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Sarhan MO, Haffez H, Elsayed NA, El-Haggar RS, Zaghary WA. New phenothiazine conjugates as apoptosis inducing agents: Design, synthesis, In-vitro anti-cancer screening and 131I-radiolabeling for in-vivo evaluation. Bioorg Chem 2023; 141:106924. [PMID: 37871390 DOI: 10.1016/j.bioorg.2023.106924] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/06/2023] [Accepted: 10/16/2023] [Indexed: 10/25/2023]
Abstract
Phenothiazines (PTZs) are a group of compounds characterized by the presence of the 10H-dibenzo-[b,e]-1,4-thiazine system. PTZs used in clinics as antipsychotic drugs with other diverse biological activities. The current aim of the study is to investigate and understand the effect of potent PTZs compounds using a group of In-vitro and In-vivo assays. A total of seventeen novel phenothiazine derivatives have been designed, synthesized, and evaluated primarily in-vitro for their ability to inhibit proliferation activity against NCI-60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. Almost all compounds were active and displayed promising cellular activities with GI50 values in the sub-micromolar range. Four of the most promising derivatives (4b, 4h, 4g and 6e) have been further tested against two selected sensitive cancer cell lines (colon cancer; HCT-116 and breast cancer; MDA-MB231). The apoptosis assay showed that all the selected compounds were able to induce early apoptosis and compound 6e was able to induce additional cellular necrosis. Cell cycle assay showed all selected compounds were able to induce cell cycle arrest at sub-molecular phase of G0-G1 with compound 6e induced cell cycle arrest at G2M in HCT-116 cells. Accordingly, the apoptotic effect of the selected compounds was extensively investigated on genetic level and Casp-3, Casp-9 and Bax gene were up-regulated with down-regulation of Bcl-2 gene suggesting the activation of both intrinsic and extrinsic pathways. In-vivo evaluation of the antitumor activity of compound 4b in solid tumor bearing mice showed promising therapeutic effect with manifestation of dose and time dependent toxic effects at higher doses. For better evaluation of the degree of localization of 4b, its 131I-congener (131I-4b) was injected intravenously in Ehrlich solid tumor bearing mice that showed good localization at tumor site with rapid distribution and clearance from the blood. In-silico study suggested NADPH oxidases (NOXs) as potential molecular target. The compounds introduced in the current study work provided a cutting-edge phenothiazine hybrid scaffold with promising anti-proliferation action that may suggest their anti-cancer activity.
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Affiliation(s)
- Mona O Sarhan
- Labelled Compounds Department, Hot Lab Centre, Egyptian Atomic Energy Authority, Egypt
| | - Hesham Haffez
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, 11795 Cairo, Egypt; Center of Scientific Excellence "Helwan Structural Biology Research, (HSBR)", Helwan University, 11795 Cairo, Egypt.
| | - Nosaiba A Elsayed
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, 11795 Cairo, Egypt
| | - Radwan S El-Haggar
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, 11795 Cairo, Egypt
| | - Wafaa A Zaghary
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, 11795 Cairo, Egypt.
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Ye J, Yang W, Xie Z, Yan Y, Li G, Li G, Li X, Ma W, Kang F, Zhang M, Wang J. Safety, Biodistribution, and Dosimetry Study of Meplazumab, a Potential COVID-19 Therapeutic Drug, with 131I-Labeling and SPECT Imaging. Mol Pharm 2023; 20:1750-1757. [PMID: 36668905 PMCID: PMC9885528 DOI: 10.1021/acs.molpharmaceut.2c00954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/03/2023] [Accepted: 01/03/2023] [Indexed: 01/21/2023]
Abstract
Coronavirus disease 2019 (COVID-19) is a serious threat to public health and is in urgent need of specific drugs. Meplazumab, a humanized monoclonal antibody targeting CD147, was confirmed to competitively block the binding between the spike of syndrome coronavirus 2 (SARS-CoV-2) and CD147, making meplazumab a promising candidate drug for COVID-19. In this study, biodistribution and dosimetry of 131I-labeled meplazumab were performed to further evaluate its potential as a therapeutic drug for COVID-19. 131I-meplazumab was both safe and tolerant in mice and healthy volunteers. A biodistribution study was performed in normal mice, and blood samples were used for pharmacokinetic analysis. Three healthy volunteers were included and subjected to single-photon-emission computed tomography (SPECT) imaging of 131I-meplazumab within 2 weeks. The distribution in mice and humans was consistent with the in vivo distribution of CD147. Biodistribution and SPECT imaging results exhibited that the liver was the organ with the highest uptake for both mice and humans. Deiodination of 131I-meplazumab can be observed in vivo, and taking Lugol's solution can protect the thyroid gland effectively. The pharmacokinetic characteristics of 131I-meplazumab in mice and humans best fit the two-compartment model. The clearance half-life (T1/2β) in mice and humans was 117.4 and 223.5 h, respectively. The results indicated that its pharmacokinetic properties in vivo were ideal. The effective dose calculated from healthy volunteers was 0.811 ± 0.260 mSv·MBq-1, which was twice the value calculated from mice. It was safe and feasible to perform human clinical imaging experiments using a diagnostic dose of 131I-meplazumab after thyroid closure by Lugol's solution. This study will provide more experimental basis for advancing the clinical translation of meplazumab and will be valuable in evaluating therapeutic interventions for patients with COVID-19, as well as providing a reference for clinical translation studies of other antibody drugs.
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Affiliation(s)
| | | | - Zhaojuan Xie
- Department of Nuclear Medicine, Xijing Hospital,
Fourth Military Medical University, Xi’an,
Shaanxi710032, China
| | - Yuhao Yan
- Department of Nuclear Medicine, Xijing Hospital,
Fourth Military Medical University, Xi’an,
Shaanxi710032, China
| | - Guoquan Li
- Department of Nuclear Medicine, Xijing Hospital,
Fourth Military Medical University, Xi’an,
Shaanxi710032, China
| | - Guiyu Li
- Department of Nuclear Medicine, Xijing Hospital,
Fourth Military Medical University, Xi’an,
Shaanxi710032, China
| | - Xiang Li
- Department of Nuclear Medicine, Xijing Hospital,
Fourth Military Medical University, Xi’an,
Shaanxi710032, China
| | - Wenhui Ma
- Department of Nuclear Medicine, Xijing Hospital,
Fourth Military Medical University, Xi’an,
Shaanxi710032, China
| | - Fei Kang
- Department of Nuclear Medicine, Xijing Hospital,
Fourth Military Medical University, Xi’an,
Shaanxi710032, China
| | - Mingru Zhang
- Department of Nuclear Medicine, Xijing Hospital,
Fourth Military Medical University, Xi’an,
Shaanxi710032, China
| | - Jing Wang
- Department of Nuclear Medicine, Xijing Hospital,
Fourth Military Medical University, Xi’an,
Shaanxi710032, China
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Rahat MA. Mini-Review: Can the Metastatic Cascade Be Inhibited by Targeting CD147/EMMPRIN to Prevent Tumor Recurrence? Front Immunol 2022; 13:855978. [PMID: 35418981 PMCID: PMC8995701 DOI: 10.3389/fimmu.2022.855978] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 03/07/2022] [Indexed: 12/05/2022] Open
Abstract
Solid tumors metastasize very early in their development, and once the metastatic cell is lodged in a remote organ, it can proliferate to generate a metastatic lesion or remain dormant for long periods. Dormant cells represent a real risk for future tumor recurrence, but because they are typically undetectable and insensitive to current modalities of treatment, it is difficult to treat them in time. We describe the metastatic cascade, which is the process that allows tumor cells to detach from the primary tumor, migrate in the tissue, intravasate and extravasate the lymphatics or a blood vessel, adhere to a remote tissue and eventually outgrow. We focus on the critical enabling role of the interactions between tumor cells and immune cells, especially macrophages, in driving the metastatic cascade, and on those stages that can potentially be targeted. In order to prevent the metastatic cascade and tumor recurrence, we would need to target a molecule that is involved in all of the steps of the process, and evidence is brought to suggest that CD147/EMMPRIN is such a protein and that targeting it blocks metastasis and prevents tumor recurrence.
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Affiliation(s)
- Michal A Rahat
- Immunotherapy Laboratory, Carmel Medical Center, Haifa, Israel.,Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
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Oliveira MC, Correia JDG. Clinical application of radioiodinated antibodies: where are we? Clin Transl Imaging 2022. [DOI: 10.1007/s40336-021-00477-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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CD147-Cyclophilin a Interactions Promote Proliferation and Survival of Cutaneous T-Cell Lymphoma. Int J Mol Sci 2021; 22:ijms22157889. [PMID: 34360654 PMCID: PMC8346093 DOI: 10.3390/ijms22157889] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/19/2021] [Accepted: 07/22/2021] [Indexed: 12/14/2022] Open
Abstract
CD147, a transmembrane glycoprotein that belongs to the immunoglobulin superfamily, and cyclophilin A (CypA), one of the binding partners of CD147, are overexpressed in tumor cells and associated with the progression of several malignancies, including both solid and hematological malignancies. However, CD147 and CypA involvement in cutaneous T-cell lymphoma (CTCL) has not been reported. In this study, we examined CD147 and CypA expression and function using clinical samples of mycosis fungoides (MF) and Sézary syndrome (SS) and CTCL cell lines. CD147 and CypA were overexpressed by tumor cells of MF/SS, and CypA was also expressed by epidermal keratinocytes in MF/SS lesional skin. Serum CypA levels were increased and correlated with disease severity markers in MF/SS patients. Anti-CD147 antibody and/or anti-CypA antibody suppressed the proliferation of CTCL cell lines, both in vitro and in vivo, via downregulation of phosphorylated extracellular-regulated kinase 1/2 and Akt. These results suggest that CD147-CypA interactions can contribute to the proliferation of MF/SS tumor cells in both a autocrine and paracrine manner, and that the disruption of CD147-CypA interactions could be a new therapeutic strategy for the treatment of MF/SS.
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Christensen SC, Hudecz D, Jensen A, Christensen S, Nielsen MS. Basigin Antibodies with Capacity for Drug Delivery Across Brain Endothelial Cells. Mol Neurobiol 2021; 58:4392-4403. [PMID: 34014436 DOI: 10.1007/s12035-021-02421-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 05/04/2021] [Indexed: 01/06/2023]
Abstract
The blood-brain barrier (BBB) poses challenges for delivering antibody-based therapeutics to the brain and is a main obstacle for the successful application of biotherapeutics for the treatment of brain disorders. As only a small fraction of monoclonal antibodies (mAbs) is penetrating the BBB, high doses of therapeutics are required to elicit a pharmacological effect. This limitation has evoked research to improve transport across the BBB through receptor-mediated transcytosis, and several receptors have been explored for mediating this process. A recently suggested candidate is the brain endothelial cells (BECs) expressed basigin. Here, we explore the transcytosis capacity of different basigin mAbs targeting distinct epitopes using the porcine in vitro BBB models and provide data showing the intracellular vesicle sorting of these basigin mAbs in porcine BECs. Our data suggest that basigin mAbs avoid the lysosomal degradation pathway and are internalized to vesicles used by recycling receptors. Engagement of basigin mAbs with basigin led to the translocation of the mAbs across the tight BECs into the astrocytes in our in vitro BBB co-culture model. Although mAbs with higher binding affinity to basigin showed a greater astrocyte internalization, based on our experiments, it is not clear whether the transcytosis is affinity- or epitope-dependent or a combination of both. Overall, this study provides information about the intra- and intercellular fate of basigin mAbs in BECs, which are valuable for the future design of basigin-mediated drug delivery platforms.
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Affiliation(s)
- Sarah Christine Christensen
- Department of Biomedicine, Aarhus University, Høegh-Guldbergsgade 10, Building 1116, 8000, Aarhus C, Denmark.,Department of Biotherapeutic Discovery, H. Lundbeck A/S, Copenhagen, Denmark
| | - Diána Hudecz
- Department of Biomedicine, Aarhus University, Høegh-Guldbergsgade 10, Building 1116, 8000, Aarhus C, Denmark
| | - Allan Jensen
- Department of Biotherapeutic Discovery, H. Lundbeck A/S, Copenhagen, Denmark
| | - Søren Christensen
- Department of Biotherapeutic Discovery, H. Lundbeck A/S, Copenhagen, Denmark
| | - Morten Schallburg Nielsen
- Department of Biomedicine, Aarhus University, Høegh-Guldbergsgade 10, Building 1116, 8000, Aarhus C, Denmark.
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Li Y, Zhang T, Pang Y, Li L, Chen ZN, Sun W. 3D bioprinting of hepatoma cells and application with microfluidics for pharmacodynamic test of Metuzumab. Biofabrication 2019; 11:034102. [DOI: 10.1088/1758-5090/ab256c] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Wang J, Wu Z, Pan G, Ni J, Xie F, Jiang B, Wei L, Gao J, Zhou W. Enhanced doxorubicin delivery to hepatocellular carcinoma cells via CD147 antibody-conjugated immunoliposomes. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2018; 14:1949-1961. [DOI: 10.1016/j.nano.2017.09.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Revised: 09/15/2017] [Accepted: 09/25/2017] [Indexed: 12/11/2022]
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Zhu ZX, Liao MH, Wang XX, Huang JW. Transcatheter Arterial Chemoembolization Plus 131I-Labelled Metuximab versus Transcatheter Arterial Chemoembolization Alone in Intermediate/Advanced Stage Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Korean J Radiol 2016; 17:882-892. [PMID: 27833404 PMCID: PMC5102916 DOI: 10.3348/kjr.2016.17.6.882] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 07/07/2016] [Indexed: 02/05/2023] Open
Abstract
Objective The aim of the study was to compare transcatheter arterial chemoembolization (TACE) plus 131I-labelled metuximab with TACE alone for hepatocellular carcinoma (HCC). Materials and Methods A comprehensive search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Chinese BioMedical Literature Database with published date from the earliest to February 29th, 2016. No language restrictions were applied, but only prospective randomized controlled trials (RCTs) or non-RCTs were eligible for a full-text review. The primary outcome was the overall survival (OS) and effective rate (the rate of partial atrophy or complete clearance of the tumor lesion). The odds ratios (ORs) were combined using either the fixed-effects model or random-effects model. Results Eight trials (3 RCTs and 5 non-RCTs) were included, involving a total of 1121 patients. Patients receiving combined therapy of TACE plus 131I-labelled metuximab showed significant improvement in effective rate {OR = 4.00, (95% confidence interval [CI]: 2.40–6.66), p < 0.001}, 1-year OS (OR = 2.03 [95% CI: 1.55–2.67], p < 0.001) and 2-year OS (OR = 2.57 [95% CI: 1.41–4.66], p = 0.002]. Conclusion TACE plus 131I-labelled metuximab is more beneficial for treating advanced HCCs than TACE alone in terms of tumor response and OS. Large, multi-center, and blinded randomized trials are required to confirm these findings.
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Affiliation(s)
- Ze-Xin Zhu
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ming-Heng Liao
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiao-Xue Wang
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ji-Wei Huang
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu 610041, China
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Ma J, Wang JH. 131I-Labeled-Metuximab Plus Transarterial Chemoembolization in Combination Therapy for Unresectable Hepatocellular Carcinoma: Results from a Multicenter Phase IV Clinical Study. Asian Pac J Cancer Prev 2016; 16:7441-7. [PMID: 26625741 DOI: 10.7314/apjcp.2015.16.17.7441] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE This study evaluated the safety and objective response of combining 131I-labeled-metuximab (Licartin) with transarterial chemoembolization (TACE) in the treatment of unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS In a multicenter open-label clinical trial, 341 enrolled patients with stage III/IV HCC according to TNM criteria were nonrandomly assigned to a trial group (n=167) and a control group (n=174), undergoing TACE following hepatic intra-arterial injection of licartin or TACE alone from July 2007 to July 2009. Radiopharmaceutical distribution was evaluated. The primary endpoint was overall survival; secondary endpoints included time-to-progression (TTP), toxicity and adverse events (AEs). RESULTS The radiobiological distribution demonstrated better localization of licartin in liver tumors than other tissues (P<0.01). The organ absorbed doses to liver and red marrow were 3.19 ± 1.01 Gy and 0.55 ± 0.22 Gy, respectively. The 1-year survival rate was significantly higher [79.47% vs. 65.59%, hazard ratio (HR), 0.598, P=0.041] and TTP significantly improved (6.82 ± 1.28 vs. 4.7 ± 1.14 months, P=0.037) compared with the control group. Patients at stage III achieved more benefit of one year survival than stage IV in the trial group (86.9% vs. 53.8%, P<0.001). There were significant different toxicities in leukocytopenia, thrombocytopenia and increased total bilirubin level [P<0.001, P=0.013, P<0.01, relative risk (RR) 1.63, 1.33, 1.43], but no differences in severe AEs of upper GI hemorrhage and severe liver dysfunction between the groups (5.39% vs. 2.3%, P=0.136). CONCLUSIONS Owing to excellent tumor-targeting, promised efficacy and favourable toxicity profile, the novel combination therapy of licartin and TACE could be applied in patients with unresectable HCC.
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Affiliation(s)
- Jun Ma
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China E-mail :
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Ding ZY, Wei YQ. Immunopathology of Hepatobiliary Tumors and Immunotherapy of Liver Cancers. CANCER IMMUNOLOGY 2015:199-215. [DOI: 10.1007/978-3-662-46410-6_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Wang Y, Yuan L, Yang XM, Wei D, Wang B, Sun XX, Feng F, Nan G, Wang Y, Chen ZN, Bian H. A chimeric antibody targeting CD147 inhibits hepatocellular carcinoma cell motility via FAK-PI3K-Akt-Girdin signaling pathway. Clin Exp Metastasis 2014; 32:39-53. [PMID: 25424030 DOI: 10.1007/s10585-014-9689-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 11/19/2014] [Indexed: 01/11/2023]
Abstract
CD147 is expressed at low levels in normal tissues but frequently highly expressed in a wide range of tumor types such as lung, breast, and liver and therefore it is a potentially unique therapeutic target for these diverse tumor types. We previously generated a murine antibody HAb18 which suppresses matrix met al.loproteinase-2 and matrix metalloproteinase-9 secretion, attenuates cell invasion by blocking the CD147 molecule in tumor cells. Here, we generated a chimeric antibody containing the variable heavy and variable light chains of murine HAb18 and the constant regions of human IgG1γ1 and human κ chain as a potential therapeutic agent (designated cHAb18). Quantitative measurement of cHAb18 antibody affinity for antigen CD147 with surface plasmon resonance showed the equilibrium dissociation constant KD was 2.66 × 10(-10) mol/L, similar to that of KD 2.73 × 10(-10) mol/L for murine HAb18. cHAb18 induced antibody-dependent cell-mediated cytotoxicity in two hepatocellular carcinoma cell lines, SMMC-7721 and Huh-7 cells. It inhibited cancer invasion and migration in hepatocellular carcinoma cells by specifically blocking CD147. Except for the depression of matrix metalloproteinase-2 and matrix metalloproteinase-9 expressions, cHAb18 antibody suppressed cell motility by rearrangement of actin cytoskeleton, which was probably induced by decreasing the phosphorylation of focal adhesion kinase, phosphatidylinositide-3 kinase (PI3K), Akt, and Girdin in the integrin signaling pathway. In an orthotopic model of hepatocellular carcinoma in BALB/c nude mice, cHAb18 treatment effectively reduced the tumor metastasis in liver and prolonged the survival. These findings reveal new therapeutic potential for cHAb18 antibody targeting CD147 on tumor therapy.
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Affiliation(s)
- Yuan Wang
- State Key Laboratory of Cancer Biology, Department of Cell Biology and Cell Engineering Research Center, Fourth Military Medical University, Xi'an, 710032, China
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Zirconium-89 labeled antibodies: a new tool for molecular imaging in cancer patients. BIOMED RESEARCH INTERNATIONAL 2014; 2014:203601. [PMID: 24991539 PMCID: PMC4058511 DOI: 10.1155/2014/203601] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 04/23/2014] [Indexed: 01/15/2023]
Abstract
Antibody based positron emission tomography (immuno-PET) imaging is of increasing importance to visualize and characterize tumor lesions. Additionally, it can be used to identify patients who may benefit from a particular therapy and monitor the therapy outcome. In recent years the field is focused on 89Zr, a radiometal with near ideal physical and chemical properties for immuno-PET. In this review we will discuss the production of 89Zr, the bioconjugation strategies, and applications in (pre-)clinical studies of 89Zr-based immuno-PET in oncology. To date, 89Zr-based PET imaging has been investigated in a wide variety of cancer-related targets. Moreover, clinical studies have shown the feasibility for 89Zr-based immuno-PET to predict and monitor treatment, which could be used to tailor treatment for the individual patient. Further research should be directed towards the development of standardized and robust conjugation methods and improved chelators to minimize the amount of released Zr4+ from the antibodies. Additionally, further validation of the imaging method is required. The ongoing development of new 89Zr-labeled antibodies directed against novel tumor targets is expected to expand applications of 89Zr-labeled immuno-PET to a valuable method in the medical imaging.
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He Q, Lu WS, Liu Y, Guan YS, Kuang AR. 131I-labeled metuximab combined with chemoembolization for unresectable hepatocellular carcinoma. World J Gastroenterol 2013; 19:9104-9110. [PMID: 24379637 PMCID: PMC3870565 DOI: 10.3748/wjg.v19.i47.9104] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 10/08/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the safety and effectiveness of combined 131I-metuximab and transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).
METHODS: One hundred and eighty-five patients (159 men and 26 women) with advanced HCC were enrolled in this study from February 2009 to July 2011. There were 95 patients in the combined metuximab and TACE group, and 90 patients in the TACE only group. The patients were followed for 12 mo. Clinical symptoms, blood cell counts, Karnofsky Performance Score (KPS) evaluation and therapeutic effects according to the Response Evaluation Criteria in Solid Tumors were recorded and evaluated.
RESULTS: The 1-mo effective rates (complete response + partial response + stable disease) of the test group and control group were 71.23% and 38.89%, respectively (P < 0.001). The 6-, 9- and 12-mo survival rates were 86.42%, 74.07% and 60.49% for the test group and 60.0%, 42.22% and 34.44% for the control group (P < 0.001). The incidence of adverse events (gastrointestinal symptoms, fever and pain) and blood cell toxicity were significantly higher for the test group than for the control group (P < 0.001). No severe 131I-metuximab-related complications were identified. With respect to efficacy, patients in the test group had greater improvement in tumor-related pain (P = 0.014) and increase in KPS (P < 0.001) than those in the control group.
CONCLUSION: Combination of 131I-metuximab and TACE prolonged the survival time in patients with HCC compared with TACE alone. The combination treatment was safe and effective.
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Zheng SG, Xu HX, Lu MD, Yue DC, Xie XY, Liu GJ. Radiofrequency ablation before intratumoral injection of (131)I-chTNT improves the tumor-to-normal tissue ratio in solid VX2 tumor. Cancer Biother Radiopharm 2013; 28:725-30. [PMID: 23964639 DOI: 10.1089/cbr.2012.1418] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
PURPOSE This study was aimed to investigate whether the tumor necrosis induced by radiofrequency ablation (RFA) can improve the ratio of tumor-to-normal tissue (T/NT) after intratumoral injection of (131)I-chTNT. MATERIALS AND METHOD Eighteen New Zealand rabbits bearing VX2 tumor on the thigh were randomly divided into two treatment groups (control group: intratumoral injection of (131)I-chTNT alone; RFA group: RFA + intratumoral injection of (131)I-chTNT 3 days after RFA) and each group was further divided into three subgroups I, II, and III (1-2 cm, 2-3 cm, and 3-4 cm in maximum diameter, respectively), by the tumor size. SPECT was performed to evaluate the T/NT on days 1, 8, and 15 after (131)I-chTNT injection. RESULTS After treatment, all rabbits underwent the SPECT whole-body scan and the T/NT was analyzed. The results showed that T/NT in the RFA group (55.45±41.83) was significantly higher compared with the control group (7.23±5.61) (F=18.89, p=0.001). Meanwhile, a linear ascending trend was found for T/NT in the RFA group along with the follow-up time (r=0.47, p=0.01). The tumor size or the dose of (131)I-TNT injection had no significant effect on the variation of T/NT in both groups (p>0.05). CONCLUSION RFA before intratumoral injection of (131)I-chTNT can dramatically improve T/NT, demonstrating the potential application of this combination therapy.
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Affiliation(s)
- Shu-Guang Zheng
- 1 Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou, China
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NIU HUANZHANG, WANG RUIHUA, CHENG JINGLIANG, GAO SHEGAN, LIU BAOPING. Treatment of 131I-labeled anti-CD147 monoclonal antibody in VX2 carcinoma-induced liver tumors. Oncol Rep 2013; 30:246-52. [DOI: 10.3892/or.2013.2418] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 02/22/2013] [Indexed: 11/06/2022] Open
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Sugyo A, Tsuji AB, Sudo H, Nagatsu K, Koizumi M, Ukai Y, Kurosawa G, Zhang MR, Kurosawa Y, Saga T. Evaluation of (89)Zr-labeled human anti-CD147 monoclonal antibody as a positron emission tomography probe in a mouse model of pancreatic cancer. PLoS One 2013; 8:e61230. [PMID: 23577210 PMCID: PMC3618331 DOI: 10.1371/journal.pone.0061230] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2012] [Accepted: 03/07/2013] [Indexed: 12/18/2022] Open
Abstract
Introduction Pancreatic cancer is an aggressive cancer and its prognosis remains poor. Therefore, additional effective therapy is required to augment and/or complement current therapy. CD147, high expression in pancreatic cancer, is involved in the metastatic process and is considered a good candidate for targeted therapy. CD147-specfic imaging could be useful for selection of appropriate patients. Therefore, we evaluated the potential of a fully human anti-CD147 monoclonal antibody 059-053 as a new positron emission tomography (PET) probe for pancreatic cancer. Methods CD147 expression was evaluated in four pancreatic cancer cell lines (MIA Paca-2, PANC-1, BxPC-3, and AsPC-1) and a mouse cell line A4 as a negative control. Cell binding, competitive inhibition and internalization assays were conducted with 125I-, 67Ga-, or 89Zr-labeled 059-053. In vivo biodistribution of 125I- or 89Zr-labeled 059-053 was conducted in mice bearing MIA Paca-2 and A4 tumors. PET imaging with [89Zr]059-053 was conducted in subcutaneous and orthotopic tumor mouse models. Results Among four pancreatic cancer cell lines, MIA Paca-2 cells showed the highest expression of CD147, while A4 cells had no expression. Immunohistochemical staining showed that MIA Paca-2 xenografts also highly expressed CD147 in vivo. Radiolabeled 059-053 specifically bound to MIA Paca-2 cells with high affinity, but not to A4. [89Zr]059-053 uptake in MIA Paca-2 tumors increased with time from 11.0±1.3% injected dose per gram (ID/g) at day 1 to 16.9±3.2% ID/g at day 6, while [125I]059-053 uptake was relatively low and decreased with time, suggesting that 059-053 was internalized into tumor cells in vivo and 125I was released from the cells. PET with [89Zr]059-053 clearly visualized subcutaneous and orthotopic tumors. Conclusion [89Zr]059-053 is a promising PET probe for imaging CD147 expression in pancreatic cancer and has the potential to select appropriate patients with CD147-expressing tumors who could gain benefit from anti-CD147 therapy.
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Affiliation(s)
- Aya Sugyo
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Atsushi B. Tsuji
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
- * E-mail:
| | - Hitomi Sudo
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Kotaro Nagatsu
- Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Mitsuru Koizumi
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Yoshinori Ukai
- Division of Antibody Project, School of Medicine, Fujita Health University, Toyoake, Japan
| | - Gene Kurosawa
- Division of Antibody Project, School of Medicine, Fujita Health University, Toyoake, Japan
| | - Ming-Rong Zhang
- Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Yoshikazu Kurosawa
- Division of Antibody Project, School of Medicine, Fujita Health University, Toyoake, Japan
| | - Tsuneo Saga
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
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Tomblyn MB, Katin MJ, Wallner PE. The New Golden Era for Radioimmunotherapy: Not Just for Lymphomas Anymore. Cancer Control 2013; 20:60-71. [DOI: 10.1177/107327481302000109] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Michael B. Tomblyn
- Department of Radiation Oncology at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
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Fujiki M, Aucejo F, Kim R. Adjuvant treatment of hepatocellular carcinoma after orthotopic liver transplantation: do we really need this? Clin Transplant 2012; 27:169-77. [PMID: 23216662 DOI: 10.1111/ctr.12042] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2012] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) continues to rise and is still a major cause of mortality. Orthotopic liver transplantation (OLT) continues to give patients the best chance for cure, but recurrence of the disease remains a problem. Even with the implementation of the Milan criteria, recurrence rates have been shown to be 8-15% in most studies and even higher in patients who are beyond the Milan criteria. Therefore, several investigators have looked into the value of adjuvant therapy using systemic cytotoxic chemotherapy in HCC after OLT. Unfortunately, most of the trials are very small, and the results have been disappointing. But trials using Licartin seem to be promising, and other drugs such as FOLFOX and sorafenib warrant further investigation based on their efficacy in the advanced disease. In this review, we will review the current data on efficacy and rationale of adjuvant treatment for HCC after OLT including novel biomarkers.
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Affiliation(s)
- M Fujiki
- Liver Transplantation and Hepatobiliary Surgery, Cleveland Clinic, Cleveland, OH, USA
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Zhang DW, Zhao YX, Wei D, Li YL, Zhang Y, Wu J, Xu J, Chen C, Tang H, Zhang W, Gong L, Han Y, Chen ZN, Bian H. HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis. J Hepatol 2012; 57:1283-91. [PMID: 22878468 DOI: 10.1016/j.jhep.2012.07.042] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Revised: 07/23/2012] [Accepted: 07/27/2012] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Activated hepatic stellate cells (HSCs) located in the Disse's space play a crucial role in liver fibrosis. HAb18G/CD147, a tumor-related glycoprotein, is highly expressed in hepatocellular carcinoma cells and fibroblasts. Whether HAb18G/CD147 plays an important role in the hepatic fibrogenesis is unknown. METHODS Immunohistochemistry for HAb18G/CD147 and α-smooth muscle actin expression in diseased liver tissues was used for correlation analysis. The function of HAb18G/CD147 in fibrogenesis was evaluated with the human HSCs LX-2 cell line and carbon tetrachloride-induced mouse liver fibrosis model. The specific antibody HAb18 targeting HAb18G/CD147 was injected intravenously into the mouse to investigate whether HAb18G/CD147 could be a potential target for liver fibrosis treatment. RESULTS HAb18G/CD147 is highly expressed on activated HSCs in the sinusoid. The positive rates of HAb18G/CD147 expression in human HBV-related liver cirrhosis, liver biopsy with HBV and liver adjacent to hemangioma were 95.6% (65/68), 14.8% (8/54) and 6.4% (8/125), respectively. HAb18G/CD147 expression was significantly correlated with the Child-Pugh grade (r=0.2848, p=0.0186) and with the expression of α-smooth muscle actin in HSCs (r=0.4434, p=0.0002) in liver cirrhosis. Transforming growth factor-β1 upregulated HAb18G/CD147 expression in LX-2 cells. Transfection of HAb18G/CD147 promoted the profibrogenic genes expression. In mouse liver fibrosis model, HAb18G/CD147 expression increased with the development of fibrogenesis and decreased during the liver fibrosis spontaneous recovery. The HAb18 targeting HAb18G/CD147 could attenuate liver fibrosis. CONCLUSIONS These data suggest that HAb18G/CD147 plays a role in HSC activation and is a potential therapeutic target in fibrosis/cirrhosis.
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Affiliation(s)
- Da-Wei Zhang
- Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an, China
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Wu L, Yang YF, Ge NJ, Shen SQ, Liang J, Wang Y, Zhou WP, Shen F, Wu MC. Hepatic artery injection of ¹³¹I-labelled metuximab combined with chemoembolization for intermediate hepatocellular carcinoma: a prospective nonrandomized study. Eur J Nucl Med Mol Imaging 2012; 39:1306-15. [PMID: 22588627 DOI: 10.1007/s00259-012-2145-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2012] [Accepted: 04/23/2012] [Indexed: 01/02/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is the fifth and seventh most common cause of cancer in men and women, respectively. Transcatheter arterial chemoembolization (TACE) is the standardized therapy for the intermediate stage of HCC. However, the 3-year overall survival remains low (<30 %) in these patients. Thus, there is a critical need for the development of treatment modalities to improve the survival rate. This study aimed to evaluate whether the combination of (131)I-metuximab with chemoembolization could improve treatment efficiency. METHODS Between January 2009 and January 2010, a prospective two-arm nonrandomized study was performed in patients with intermediate HCC. Of 138 patients, 68 (combination therapy group) received 132 courses of intraarterial (131)I-metuximab injections combined with chemoembolization (mean 1.94 per patient, median 2, range 1-2), followed by 152 sessions of TACE (mean 2.24 per patient, median 2, range 0-4). The remaining 70 patients (monotherapy group) received 296 sessions of TACE (mean 4.23 per patient, median 4, range 1-7). RESULTS The overall median survival times for the combination therapy group and the group treated only with TACE were 26.7 months (95 % CI 20.7-31.3 months) and 20.6 months (95 % CI 15.3-24.7 months), respectively. The combination therapy group had a significantly higher survival rate than the TACE-only group (P = 0.038). Age ≥65 years, serum albumin ≤35 g/l, and treatment category (combination therapy or TACE only) were independent prognostic factors for survival according to multivariate analysis. CONCLUSION The combination of (131)I-metuximab and chemoembolization extended survival in patients with intermediate HCC compared with TACE only, and was well tolerated by patients with Child-Pugh class A or B disease. This combination seems to be a promising treatment modality for patients with intermediate HCC.
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Affiliation(s)
- Lu Wu
- The First Department of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
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Wu L, Yang YF, Ge NJ, Shen SQ, Liang J, Wang Y, Zhou WP, Shen F, Wu MC. Hepatic arterial iodine-131-labeled metuximab injection combined with chemoembolization for unresectable hepatocellular carcinoma: interim safety and survival data from 110 patients. Cancer Biother Radiopharm 2011; 25:657-63. [PMID: 21204759 DOI: 10.1089/cbr.2010.0801] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Few options are available to treat patients with hepatocellular carcinoma (HCC). It was tested whether the combination of iodine-131(¹³¹I)-metuximab with chemoembolization could improve outcomes in patients with intermediate HCC. Between April 2008 and April 2009, 110 patients with unresectable HCC were treated with 113 intra-arterial ¹³¹I-metuximab injections combined with chemoembolization (mean, 1.03 per patient; median, 1; range, 1-2), followed by 264 sessions of transcatheter arterial chemoembolization (mean, 2.4 per patient; median, 3; range, 1-6). The survival rates at 6, 12, and 18 months were 88.2%, 79.1%, and 57.4%, respectively, by the Kaplan-Meier method. Of these patients, 12% exhibited grade 3/4 bilirubin toxicity, 5% exhibited grade 3/4 white blood count toxicity, and 7% exhibited grade 3/4 platelet toxicity. Response rates based on World Health Organization and European Association for the Study of the Liver criteria were 42.73% and 61.82%, respectively. The combination of ¹³¹I-metuximab and chemoembolization appeared to extend survival in patients with unresectable HCC compared with historical controls, as well as being well tolerated by patients with Child-Pugh A and B. This combination may represent a promising treatment modality for patients with intermediate HCC.
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Affiliation(s)
- Lu Wu
- The First Department of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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Zhang Z, Yang X, Yang H, Yu X, Li Y, Xing J, Chen Z. New strategy for large-scale preparation of the extracellular domain of tumor-associated antigen HAb18G/CD147 (HAb18GED). J Biosci Bioeng 2010; 111:1-6. [PMID: 20863755 DOI: 10.1016/j.jbiosc.2010.08.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2010] [Revised: 08/12/2010] [Accepted: 08/23/2010] [Indexed: 11/26/2022]
Abstract
HAb18G/CD147, a cancer-associated biomarker, can promote tumor growth, invasion and metastasis. Here, we established a new strategy to express the extracellular domain of HAb18G/CD147 (HAb18GED) by using the FRT/Flp-In recombinase-based site-directed integration system. Two clones expressing HAb18GED were established, and 600 mg HAb18GED was obtained with more than 95% purity. Our results showed that purified HAb18GED exhibited strong activities to stimulate the secretion of pro-MMP2 and MMP-2 and promote the invasion of HCC cells. Overall, our study effectively overcame the difficulty of large-scale HAb18GED preparation and laid a solid foundation for the further studies on structure and functions of HAb18G/CD147.
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Affiliation(s)
- Zheng Zhang
- State Key Laboratory of Cancer Biology, Cell Engineering Research Centre & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, PR China
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Wei J, Yang X, Zheng M, Wang M, Dai Y, Chen Z, Li N. The recombinant chimeric antibody chHAb18 against hepatocellular carcinoma can be produced in milk of transgenic mice. Transgenic Res 2010; 20:321-30. [DOI: 10.1007/s11248-010-9408-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2010] [Accepted: 05/21/2010] [Indexed: 12/22/2022]
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Xu J, Xu HY, Zhang Q, Song F, Jiang JL, Yang XM, Mi L, Wen N, Tian R, Wang L, Yao H, Feng Q, Zhang Y, Xing JL, Zhu P, Chen ZN. HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma. Mol Cancer Res 2007; 5:605-14. [PMID: 17579119 DOI: 10.1158/1541-7786.mcr-06-0286] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
CD147 molecule is reported to be correlated with the malignancy of some cancers; however, it remains unclear whether it is involved in the progression of hepatocellular carcinoma (HCC). Here, we investigated the function of HAb18G/CD147, a member of CD147 family, and its antibodies, HAb18 and LICARTIN, in HCC invasion and metastasis. We observed that HAb18G/CD147 gene silence in HCC cells significantly decreased the secretion of matrix metalloproteinase (MMP) and the invasive potential of HCC cells (P < 0.001). MMP silence in HCC cells also significantly suppressed the invasion of the cells when cocultured with fibroblasts; however, its inhibitory effect was significantly weaker than that of both HAb18G/CD147 silence in HCC cells and that of MMP silence in fibroblasts (P < 0.001). Blocking theHAb18G/CD147 molecule on HCC cells with HAb18 monoclonal antibody resulted in a similar suppressive effect on MMP secretion and cell invasion, but with no significant effects on the cell growth. (131)I-labeled HAb18 F(ab')(2) (LICARTIN), however, significantly inhibited the in vitro growth of HCC cells (P < 0.001). In an orthotopic model of HCC in nude mice, HAb18 and LICARTIN treatment effectively reduced the tumor growth and metastasis as well as the expression of three major factors in the HCC microenviroment (MMPs, vascular endothelial growth factor, and fibroblast surface protein) in the paracancer tissues. Overall, these results suggest that HAb18G/CD147 plays an important role in HCC invasion and metastasis mainly via modulating fibroblasts, as well as HCC cells themselves to disrupt the HCC microenviroment. LICARTIN can be used as a drug targeting to HAb18G/CD147 in antimetastasis and recurrence therapy of HCC.
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Affiliation(s)
- Jing Xu
- Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 17 West Changle Street, Xi'an 710032, China
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Xu J, Shen ZY, Chen XG, Zhang Q, Bian HJ, Zhu P, Xu HY, Song F, Yang XM, Mi L, Zhao QC, Tian R, Feng Q, Zhang SH, Li Y, Jiang JL, Li L, Yu XL, Zhang Z, Chen ZN. A randomized controlled trial of Licartin for preventing hepatoma recurrence after liver transplantation. Hepatology 2007; 45:269-76. [PMID: 17256759 DOI: 10.1002/hep.21465] [Citation(s) in RCA: 137] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
UNLABELLED Orthotopic liver transplantation (OLT) is the only curative therapy of HCC with underlying cirrhosis, but due to HCC metastasis and recurrence, its benefit is limited to a small population who meet the strict selection criteria. We previously reported that Licartin ([131I] mAb HAb18G/CD147) was safe and effective in treating HCC patients, and its antigen, HAb18G/CD147, was closely related to HCC invasion and metastasis. Here, we reported a randomized controlled trial to assess the post-OLT antirecurrence efficacy of Licartin in advanced HCC patients. We randomized 60 post-OLT patients with HCC, who were at tumor stage 3/4 and outside the Milan criteria before OLT, into 2 groups. Three weeks after OLT, the treatment group received 15.4 MBq/kg of Licartin, while the control group received placebo intravenously for 3 times with an interval of 28 days. At 1-year follow-up, the recurrence rate significantly decreased by 30.4% (P = 0.0174) and the survival rate increased by 20.6% (P = 0.0289) in the treatment group, compared with those in the control group. For the control group versus the treatment group, the hazard ratio for recurrence was 3.60 (95% confidence interval [CI], 1.50-8.60) and that for death was 3.87 (95% CI, 1.23-12.21). Licartin treatment also resulted in an earlier decreased AFP level and a longer time of normal AFP level than placebo (P = 0.0016). No Licartin-related toxic effects were observed. CONCLUSION Licartin is a promising drug for preventing post-OLT tumor recurrence in advanced HCC patients excluded by the currently strict criteria for OLT. HAb18G/CD147 can be a good drug target.
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Affiliation(s)
- Jing Xu
- Cell Engineering Research Centre, Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China
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