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Shang HS, Liu JY, Lu HF, Chiang HS, Lin CH, Chen A, Lin YF, Chung JG. Casticin induced apoptotic cell death and altered associated gene expression in human colon cancer colo 205 cells. ENVIRONMENTAL TOXICOLOGY 2017; 32:2041-2052. [PMID: 27862857 DOI: 10.1002/tox.22381] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 10/24/2016] [Accepted: 10/24/2016] [Indexed: 06/06/2023]
Abstract
Casticin, a polymethoxyflavone, derived from natural plant Fructus Viticis exhibits biological activities including anti-cancer characteristics. The anti-cancer and alter gene expression of casticin on human colon cancer cells and the underlying mechanisms were investigated. Flow cytometric assay was used to measure viable cell, cell cycle and sub-G1 phase, reactive oxygen species (ROS) and Ca2+ productions, level of mitochondria membrane potential (ΔΨm ) and caspase activity. Western blotting assay was used to detect expression of protein level associated with cell death. Casticin induced cell morphological changes, decreased cell viability and induced G2/M phase arrest in colo 205 cells. Casticin increased ROS production but decreased the levels of ΔΨm , and Ca2+ , increased caspase-3, -8, and -9 activities. The cDNA microarray indicated that some of the cell cycle associated genes were down-regulated such as cyclin-dependent kinase inhibitor 1A (CDKN1A) (p21, Cip1) and p21 protein (Cdc42/Rac)-activated kinase 3 (PAK3). TNF receptor-associated protein 1 (TRAP1), CREB1 (cAMP responsive element binding protein 1) and cyclin-dependent kinase inhibitor 1B (CDKN1B) (p27, Kip1) genes were increased but matrix metallopeptidase 2 (MMP-2), toll-like receptor 4 (TLR4), PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, bet), and CaMK4 (calcium/calmodulin-dependent protein kinase IV) genes were inhibited. Results suggest that casticin induced cell apoptosis via the activation of the caspase- and/or mitochondria-dependent signaling cascade, the accumulation of ROS and altered associated gene expressions in colo 205 human colon cancer cells.
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Affiliation(s)
- Hung-Sheng Shang
- Graduate Institute of Clinical of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jia-You Liu
- Department of Clinical Pathology, Cheng-Hsin General Hospital, Taipei, Taiwan
| | - Hsu-Feng Lu
- Department of Clinical Pathology, Cheng-Hsin General Hospital, Taipei, Taiwan
- Department of Restaurant, Hotel and Institutional Management, Fu-Jen Catholic University, New Taipei city, Taiwan
| | - Han-Sun Chiang
- Graduate Institute of Basic Medicine, Fu-Jen Catholic University, New Taipei city, Taiwan
| | - Chia-Hain Lin
- Department of Chinese Medicine Resources, China Medical University, Taichung, Taiwan
| | - Ann Chen
- Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yuh-Feng Lin
- Graduate Institute of Clinical of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Medicine, Shuang Ho Hospital, New Taipei City, Taiwan
| | - Jing-Gung Chung
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
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LIU YINGYING, XIA TINGTING, JIN CHUNHUI, GU DONGMEI, YU JIE, SHI WEIQIANG, ZHANG KE, ZHANG LIPING, YE JIANXIN, LI LING. FOXP3 and CEACAM6 expression and T cell infiltration in the occurrence and development of colon cancer. Oncol Lett 2016; 11:3693-3701. [PMID: 27284373 PMCID: PMC4888014 DOI: 10.3892/ol.2016.4439] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2015] [Accepted: 03/18/2016] [Indexed: 12/22/2022] Open
Abstract
The transcription factor forkhead box P3 (FOXP3) is involved in immune cell regulation, and carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is an adhesion molecule of the immunoglobulin superfamily. These two genes are associated with cancer progression. In the current study, colon tissue specimens from 78 cases of colon cancer (including 40 of stage I-II and 38 of stage III-IV), 30 cases of colonic adenoma and 12 healthy controls were collected from the First Affiliated Hospital of Soochow University between January 2010 and December 2011. The expression of cluster of differentiation (CD) 3, CD4, CD8, CD45RO, CEACAM6 and FOXP3 in colon tissues was examined by immunohistochemical analysis. In addition, a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay, based on SYBR Green I, was used to detect CD3, CD4, CD8, CD45RO, CEACAM6 and FOXP3 mRNA levels in the paraffin block specimens. CD3+, CD8+ and CD45RO+ T cell infiltrations in colonic adenoma were significantly higher than in normal colonic mucosa (P<0.001, P=0.001 and P<0.001, respectively). However, CD3+, CD8+ and CD45RO+ lymphocytes in stage III-IV colon cancer tissues were lower than in normal control tissues (P=0.015, P=0.002 and P=0.041, respectively); consistently, CD3+, CD4+, CD8+ and CD45RO+ lymphocytes in stage III-IV tissues were even more markedly lower compared with adenoma (P=0.001, P<0.001, P<0.001 and P<0.001, respectively). Similarly, CD3+, CD8+ and CD45RO+ T cell infiltration was lower in stage I-II cancer tissues compared with adenoma (P=0.001, P<0.001 and P<0.001). CD3+, CD4+, CD8+ and CD45RO+ T cell infiltrations were also significantly higher in stage I-II compared with stage III-IV cancer tissues (P<0.001, P=0.045, P<0.001 and P<0.001, respectively). CEACAM6 was found to gradually increase from normal colon tissue to adenoma and cancer tissue. FOXP3 was expressed more highly in stage I-II compared with normal tissues (P=0.014), and was even higher in stage III-IV (P<0.001). These results were verified using RT-qPCR, which yielded almost identical results. In summary, the current study demonstrates that FOXP3, CEACAM6 and T cell infiltration are significantly associated with the occurrence and progression of colon cancer, and that immune reactions vary between different stages of colon cancer development.
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Affiliation(s)
- YINGYING LIU
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - TINGTING XIA
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - CHUNHUI JIN
- Department of Oncology, Wuxi Hospital of Traditional Chinese Medicine, Wuxi, Jiangsu 214000, P.R. China
| | - DONGMEI GU
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - JIE YU
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - WEIQIANG SHI
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - KE ZHANG
- Department of Gastroenterology, The Second People's Hospital of Changshu, Changshu, Jiangsu 215500, P.R. China
| | - LIPING ZHANG
- Department of Gastroenterology, Suzhou Municipal Hospital (North), Suzhou, Jiangsu 215008, P.R. China
| | - JIANXIN YE
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - LING LI
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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Abstract
Diabetic macular edema (DME) is the main cause of visual impairment in diabetic patients. Macular edema within 1 disk diameter of the fovea is present in 9% of the diabetic population. The management of DME is complex and often multiple treatment approaches are needed. This review demonstrates the benefits of intravitreal triamcinolone, bevacizumab and ranibizumab as adjunctive therapy to macular laser treatment in DME. The published results indicate that intravitreal injections of these agents may have a beneficial effect on macular thickness and visual acuity, independent of the type of macular edema that is present. Therefore, pharmacotherapy could complement focal/grid laser photocoagulation in the management of DME. For this review, we performed a literature search and summarized recent findings regarding combined therapy for DME.
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Affiliation(s)
- Saba Al Rashaed
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia
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Ishigami S, Arigami T, Uenosono Y, Okumura H, Kurahara H, Uchikado Y, Setoyama T, Kita Y, Kijima Y, Nishizono Y, Nakajo A, Owaki T, Ueno S, Natsugoe S. Clinical implications of DLL4 expression in gastric cancer. J Exp Clin Cancer Res 2013; 32:46. [PMID: 23898884 PMCID: PMC3751047 DOI: 10.1186/1756-9966-32-46] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Accepted: 07/16/2013] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Delta-like ligand 4 (DLL4)-Notch signaling plays a key role in tumor neovascular development and angiogenesis during tumor growth. The clinical significance of DLL4 expression in gastric cancer has not been clarified. METHODS Gastric cancer cell lines and 180 gastric cancer patients were enrolled. DLL4 expression in gastric cancer cells and stroma was identified and evaluated immunohistochemically. The association between DLL4 and clinicopathological factors was also assessed. RESULTS DLL4 expression was identified in the cellular membrane and cytoplasm of gastric cancer cells by immunoblotting and immunohistochemical staining. DLL4 positivity in cancer cells and stroma was found in 88 (48%) and 41 (22%) of the 180 gastric cancer patients respectively. Both cancer and stromal DLL4 expression significantly correlated with more advanced tumor depth, nodal involvement, and lymphatic and venous invasion. A strongly positive association between cancerous and stromal DLL4 expression was identified (p < 0.01). Both cancerous and stromal DLL4 expression were prognostic markers in gastric cancer as determined by univariate analysis. CONCLUSIONS Cancerous and stromal DLL4 expression was found in 48% and 22% in gastric cancer, and significantly affected postoperative clinical outcomes. Cancerous and stromal DLL4 expression may be an effective target of anti-DLL4 treatment in gastric cancer.
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Affiliation(s)
- Sumiya Ishigami
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Takaaki Arigami
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Yoshikazu Uenosono
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Hiroshi Okumura
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Hiroshi Kurahara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Yasuto Uchikado
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Tetsuro Setoyama
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Yoshiaki Kita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Yuko Kijima
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Yuka Nishizono
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Akihiro Nakajo
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Tetsuro Owaki
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Shinichi Ueno
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
| | - Shoji Natsugoe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima 890-8520, Japan
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Qu JL, Liu YP. Molecularly targeted therapy for gastric cancer: current status and future prospects. Shijie Huaren Xiaohua Zazhi 2011; 19:919-924. [DOI: 10.11569/wcjd.v19.i9.919] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer remains the second leading cause of cancer death worldwide. Currently, chemotherapy is the mainstay of treatment for patients with metastatic gastric cancer. Although new chemotherapeutic regimens improved the survival of patients with advanced gastric cancer, the median survival in all randomized trials remains unsatisfactory. Novel treatment options are urgently needed to improve the outcome of patients with advanced gastric cancer. Understanding the molecular pathways that characterize cell growth, apoptosis, angiogenesis and invasion has enabled us to use new approaches to treat this disease in clinical situations. The aim of this review is to summarize the most recent publications on targeted therapies for advanced gastric cancer.
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Goyal S, LaValley M, Subramanian ML. Meta-analysis and review on the effect of bevacizumab in diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 2010; 249:15-27. [DOI: 10.1007/s00417-010-1452-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2010] [Revised: 06/17/2010] [Accepted: 07/04/2010] [Indexed: 11/30/2022] Open
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Aronica SM, Raiber L, Hanzly M, Kisela C. Antitumor/antiestrogenic effect of the chemokine interferon inducible protein 10 (IP-10) involves suppression of VEGF expression in mammary tissue. J Interferon Cytokine Res 2009; 29:83-92. [PMID: 19014340 DOI: 10.1089/jir.2008.0034] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) promotes angiogenesis in a number of tumor model systems. We reported previously that estrogen supports the growth of CCL-51 cell-based mammary tumors in mice, which could be blocked with specific chemokines. We investigated whether promotion of tumor growth by estrogen, and suppression of tumor growth by chemokines, was associated with VEGF protein expression. Female C3H mice were treated with vehicle, estradiol, or with one of several chemokines for 72 h. The presence of VEGF in mammary tissue samples was detected and quantified by sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunoblotting using antimurine VEGF antibodies. Estrogen significantly increased mammary VEGF expression. Cotreatment with tamoxifen or the chemokine interferon-inducible protein-10 (IP-10) suppressed the action estrogen on VEGF expression. CCL-51 tumor cells were placed into mammary tissue of C3H mice. Mice were treated every 72-h with either vehicle or estradiol, in the presence or absence of IP-10 for 21 days. Estrogen supported CCL-51 tumor growth, with an average of 2.3 tumors present/animal. Cotreatment of mice with estrogen and IP-10 resulted in significantly lower numbers of tumors in mammary tissue in comparison to animals treated with estrogen alone. VEGF levels in mammary tissue and tumors of IP-10 and estrogen cotreated mice were 40-50% less than those detected in mammary tissue of estrogen-treated mice. Our results suggest that estrogenic support of CCL-51 mammary tumor growth is related to increased VEGF expression, and that the inhibitory action of IP-10 may be related to suppressing VEGF levels in mammary tissue.
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Affiliation(s)
- Susan M Aronica
- Department of Biology, Canisius College, Buffalo, New York 14208, USA.
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Li Q, Zhang N, Jia Z, Le X, Dai B, Wei D, Huang S, Tan D, Xie K. Critical role and regulation of transcription factor FoxM1 in human gastric cancer angiogenesis and progression. Cancer Res 2009; 69:3501-9. [PMID: 19351851 DOI: 10.1158/0008-5472.can-08-3045] [Citation(s) in RCA: 185] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The mammalian forkhead box (Fox) transcription factor FoxM1b is implicated in tumorigenesis. However, the presence of expression and role of FoxM1b in gastric cancer remain unknown. Therefore, we investigated FoxM1b expression in 86 cases of primary gastric cancer and 57 normal gastric tissue specimens. We further investigated the underlying mechanisms of altered FoxM1b expression in and the effect of this altered expression on gastric cancer growth and metastasis using in vitro and animal models of gastric cancer. We found weak expression of FoxM1b protein in the mucous neck region of gastric mucosa, whereas we observed strong staining for FoxM1b in tumor cell nuclei in various gastric tumors and lymph node metastases. A Cox proportional hazards model revealed that FoxM1b expression was an independent prognostic factor in multivariate analysis (P < 0.001). Experimentally, overexpression of FoxM1b by gene transfer significantly promoted the growth and metastasis of gastric cancer cells in orthotopic mouse models, whereas knockdown of FoxM1b expression by small interfering RNA did the opposite. Promotion of gastric tumorigenesis by FoxM1b directly and significantly correlated with transactivation of vascular endothelial growth factor expression and elevation of angiogenesis. Given the importance of FoxM1b to regulation of the expression of genes key to cancer biology overall, dysregulated expression and activation of FoxM1b may play important roles in gastric cancer development and progression.
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Affiliation(s)
- Qiang Li
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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Lv W, Chen L. Current status and recent developments in molecular targeted therapy against gastric cancer. Shijie Huaren Xiaohua Zazhi 2007; 15:2672-2678. [DOI: 10.11569/wcjd.v15.i25.2672] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies of the digestive system and is a major cause of cancer death in China. Recent improvements in both surgical techniques and adjuvant/neoadjuvant chemotherapy, radiotherapy or both have increased the survival rate of patients with early-stage disease. However, most patients with GC have advanced disease at diagnosis. Thus, despite recent advances, these patients still do poorly. Understanding the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has enabled us to use new approaches to treat this disease in clinical situations. These therapeutic strategies include epidermal growth factor receptor inhibitors, angiogenesis inhibitors, cell cycle inhibitors, apoptosis promoters and matrix metalloproteinase inhibitors. This review presents a brief introduction to the current status and advancement of molecular targeted therapies in the treatment of GC.
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Yasuda A, Sawai H, Takahashi H, Ochi N, Matsuo Y, Funahashi H, Sato M, Okada Y, Takeyama H, Manabe T. Stem cell factor/c-kit receptor signaling enhances the proliferation and invasion of colorectal cancer cells through the PI3K/Akt pathway. Dig Dis Sci 2007; 52:2292-2300. [PMID: 17410437 DOI: 10.1007/s10620-007-9759-7] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2006] [Accepted: 01/01/2007] [Indexed: 01/10/2023]
Abstract
In this study, we examined the role of c-kit receptor (KIT) signal transduction on the proliferation and invasion of colorectal cancer cells. We found that c-kit was expressed in 2 colorectal cancer cell lines as determined by RT-PCR, Western blot, and flow cytometry. In KIT-positive lines, KIT was activated by stem cell factor (SCF). SCF enhanced cellular proliferation of positive lines as demonstrated by the WST-1 proliferation assay. Furthermore, SCF enhanced the invasive ability of KIT-positive cell lines. SCF stimulation upregulated p44/42 mitogen-activated protein kinase (MAPK) and Akt as shown by Western blot. We examined the roles played by p44/42 MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways in proliferation and invasion. PI3K/Akt activity strongly correlated with proliferation and invasion and p44/42 MAPK was correlated with only invasion. In conclusion, the SCF-enhanced proliferation and invasion of KIT-positive colorectal cancer cells is achieved mainly through the PI3K/Akt pathway.
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Affiliation(s)
- Akira Yasuda
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 4678601, Japan.
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Satoh M, Iida S, Shitara K. Non-fucosylated therapeutic antibodies as next-generation therapeutic antibodies. Expert Opin Biol Ther 2006; 6:1161-73. [PMID: 17049014 DOI: 10.1517/14712598.6.11.1161] [Citation(s) in RCA: 128] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Most of the existing therapeutic antibodies that have been licensed and developed as medical agents are of the human IgG1 isotype, the molecular weight of which is approximately 150 kDa. Human IgG1 is a glycoprotein bearing two N-linked biantennary complex-type oligosaccharides bound to the antibody constant region (Fc), in which the majority of the oligosaccharides are core fucosylated, and it exercises the effector functions of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity through the interaction of the Fc with either leukocyte receptors (FcgammaRs) or complement. Recently, therapeutic antibodies have been shown to improve overall survival as well as time to disease progression in a variety of human malignancies, such as breast, colon and haematological cancers, and genetic analysis of FcgammaR polymorphisms of cancer patients has demonstrated that ADCC is a major antineoplasm mechanism responsible for clinical efficacy. However, the ADCC of existing licensed therapeutic antibodies has been found to be strongly inhibited by serum due to nonnpecific IgG competing for binding of the therapeutics to FcgammaRIIIa on natural killer cells, which leads to the requirement of a significant amount of drug and very high costs associated with such therapies. Moreover, enhanced ADCC of non-fucosylated forms of therapeutic antibodies through improved FcgammaRIIIa binding is shown to be inhibited by the fucosylated counterparts. In fact, non-fucosylated therapeutic antibodies, not including the fucosylated forms, exhibit the strongest and most saturable in vitro and ex vivo ADCC among such antibody variants with improved FcgammaRIIIa binding as those bearing naturally occurring oligosaccharide heterogeneities and artificial amino acid mutations, even in the presence of plasma IgG. Robust stable production of completely non-fucosylated therapeutic antibodies in a fixed quality has been achieved by the generation of a unique host cell line, in which the endogenous alpha-1,6-fucosyltransferase (FUT8) gene is knocked out. Thus, the application of non-fucosylated antibodies is expected to be a promising approach as next-generation therapeutic antibodies with improved efficacy, even when administrated at low doses in humans in vivo. Clinical trials using non-fucosylated antibody therapeutics are underway at present.
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Affiliation(s)
- Mitsuo Satoh
- Kyowa Hakko Kogyo Co. Ltd, Tokyo Research Laboratories, 3-6-6 Asahi-machi, Machida-shi, Tokyo 194-8533, Japan.
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Abstract
Colon cancer is still one of the leading causes of cancer death worldwide. Although the host immune system has been shown to react against tumor cells, mainly through tumor infiltrating lymphocytes and NK cells, tumor cells may utilize different ways to escape anti-tumor immune response. Tumor infiltration of CD8+ and CD4+ (T-bet+) effector T cells has been attributed to a beneficial outcome, and the enhancement of T cell activation through T cell receptor stimulation and co-stimulatory signals provides promising strategies for immunotherapy of colon cancer. Growing evidence supports a role for the Fas/FasL system in tumor immunology, although the mechanisms and consequences of FasL activation in colon cancer are not completely understood. In animal models, depletion of regulatory T cells (CD4+ CD25+ T cells) can enhance the anti-tumor immune response under certain conditions. Taken together, recent insights in the immune reaction against colon carcinoma have provided new approaches to immunotherapy, although much remains to be learned about the exact mechanisms.
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