization of a human adenocarcinoma/epithelial cell surface antigen complementary DNA.Cancer Res. 1989;49:314-317.
5 Thampoe I, Ng J, Lloyd K. Biochemical analysis of a human epithelial surface antigen: differential cell expression and processing. Arch Biochem Biophys.1988;267.342-352.
6 Pauli C, Munz M, Kieu C, et al. Tumor-specific glycosylation of the carcinoma-associated epithelial cell adhesion molecule EpCAM in head and neck carcinomas. Cancer Lett. 2003; 193:25-32.
7 Schmelzer E, Reid LM. EpCAM expression in normal, non-pathological tissues. Front Biosci. 2008;13:3096-3100.
8 Shawler DL, Bartholonew RM, Garrett MA, et al. Antigenic and immunologic characterization of an allogeneic colon carcinoma vaccine. Clin Exp Immunol.2002;129:99-106.
9 Went P, Vassei M, Bubendorf L, et al. Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate, and lung cancers.Br J Cancer.2006;94:128-135.
10 Osta WA, Chen Y, Mikhitarian K, et al. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res.2004;64:5818-5824.
11 Went PT, Lugli A, Meier S, et al. Frequent EpCam protein expression in human carcinomas. Hum Pahtol. 2004;35:122-128.
12 Joo M , Kim H, Kim HK, et al. Expression of Ep-CAM in intestinal metaplasia ,gastric epithelia dysplasia and gastric adenocarcinoma. J Gastroenterol Hepatol.2005;20:1039-1045.
13 Kuhn S, Koch M, Nubel T, et al. A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression. Mol Cancer Res.2007;5:553-567.
14 Abe H, Kuroki M, Imakiire T, et al. Preparation of recombinant MK-1 Ep-CAM and establishment of an ELISA system for determining soluble MK-1 Ep-CAM levels in sera of cancer patients. J Immunol Methods. 2002;270:227-233.
15 Rao CG, Chianese D, Dolye GV, et al. Expression of epithelial cell adhesion molecule in carcinoma cells iin blood and primary and metastatic tumors. Int J Oncol. 2005;27:49-57.
16 Flieger D, Hoff AS, Sauerbruch T, et al. Influence of cytokines, monoclonal antibodies and chemotherapeutic drugs on epithelial cell adhesion molecule (EpCAM) and LewisY antigen expression. Clin Exp Immunol. 2001;123:9-14.
17 Molloy T J, Bosma A J, Laura J, et al. Towards an optimized platform for the detection, enrichment, and semi-quantitation circulating tumor cells. Breast Cancer Res Treat.2008;57:379-388.
18 Tveito S, Gunhild M, Maelandsmo, et al. Specific isolation of disseminated cancer cells: a new method permitting sensitive detection of target molecules of diagnostic and therapeutic value. Clin Exp Metastasis. 2007;24:317-327.
19 Spizzo G, Went P, Dirnhofer S, et al. Overexpression of epithelial cell adhesion molecule (Ep-CAM) is an independent prognostic marker for reduced survival of patients with epithelial ovarian cancer. Gynecol Oncol. 2006;103:483-488.
20 Prince S, Zeidman A, Dekel Y et al . Expression of epithelial cell adhesion molecule in gallbladder carcinoma and its correlation with clinicopathologic variables. Am J Clin Pathol. 2008; 129:424-429.
21 Yovchev MI, Grozdanov PN, Zhou H, et al. Identification of adult hepatic progenitor cells capable of - repopulating injured rat liver. Hepatology.2008;47:636-647.
22 Trzpis M, McLaughlin PM, de Leij LM, et al. Epithelial cell adhesion molecule:more than a carcinoma marker and adhesion molecule. Am J Pathol.2007;171:386-395.
23 Munz M, Kieu C, Mack B, et al. The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene. 2004;23:5748-5758.
24 Litvinov SV, Balzar M, Winter MJ, et al. Epithelial Cell Adhesion Molecule (Ep-CAM) Modulates Cell- Cell Interaction Mediated by Classic Cadherins. J Cell Biol. 1997; 139:1337-1348.
25 Meyarrd L, van der Vuurst, de Vries, et al. The epithelial cell adhesion molecule (Ep-CAM) is a ligand for the leukocyte-associate immunoglobulin-like receptor (LAIR-l).J Exp Med.2001; 194:107-112.
26 Skiados M, Karina. The use of a novel chromatographic molecular method for the detection of the membrane cancer antigen Ep-cam (17-1 A) in peripheral blood and bone marrow of patients with metastatic colorectal cancer. Colorectal Cancer.Poster,2003.
27 Dalerba P, Dylla SJ, Park IK , et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci.2007; 104:158-163.
28 Zhang KH, Cao F, Fu QB, et al. Detection of mRNAs of GA733 genes by RT-PCR in exfoliated cells of pleural and peritoneal effusions and its clinical values. Intern Med.2007;46:1489-1494.
29 Muenz M, Hofmann T, Scheibe B, et al. The carcinoma-associat ed antigen EpCAM induces glyoxalase 1 resulting in enhanced methylglyoxal turnover. Cancer Genom Proteom. 2004;1:241-247.
30 Muenz M, Zeidler R, Gires O. The tumour-associated antigen EpCAM upregulates the fatty acid binding protein E-FABP. Cancer Lett. 2005;225:151-157.
31 Goel S, Bauer RJ, Desai K, et al. Pharmacokinetic and safety study of subcutaneously administered weekly ING-1, α human engineered monoclonal antibody targeting human EpCAM, in patients with advanced solid tumors. Ann Oncol. 2007; 18:1704-1707.
32 Hussain S, Pluckthun A, Allen TM, et al. Antitumor activity of an epithelial cell adhesion molecule targeted nanovesicular drug delivery system. Mol Cancer Ther.2007;6:3019-3027.
33 Haisma HJ, Pinedo HM, Rijswijk AV, et al. Tumor-specific gene transfer via an adenoviral vector targeted to pan-carcinoma antigen EpCAM. Gene Ther.1999;6:1469-1474.
34 Kirman I, Maydelman A, Asi Z, et al. Effect of surgical trauma on epithelial cell adhesion molecule (GA-733) vaccine-induced tumor resistance. Surg Endosc.2003;17:505-509.
35 Kirman I, Jenkins D, Fowler R, et al. Naturally Occurring Antibodies to Epithelial Cell Adhesion Molecule (EpCAM). Dig Dis Sci. 2003;48:2306-2309.
36 Kirman I, Whelan RL. Drug evaluation: adecatumumab, an engineered human anti-EpCAM antibody. Curr Opin Mol Ther. 2007;9:190-196.
37 Fogler W, Klinger M, Abraham K, et al. Enhanced cytotoxicity against colon carcinoma by combinations of non-competing monoclonal antibodies to 17-1A antigen. Cancer Res.l998;48:6303-6308.
38 Riethmuller G, Holz E, and Schiimok G, et al. Monoclonal antibody therapy for resected Dukes'C colorectal cancer: seven-year outcome of a multicenter randomized triad. J Clin Onco. 1998;16:1788-1794.
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