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Kim R, Kin T, Beck WT. Impact of Complex Apoptotic Signaling Pathways on Cancer Cell Sensitivity to Therapy. Cancers (Basel) 2024; 16:984. [PMID: 38473345 DOI: 10.3390/cancers16050984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 02/25/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the c-Jun/activator protein 1 (AP-1)/p53 signaling pathway leading to apoptotic death is altered. Cancer cells treated with anticancer drugs undergo c-Jun/AP-1-mediated apoptotic death and are involved in c-Jun N-terminal kinase activation and growth arrest- and DNA damage-inducible gene 153 (Gadd153)/CCAAT/enhancer-binding protein homologous protein pathway induction, regardless of the p53 genotype. Gadd153 induction is associated with mitochondrial membrane permeabilization after anticancer drug treatment and involves a coupled endoplasmic reticulum stress response. The induction of apoptosis by anticancer drugs is mediated by the intrinsic pathway (cytochrome c, Cyt c) and subsequent activation of the caspase cascade via proapoptotic genes (e.g., Bax and Bcl-xS) and their interactions. Anticancer drug-induced apoptosis involves caspase-dependent and caspase-independent pathways and occurs via intrinsic and extrinsic pathways. The targeting of antiapoptotic genes such as Bcl-2 enhances anticancer drug efficacy. The modulation of apoptotic signaling by Bcl-xS transduction increases the sensitivity of multidrug resistance-related protein-overexpressing epidermoid carcinoma cells to anticancer drugs. The significance of autophagy in cancer therapy remains to be elucidated. In this review, we summarize current knowledge of cancer cell death-related signaling pathways and their alterations during anticancer drug treatment and discuss potential strategies to enhance treatment efficacy.
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Affiliation(s)
- Ryungsa Kim
- Department of Breast Surgery, Hiroshima Mark Clinic, 1-4-3F, 2-Chome Ohte-machi, Naka-ku, Hiroshima 730-0051, Japan
| | - Takanori Kin
- Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - William T Beck
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA
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2
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Kobayashi S, Hiwasa T, Kitamura K, Kano M, Hoshino T, Hirano S, Hashimoto M, Seimiya M, Shimada H, Nomura F, Matsubara H, Matsushita K. Combinational antibody detection approach increases the clinical validity of colorectal cancer screening. J Clin Lab Anal 2023; 37:e24978. [PMID: 37964630 PMCID: PMC10749486 DOI: 10.1002/jcla.24978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 09/27/2023] [Accepted: 10/15/2023] [Indexed: 11/16/2023] Open
Abstract
BACKGROUND At different stages of the disease, biomarkers can help to determine disease progression and recurrence and provide a personalized indicator of therapeutic effectiveness. The serological identification of antigens by recombinant cDNA expression cloning (SEREX) has identified five SEREX antigens. RESULTS Compared with healthy donors, anti-FIRΔexon2 and anti-SOHLH antibodies (Abs) in the sera of patients with colorectal cancer (CRC) were markedly higher. Furthermore, no correlation was noted between five SEREX antigens and the three tumor markers (CEA, CA19-9, and anti-p53 Abs), indicating that anti-FIRΔexon2 Abs are an independent candidate marker for patients with CRC. Generally, the levels of anti-FIRΔexon2 Abs combined with clinically available tumor markers were determined to be significantly higher compared with CEA, CA19-9. Moreover, in early-stage CRC, the levels of anti-FIRΔexon2 Abs combined with existing tumor markers were higher than those of CEA, CA19-9. CONCLUSION Due to the highly heterogeneous nature of CRC, a single tumor marker is unlikely to become a standalone diagnostic test due to its commonly insufficient sensitivity and/or specificity. Using a combination antibody detection approach of tumor markers for CRC diagnosis has the potential to be an effective approach. Therefore, the use of serum protein biomarker candidates holds promise for the development of inexpensive, noninvasive, and inexpensive tests for the detection of CRC.
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Affiliation(s)
- Sohei Kobayashi
- Department of Laboratory Medicine & Division of Clinical GeneticsChiba University HospitalChibaJapan
- Department of Medical Technology & Sciences, School of Health Sciences at NaritaInternational University of Health and WelfareChibaJapan
| | - Takaki Hiwasa
- Department of Neurological Surgery, Graduate School of MedicineChiba UniversityChibaJapan
| | - Kouichi Kitamura
- Department of Laboratory Medicine & Division of Clinical GeneticsChiba University HospitalChibaJapan
| | - Masayuki Kano
- Department of Frontier Surgery, Graduate School of MedicineChiba UniversityChibaJapan
| | - Tyuji Hoshino
- Department of Physical Chemistry, Graduate School of Pharmaceutical SciencesChiba UniversityChibaJapan
| | - Sho Hirano
- Department of Medical Technology & Sciences, School of Health Sciences at NaritaInternational University of Health and WelfareChibaJapan
| | - Mayuko Hashimoto
- Department of Medical Technology & Sciences, School of Health Sciences at NaritaInternational University of Health and WelfareChibaJapan
| | - Masanori Seimiya
- Department of Medical Technology & Sciences, School of Health Sciences at NaritaInternational University of Health and WelfareChibaJapan
| | - Hideaki Shimada
- Department of Gastroenterological Surgery, Graduate School of MedicineToho UniversityTokyoJapan
| | - Fumio Nomura
- Department of Laboratory Medicine & Division of Clinical GeneticsChiba University HospitalChibaJapan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of MedicineChiba UniversityChibaJapan
| | - Kazuyuki Matsushita
- Department of Laboratory Medicine & Division of Clinical GeneticsChiba University HospitalChibaJapan
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Lundstrom K. Viral vectors engineered for gene therapy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 379:1-41. [PMID: 37541721 DOI: 10.1016/bs.ircmb.2023.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/06/2023]
Abstract
Gene therapy has seen major progress in recent years. Viral vectors have made a significant contribution through efficient engineering for improved delivery and safety. A large variety of indications such as cancer, cardiovascular, metabolic, hematological, neurological, muscular, ophthalmological, infectious diseases, and immunodeficiency have been targeted. Viral vectors based on adenoviruses, adeno-associated viruses, herpes simplex viruses, retroviruses including lentiviruses, alphaviruses, flaviviruses, measles viruses, rhabdoviruses, Newcastle disease virus, poxviruses, picornaviruses, reoviruses, and polyomaviruses have been used. Proof-of-concept has been demonstrated for different indications in animal models. Therapeutic efficacy has also been achieved in clinical trials. Several viral vector-based drugs have been approved for the treatment of cancer, and hematological, metabolic, and neurological diseases. Moreover, viral vector-based vaccines have been approved against COVID-19 and Ebola virus disease.
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Kobayashi S, Hiwasa T, Ishige T, Kano M, Hoshino T, Rahmutulla B, Seimiya M, Shimada H, Nomura F, Matsubara H, Matsushita K. Anti-FIRΔexon2 autoantibody as a novel indicator for better overall survival in gastric cancer. Cancer Sci 2021; 112:847-858. [PMID: 33306856 PMCID: PMC7894018 DOI: 10.1111/cas.14767] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/30/2020] [Accepted: 12/08/2020] [Indexed: 02/06/2023] Open
Abstract
There is no clinically available biomarker for efficiently indicating the overall survival or therapy response of gastric cancer (GC). The autoantibodies (Abs) in the sera of anti‐far‐upstream element‐binding protein‐interacting repressor‐lacking exon2 (FIRΔexon2), anti‐sorting nexin 15, and anti‐spermatogenesis and oogenesis–specific basic helix–loop–helix 1 were markedly higher in GC patients than in healthy donors (HDs). These Abs were identified by large‐scale serological identification of antigens by recombinant cDNA expression cloning screenings and their expression levels were evaluated by amplified luminescence proximity homogeneous assay. In particular, compared with age‐matched HDs, the level of anti‐FIRΔexon2 Abs in GC patients was significantly higher (P < .001). The Spearman's rank correlation analysis between anti‐FIRΔexon2 Abs and clinically available tumor markers such as carcinoembryonic antigen (CEA) was statistically insignificant, indicating that FIRΔexon2 Abs is an independent biomarker. We performed receiver‐operating curve analysis to evaluate the anti‐FIRΔexon2 Ab as a candidate biomarker with CEA and carbohydrate antigen 19‐9 (CA19‐9). The overall survival of GC patients with high anti‐FIRΔexon2 Abs titer was significantly favorable (P = .04) than that of GC patients who were below detection level of anti‐FIRΔexon2 Abs. However, clinical stages were not apparently correlated with the levels of anti‐FIRΔexon2 Ab, CEA, and CA19‐9. In conclusion, anti‐FIRΔexon2 Abs detected in GC patients is a potential biomarker for monitoring a better prognosis. Hence, anti‐FIRΔexon2 Abs is a promising biomarker for indicating better overall survival of gastric cancer patients.
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Affiliation(s)
- Sohei Kobayashi
- Department of Laboratory Medicine & Division of Clinical Genetics, Chiba University Hospital, Chiba, Japan.,Department of Medical Technology & Sciences, School of Health Sciences at Narita, International University of Health and Welfare, Chiba, Japan
| | - Takaki Hiwasa
- Department of Neurological Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takayuki Ishige
- Department of Laboratory Medicine & Division of Clinical Genetics, Chiba University Hospital, Chiba, Japan
| | - Masayuki Kano
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tyuji Hoshino
- Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Bahityar Rahmutulla
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masanori Seimiya
- Department of Medical Technology & Sciences, School of Health Sciences at Narita, International University of Health and Welfare, Chiba, Japan
| | - Hideaki Shimada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Toho University, Tokyo, Japan
| | - Fumio Nomura
- Department of Laboratory Medicine & Division of Clinical Genetics, Chiba University Hospital, Chiba, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kazuyuki Matsushita
- Department of Laboratory Medicine & Division of Clinical Genetics, Chiba University Hospital, Chiba, Japan
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5
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Kobayashi S, Hiwasa T, Ishige T, Rahmutulla B, Kano M, Hoshino T, Minamoto T, Shimada H, Nomura F, Matsubara H, Matsushita K. Anti-FIRΔexon2, a splicing variant form of PUF60, autoantibody is detected in the sera of esophageal squamous cell carcinoma. Cancer Sci 2019; 110:2004-2013. [PMID: 30980774 PMCID: PMC6549911 DOI: 10.1111/cas.14024] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 04/08/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023] Open
Abstract
Anti‐PUF60 autoantibodies are reportedly detected in the sera of patients with dermatomyositis and Sjögren's syndrome; however, little is known regarding its existence in the sera of cancer patients. FIR, a splicing variant of the PUF60 gene, is a transcriptional repressor of c‐myc. In colorectal cancer, there is an overexpression of the dominant negative form of FIR, in which exon 2 is lacking (FIRΔexon2). Previously, large‐scale SEREX (serological identification of antigens by recombinant cDNA expression cloning) screenings have identified anti‐FIR autoantibodies in the sera of cancer patients. In the present study, we revealed the presence and significance of anti‐FIR (FIR/FIRΔexon2) Abs in the sera of patients with esophageal squamous cell carcinoma (ESCC). Our results were validated by an amplified luminescence proximity homogeneous assay using sera of patients with various cancer types. We revealed that anti‐FIRΔexon2 Ab had higher sensitivity than anti‐FIR Ab. Receiver operating characteristic (ROC) analysis was applied for evaluating the use of anti‐FIRΔexon2 Ab as candidate markers such as anti‐p53 Ab and carcinoembryonic antigen, and the highest area under the ROC curve was observed in the combination of anti‐FIRΔexon2 Ab and anti‐p53 Ab. In summary, our results suggest the use of anti‐FIRΔexon2 Ab in combination with the anti‐p53 Ab as a predictive marker for ESCC. The area under the ROC curve was further increased in the advanced stage of ESCC. The value of anti‐FIRΔexon2 autoantibody as novel clinical indicator against ESCC and as a companion diagnostic tool is discussed.
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Affiliation(s)
- Sohei Kobayashi
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.,Department of Laboratory Medicine & Division of Clinical Genetics and Proteomics, Chiba University Hospital, Chiba, Japan
| | - Takaki Hiwasa
- Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takayuki Ishige
- Department of Laboratory Medicine & Division of Clinical Genetics and Proteomics, Chiba University Hospital, Chiba, Japan
| | - Bahityar Rahmutulla
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masayuki Kano
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tyuji Hoshino
- Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Toshinari Minamoto
- Kanazawa University, Cancer Research Institute, Division of Translational and Clinical Oncology, Ishikawa, Japan
| | - Hideaki Shimada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Toho University, Tokyo, Japan
| | - Fumio Nomura
- Divisions of Clinical Mass Spectrometry and Clinical Genetics, Chiba University Hospital, Chiba, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kazuyuki Matsushita
- Department of Laboratory Medicine & Division of Clinical Genetics and Proteomics, Chiba University Hospital, Chiba, Japan
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6
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Shimada H. p53 molecular approach to diagnosis and treatment of esophageal squamous cell carcinoma. Ann Gastroenterol Surg 2018; 2:266-273. [PMID: 30003189 PMCID: PMC6036386 DOI: 10.1002/ags3.12179] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 05/04/2018] [Indexed: 01/20/2023] Open
Abstract
We reviewed our research concerning p53 molecules in esophageal squamous cell carcinoma by focusing on the p53 molecular diagnosis and treatment of esophageal squamous cell carcinoma. First, we developed diagnostic tools to analyze serum p53 autoantibodies to detect esophageal squamous cell carcinoma. Positive rate was around 25% to 30% in all patients and around 20% even in stage I patients. Presence of serum p53 antibodies was significantly associated with overexpression of p53 protein in tumor cells. Seropositive patients were more likely than seronegative patients to be resistant to chemotherapy. Monitoring of the titer of serum p53 autoantibodies was useful in predicting patients at high risk of recurrence and/or treatment response. Second, using Ad5CMV-p53 for 10 patients with advanced esophageal squamous cell carcinoma, we carried out a phase I/II study of adenoviral-mediated p53 gene therapy. Although no complete response was observed, local tumor was stabilized in nine patients. No serious adverse events related to Ad5CMV-p53 were observed in these patients. One patient survived for over 5 years after the start of p53 gene therapy. Intratumoral injection of Ad5CMV-p53 is therefore safe, feasible, and biologically active when given in multiple doses to patients with esophageal squamous cell carcinoma. Our observations from these clinical studies indicate that p53 is a useful molecular target both in the diagnosis and in the treatment of esophageal squamous cell carcinoma.
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Affiliation(s)
- Hideaki Shimada
- Department of SurgeryToho University Graduate School of MedicineTokyoJapan
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7
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Mo J, Lin M, He B, Tan K, Jin C, Jiang H, Pan X, Lin W. Recombinant human adenovirus-p53 improves the outcome of mid-late stage pancreatic cancer via arterial infusion. Oncol Lett 2017; 14:6829-6832. [PMID: 29181104 DOI: 10.3892/ol.2017.7058] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 06/21/2017] [Indexed: 11/05/2022] Open
Abstract
The present study aimed to investigate the therapeutic efficacy and clinical value of recombinant human adenovirus-p53 (rAd-p53) perfusion via the pancreatic artery for the treatment of mid-late stage pancreatic cancer. rAd-p53 (2×1012 virus particles) in 6 ml normal saline was pushed (intravenous bolus) into the gastroduodenal and superior pancreaticoduodenal arteries via interventional superselection, with the catheter retained for subsequent drug administration at a 3-day interval for 4 cycles. Tumor changes in all patients were observed to evaluate tumor response by computed tomography (CT) at 2, 8 and 16 weeks post-treatment. The following improvements were noted in the 23-patient cohort: A total of 73.9% (17/23) of patients demonstrated significant tumor shrinkage (>20%); the symptoms of abdominal and back pain were relieved in 15 patients; the survival time was >12 months in 1 patient and >6 months in 14 patients; the patient's general condition, including appetite, was improved in 13 patients; body weight was increased in 9 patients; jaundice was attenuated in 12 patients; and ascites subsided in 10 patients. However, the therapeutic outcome was poor in 2 patients whose tumors size did not show significant change after treatment as detected by CT. These 2 patients succumbed within 6 months. In conclusion, rAd-p53 perfusion via the pancreatic artery is a safe and minimally invasive option for the treatment of mid-late stage pancreatic cancer.
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Affiliation(s)
- Jinggang Mo
- Department of Hepatobiliary Surgery, First Clinical College, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Hepatobiliary Surgery, Taizhou Central Hospital, Taizhou, Zhejiang 318000, P.R. China
| | - Meihua Lin
- Research Center of Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Bin He
- Department of Gastrointestinal Surgery, Taizhou Central Hospital, Taizhou, Zhejiang 325000, P.R. China
| | - Kai Tan
- Department of Radiology, Taizhou Central Hospital, Taizhou, Zhejiang 325000, P.R. China
| | - Chong Jin
- Department of Hepatobiliary Surgery, Taizhou Central Hospital, Taizhou, Zhejiang 318000, P.R. China
| | - Hao Jiang
- Department of Hepatobiliary Surgery, Taizhou Central Hospital, Taizhou, Zhejiang 318000, P.R. China
| | - Xuefeng Pan
- Department of Hepatobiliary Surgery, Taizhou Central Hospital, Taizhou, Zhejiang 318000, P.R. China
| | - Weidong Lin
- Department of Hepatobiliary Surgery, Taizhou Central Hospital, Taizhou, Zhejiang 318000, P.R. China
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8
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DONG MEI, HIWASA TAKAKI, CONG BIN, SHI QINGWEN, WANG SIMING, KITA KAZUKO, SUGAYA SHIGERU, SUZUKI NOBUO. Protein kinase Cα-mediated cytotoxic activity of ineupatorolide B from Inula cappa DC. in HeLa cells. Int J Oncol 2015; 47:1839-44. [DOI: 10.3892/ijo.2015.3172] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 09/04/2015] [Indexed: 11/06/2022] Open
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Chen GX, Zhang S, He XH, Liu SY, Ma C, Zou XP. Clinical utility of recombinant adenoviral human p53 gene therapy: current perspectives. Onco Targets Ther 2014; 7:1901-9. [PMID: 25364261 PMCID: PMC4211860 DOI: 10.2147/ott.s50483] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Gene therapy has promised to be a highly effective antitumor treatment by introducing a tumor suppressor gene or the abrogation of an oncogene. Among the potential therapeutic transgenes, the tumor suppressor gene p53 serves as an attractive target. Restoration of wild-type p53 function in tumors can be achieved by introduction of an intact complementary deoxyribonucleic acid copy of the p53 gene using a suitable viral vector, in most cases an adenoviral vector (Adp53). Preclinical in vitro and in vivo studies have shown that Adp53 triggers a dramatic tumor regression response in various cancers. These viruses are engineered to lack certain early proteins and are thus replication defective, including Gendicine, SCH-58500, and Advexin. Several types of tumor-specific p53-expressing conditionally replicating adenovirus vectors (known as replication-competent CRAdp53 vectors) have been developed, such as ONYX 015, AdDelta24-p53, SG600-p53, OBP-702, and H101. Various clinical trials have been conducted to investigate the safety and efficiency of these adenoviral vectors. In this review we will talk about the biological mechanisms, clinical utility, and therapeutic potentials of the replication-deficient Adp53-based and replication-competent CRAdp53-based gene therapy.
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Affiliation(s)
- Guang-Xia Chen
- Department of Gastroenterology, First People's Hospital of Xuzhou, Xuzhou, Jiangsu Province, People's Republic of China
| | - Shu Zhang
- Department of Gastroenterology, Drum Tower Hospital, Nanjing, People's Republic of China ; Medical School of Nanjing University, Nanjing, People's Republic of China ; Jiangsu Clinical Medical Center of Digestive Disease, Nanjing, People's Republic of China
| | - Xiao-Hua He
- Department of Gastroenterology, First People's Hospital of Xuzhou, Xuzhou, Jiangsu Province, People's Republic of China
| | - Shi-Yu Liu
- Department of Gastroenterology, First People's Hospital of Xuzhou, Xuzhou, Jiangsu Province, People's Republic of China
| | - Chao Ma
- Department of Gastroenterology, Drum Tower Hospital, Nanjing, People's Republic of China ; Medical School of Nanjing University, Nanjing, People's Republic of China ; Jiangsu Clinical Medical Center of Digestive Disease, Nanjing, People's Republic of China
| | - Xiao-Ping Zou
- Department of Gastroenterology, Drum Tower Hospital, Nanjing, People's Republic of China ; Medical School of Nanjing University, Nanjing, People's Republic of China ; Jiangsu Clinical Medical Center of Digestive Disease, Nanjing, People's Republic of China
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Tazawa H, Kagawa S, Fujiwara T. Advances in adenovirus-mediated p53 cancer gene therapy. Expert Opin Biol Ther 2014; 13:1569-83. [PMID: 24107178 DOI: 10.1517/14712598.2013.845662] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION The tumor suppressor p53 gene regulates diverse cellular processes, such as cell-cycle arrest, senescence, apoptosis and autophagy, and it is frequently inactivated by genetic alterations in ∼ 50% of all types of human cancers. To restore wild-type p53 function in p53-inactivated tumors, adenovirus-mediated p53 gene therapy has been developed as a promising antitumor strategy in preclinical experiments and clinical studies. AREAS COVERED This review focuses on the clinical relevance of replication-deficient adenovirus vectors that carry the wild-type p53 gene (Ad-p53; Advexin, Gendicine and SCH-58500) in clinical studies of patients with various cancers and the future perspectives regarding conditionally replicating adenovirus vectors expressing the wild-type p53 gene (CRAd-p53; AdDelta24-p53, SG600-p53, OBP-702) in preclinical experiments. Moreover, the recent advances in our understanding of the molecular basis for the p53-mediated tumor suppression network induced by Ad-p53 and CRAd-p53 vectors and the combination therapies for promoting the therapeutic potential of adenovirus-mediated p53 gene therapy are discussed. EXPERT OPINION Exploration of the molecular mechanism underlying the p53-mediated tumor suppression network and the effective strategy for enhancing the p53-mediated cell death signaling pathway would provide novel insights into the improvement of clinical outcome in p53-based cancer gene therapy.
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Affiliation(s)
- Hiroshi Tazawa
- Okayama University Hospital, Center for Innovative Clinical Medicine , Okayama 700-8558 , Japan
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11
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WANG JINGHAN, YU YONG, YAN ZI, HU ZHENLI, LI LINFANG, LI JIANG, JIANG XIAOQING, QIAN QIJUN. Anticancer activity of oncolytic adenoviruses carrying p53 is augmented by 11R in gallbladder cancer cell lines in vitro and in vivo. Oncol Rep 2013; 30:833-41. [DOI: 10.3892/or.2013.2511] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Accepted: 04/19/2013] [Indexed: 01/10/2023] Open
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12
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Xie Q, Liang BL, Wu YH, Zhang J, Chen MW, Liu HY, Gu XF, Xu J. Synergistic anticancer effect of rAd/P53 combined with 5-fluorouracil or iodized oil in the early therapeutic response of human colon cancer in vivo. Gene 2012; 499:303-308. [PMID: 22441128 DOI: 10.1016/j.gene.2012.02.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 02/07/2012] [Accepted: 02/08/2012] [Indexed: 01/10/2023]
Abstract
Exogenous wild-type p53 (wt-p53) tumor suppression increases the sensitivity of tumor cells to radiotherapy and chemotherapy. An iodized oil emulsion was used as a p53 vector for intra-arterial gene delivery to treat hepatic tumors. Whether the chemotherapeutic agent or the iodized oil affects exogenous wt-p53 activity remains poorly understood. In the present study, the early therapeutic response of rAd/p53, combined with 5-fluorouracil (5-FU) or with iodized oil, was observed in a human colon cancer model. Allograft models in 82 nude mice with human colon carcinoma SW480 were divided randomly into four groups and administered with physiologic saline, rAd/p53, rAd/p53+5-FU, and rAd/p53+iodized oil by intratumoral injection. At 24, 48, 72, 120, and 168 h after treatment, p53 expression, the Ki-67 index (KI), and the degree of tumor necrosis were assessed. The p53 expression and tumor necrosis in the therapeutic groups were higher than those in the control group. p53 expression reached its peak at 120 h in the rAd/p53 group, at 72 h in the rAd/p53+5-FU group, and at 48 h in the rAd/p53+iodized oil group. The p53 expression in the rAd/P53+5-FU group and the iodized oil group was significantly higher than those in the rAd/P53 group at 24 and 48 h. The results revealed that tumor necrosis is positively correlated with p53 expression. The KI of the rAd/p53+5-FU group increased significantly at 24 h. 5-FU and iodized oil increase the anticancer effect of rAd/p53, and 5-FU combined with rAd/p53 has a synergistic anticancer effect.
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Affiliation(s)
- Qi Xie
- Department of Imaging, Nan Sha Center Hospital, Guangzhou Municipal First People's Hospital, Guangzhou Medical College, Guangzhou 510240, Guangdong Province, China.
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Antitumor activity of a combination of rAd2p53 adenoviral gene therapy and radiotherapy in esophageal carcinoma. Cell Biochem Biophys 2011; 59:147-52. [PMID: 21350839 DOI: 10.1007/s12013-010-9122-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The objective of this study was to determine if a combination of recombinant adenovirus 2 p53 (rAd2p53) gene therapy and radiotherapy would have significantly improved outcome from esophageal carcinoma when compared to radiotherapy (RT) alone. Forty-five patients diagnosed with esophageal carcinoma (confirmed squamous cell carcinoma) were randomly assigned to one of two study arms: treatment group: rAd2p53 gene therapy + RT (n = 22); and control group: radiotherapy (n = 23). For the treatment group, rAd2p53 was injected into multiple areas of the lesion once a week for 6 weeks avoiding deep ulcers points. RT was administered after 3 days of injection of rAd2p53. Patients in the control group only received radiotherapy. The overall response rate was significantly higher in the treatment group than in control group (P < 0.05). Furthermore, the complete response rate was 3 times higher in the treatment group than in the control group (P < 0.05). Transient fever and pain at injection site were the only side effects mentioned in the treatment group. In conclusion, this recombinant virus-RT combination is significantly more beneficial in palliation than RT alone, with minor side affects. However, its role as neoadjuvant therapy prior to surgical resection needs to be further investigated.
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Kagaya A, Shimada H, Shiratori T, Kuboshima M, Nakashima-Fujita K, Yasuraoka M, Nishimori T, Kurei S, Hachiya T, Murakami A, Tamura Y, Nomura F, Ochiai T, Matsubara H, Takiguchi M, Hiwasa T. Identification of a novel SEREX antigen family, ECSA, in esophageal squamous cell carcinoma. Proteome Sci 2011; 9:31. [PMID: 21696638 PMCID: PMC3135497 DOI: 10.1186/1477-5956-9-31] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2010] [Accepted: 06/23/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Diagnosis of esophageal squamous cell carcinoma (SCC) may improve with early diagnosis. Currently it is difficult to diagnose SCC in the early stage because there is a limited number of tumor markers available. RESULTS Fifty-two esophageal SCC SEREX antigens were identified by SEREX (serological identification of antigens by recombinant cDNA expression cloning) using a cDNA phage library and sera of patients with esophageal SCC. Sequence analysis revealed that three of these antigens were similar in amino acid sequences, and they were designated as ECSA (esophageal carcinoma SEREX antigen)-1, -2 and -3. The ECSA family was also similar to an EST clone, hepatocellular carcinoma-associated antigen 25a (HCA25a). Serum antibody levels to ECSA-1, -2 and -3 were significantly higher in patients with esophageal SCC than in healthy donors. Based on the conserved amino acid sequences, three peptides were synthesized and used for enzyme-linked immunosorbent assays (ELISA). The serum antibody levels against one of these peptides were significantly higher in patients with esophageal SCC. This peptide sequence was also conserved in FAM119A, GOSR1 and BBS5, suggesting that these are also ECSA family members. Reverse transcription followed by quantitative PCR analysis showed that the mRNA expression levels of ECSA-1, -2 and -3 and FAM119A but not of HCA25a, GOSR1 and BBS5 were frequently elevated in esophageal SCC tissues. CONCLUSIONS We have identified a new gene family designated ECSA. Serum antibodies against the conserved domain of the ECSA family may be a promising tumor marker for esophageal SCC.
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Affiliation(s)
- Akiko Kagaya
- Department of Biochemistry and Genetics, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan.,Department of Frontier Surgery, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Hideaki Shimada
- Department of Surgery, School of Medicine, Toho University, Ota-ku, Tokyo 143-8541, Japan
| | - Tooru Shiratori
- Department of Frontier Surgery, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Mari Kuboshima
- Department of Biochemistry and Genetics, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan.,Department of Frontier Surgery, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Kazue Nakashima-Fujita
- Department of Biochemistry and Genetics, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan.,Department of Frontier Surgery, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Mari Yasuraoka
- Department of Biochemistry and Genetics, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Takanori Nishimori
- Department of Frontier Surgery, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Shunsuke Kurei
- Department of Surgery, School of Medicine, Toho University, Ota-ku, Tokyo 143-8541, Japan
| | - Takahisa Hachiya
- Product Development Department, Medical & Biological Laboratories Co., Ltd., Ina, Nagano 396-0002, Japan
| | - Akihiro Murakami
- Product Development Department, Medical & Biological Laboratories Co., Ltd., Ina, Nagano 396-0002, Japan
| | - Yutaka Tamura
- Department of Bioinfomatics, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Fumio Nomura
- Department of Molecular Diagnosis, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Takenori Ochiai
- Gastroenterological Center, San-Ai Memorial Hospital, Chuo-ku, Chiba 260-0806, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Masaki Takiguchi
- Department of Biochemistry and Genetics, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Takaki Hiwasa
- Department of Biochemistry and Genetics, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
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15
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Yamasaki M, Miyata H, Fujiwara Y, Takiguchi S, Nakajima K, Nishida T, Yasuda T, Matsuyama J, Mori M, Doki Y. p53 genotype predicts response to chemotherapy in patients with squamous cell carcinoma of the esophagus. Ann Surg Oncol 2009; 17:634-42. [PMID: 19941080 DOI: 10.1245/s10434-009-0851-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2009] [Indexed: 11/18/2022]
Abstract
BACKGROUND Response to chemotherapy and anatomical spread are significant prognostic factors in patients with esophageal squamous cell carcinoma (ESCC) treated by chemotherapy then surgery. Predicting the response to chemotherapy would allow significant optimization of cancer treatment. METHODS Genomic mutation and protein expression of p53 were investigated retrospectively by polymerase chain reaction (PCR) single-strand conformation polymorphism (SSCP) and immunohistochemistry (IHC) using biopsy specimens from 77 ESCC patients before chemotherapy with 5-fluorouracil, adriamycin, and cisplatin. p53 status was correlated with various clinicopathological factors. Thereafter, we performed a prospective study of 20 consecutive patients to test our prediction model. RESULTS The retrospective study showed mutant p53 genotype and positive p53 IHC staining in 46.8 and 55.8% of patients, respectively, which was not associated with patient's clinicopathological findings including initial tumor stage. Objective response to chemotherapy was observed in 65.9% of patients with wild genotype, but in only 16.7% of patients with mutant genotype. Patients with mutations in p53 therefore showed significantly poorer prognosis than those without mutant p53. In contrast, p53 IHC staining did not correlate with response to chemotherapy, curative resection rate or prognosis. In the prospective study, p53 mutation was seen in 50% (10/20) of patients and was again consistently associated with poorer response to chemotherapy and poorer prognosis. CONCLUSIONS p53 genotype of pretreatment biopsy is a potentially useful predictor of response to chemotherapy and prognosis in ESCC patients. This information might be valuable to clinicians in deciding on the optimal clinical strategy in patients with ESCC.
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Affiliation(s)
- Makoto Yamasaki
- Departments of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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16
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Shimada H, Shiratori T, Yasuraoka M, Kagaya A, Kuboshima M, Nomura F, Takiguchi M, Ochiai T, Matsubara H, Hiwasa T. Identification of Makorin 1 as a novel SEREX antigen of esophageal squamous cell carcinoma. BMC Cancer 2009; 9:232. [PMID: 19604354 PMCID: PMC2722670 DOI: 10.1186/1471-2407-9-232] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2008] [Accepted: 07/15/2009] [Indexed: 11/21/2022] Open
Abstract
Background Esophageal squamous cell carcinoma (SCC) represents one of the most malignant tumors. To improve the poor prognosis, it is necessary to diagnose esophageal SCC at early stages using new tumor markers. SEREX (serological identification of antigens by recombinant cDNA expression cloning) is suitable for large-scale screening of tumor antigens and has been applied for various types of human tumors. Methods Tumor markers of esophageal squamous cell carcinoma (SCC) were screened by SEREX method. The presence of serum anti-makorin 1 (MKRN1) antibodies (s-MKRN1-Abs) was examined by Western blotting using bacterially expressed MKRN1 protein. The expression levels of MKRN1 mRNA in tissues were examined by RT-PCR. The biological activity of MKRN1 was examined by transfection of ras-NIH3T3 mouse fibroblasts with MKRN1 cDNA. Major ubiquitinated proteins in MKRN1-transfected cells were identified by immunoprecipitation with anti-ubiquitin antibody followed by mass spectrometry. Results MKRN1 was identified as a novel SEREX antigen of esophageal SCC. Although a total of 18 (25%) of 73 patients with esophageal SCC had s-MKRN1-Abs, none of the 43 healthy donors had a detectable level of s-MKRN1-Abs. There was no correlation between the presence of s-MKRN1-Abs and clinicopathological variables other than histological grading. Well-differentiated tumors were associated significantly with the presence of s-MKRN1-Abs in the patients. The mRNA levels of MKRN1 were frequently higher in esophageal SCC tissues than in the peripheral normal esophageal mucosa. Stable transfection of ras-NIH3T3 cells with MKRN1 cDNA induced prominent morphological changes such as enlargement of the cell body and spreading. Ubiquitination of 80- and 82-kDa proteins were clearly observed in MKRN1-transfected cells but not in the parental cells, which were identified as L-FILIP (filamin A interacting protein 1). Conclusion MKRN1 is a novel SEREX antigen of esophageal SCC, and s-NKRN1-Abs can be a candidate of diagnostic markers of esophageal SCC with high specificity. It is plausible that MKRN1 is involved in carcinogenesis of the well-differentiated type of tumors possibly via ubiquitination of L-FILIP.
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Affiliation(s)
- Hideaki Shimada
- Department of Biochemistry and Genetics, Chiba University, Graduate School of Medicine, Chiba, Japan.
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17
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Ma G, Kawamura K, Li Q, Suzuki N, Liang M, Namba M, Shimada H, Tagawa M. Cytotoxicity of adenoviruses expressing the wild-type p53 gene to esophageal carcinoma cells is linked with the CAR expression level and indirectly with the endogenous p53 status. Cancer Gene Ther 2009; 16:832-40. [PMID: 19363469 DOI: 10.1038/cgt.2009.21] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We examined cytotoxic effects of adenoviruses (Ad) expressing the p53 gene (Ad-p53) in nine human esophageal carcinoma cell lines with respect to the Ad receptor expression and the endogenous p53 gene status. Ad-p53-mediated cytotoxicity was related with an expression level of the coxsackievirus adenovirus receptor (CAR) but not with that of CD51, both of which are type 5 Ad receptors. Contrary to earlier studies, we found that the cytotoxicity was greater in tumor cells with the wild-type p53 gene than in those with mutated p53. The cytotoxic activity of Ad defective of E1B55kDa molecules (Ad-delE1B55), however, was not linked with the CAR expression level or the endogenous p53 status. We noticed that the tumor cells with the wild-type p53 gene showed greater CAR expression levels, although transduction with Ad-p53 did not upregulate the CAR expression in the mutated cells. We also examined the Ad-53-mediated cytotoxicity in two kinds of paired fibroblasts, parent and immortalized with loss of the p53 functions, and showed that the CAR expression level was more influential than the endogenous p53 status in the cytotoxicity. These data suggest that CAR expression level is a better predictive marker than endogenous p53 status for Ad-p53-mediated cytotoxicity in esophageal carcinoma.
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Affiliation(s)
- G Ma
- Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chuo-ku, Chiba 260-8717, Japan
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18
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Xie Q, Liang B, Zhang J, Yang Q, Gu X, Xu J, Chen M. In vivo comparison of transduction efficiency with recombinant adenovirus-mediated p53 in a human colon cancer mouse model by different delivery routes. THE CHINESE-GERMAN JOURNAL OF CLINICAL ONCOLOGY 2008; 7:704-708. [DOI: 10.1007/s10330-008-0123-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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19
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Liu TL, Shimada H, Ochiai T, Shiratori T, Lin SE, Kitagawa M, Harigaya K, Maki M, Oka M, Abe T, Takiguchi M, Hiwasa T. Enhancement of chemosensitivity toward peplomycin by calpastatin-stabilized NF-kappaB p65 in esophageal carcinoma cells: possible involvement of Fas/Fas-L synergism. Apoptosis 2007; 11:1025-37. [PMID: 16547594 DOI: 10.1007/s10495-006-6353-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Chemosensitivity to anticancer drugs was compared between two human esophageal carcinoma cell lines, T.Tn and YES-6 cells. T.Tn cells were more resistant than YES-6 cells to peplomycin (PEP) but not to the other anticancer drugs such as camptothecin, mitomycin C and cytosine arabinoside. Western blot analysis showed higher expression levels of m-calpain and activated mu-calpain in T.Tn cells than in YES-6 cells. On the other hand, YES-6 cells showed a high expression level of calpastatin, which is a calpain-specific endogenous inhibitor. To investigate whether calpain activity was involved in the chemosensitivity, T.Tn cells were transfected with calpastatin cDNA in an inducible expression vector. The induction of calpastatin was accompanied by increased chemosensitivity to PEP. The increases in calpastatin levels were followed by serial increases in the expression levels of NF-kappaB p65 and Fas. Since purified m- or mu-calpain degraded NF-kappaB p65 in vitro, it is possible that calpastatin suppressed calpain-mediated degradation of NF-kappaB p65. Fas ligand (Fas-L) protein levels increased after treatment of the parental T.Tn and calpastatin-transfected cells with PEP, suggesting the synergism between calpastatin-induced Fas and PEP-induced Fas-L. These results suggest that calpain/calpastatin expression levels are effective markers for predicting the sensitivity of human esophageal carcinoma cells to PEP.
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Affiliation(s)
- T-L Liu
- Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
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20
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Yamada K, Moriyama H, Yasuda H, Hara K, Maniwa Y, Hamada H, Yokono K, Nagata M. Modification of the Rb-binding domain of replication-competent adenoviral vector enhances cytotoxicity against human esophageal cancers via NF-kappaB activity. Hum Gene Ther 2007; 18:389-400. [PMID: 17518613 DOI: 10.1089/hum.2006.126] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
A replication-competent adenoviral vector deficient for expression of the early E1B55K protein has been applied in clinical studies. The vector, however, was not fully effective for the treatment of human cancer. In this study, the E1A gene (which encodes an Rb-binding domain protein) of the adenoviral vector AxE1AdB was further engineered with a point mutation designed to abolish binding to Rb protein (pRb) and arrest the cell cycle (AxdAdB-3). The difference in the cytotoxicity of these vectors in two cancer cell lines was observed in association with differences in replication, infection efficiency, and expression levels of adenovirus receptors. Relative to the parent vector (AxE1AdB), which worked in a manner similar to ONYX-015, AxdAdB-3 with the mutated pRb-binding motif demonstrated increased cytotoxicity against p53-mutant human esophageal cancer cell lines EC-GI-10 and T.Tn. AxdAdB-3 showed a greater oncolytic effect than AxE1AdB in vivo despite almost the same replication efficiency in vitro. Unexpectedly, cell cycle arrest in AxdAdB-3-infected cells was less efficient than that in cell lines infected with AxE1AdB. However, AxdAdB-3 strongly reduced NF-kappaB activity and thereby enhanced apoptosis more than AxE1AdB did. These data demonstrate that the Rb-binding domain of E1A can regulate NF-kappaB activity and that modifications to this domain may lead to advances in gene therapies for the treatment of human cancers.
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Affiliation(s)
- Katsumi Yamada
- Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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21
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Shimada H, Matsubara H, Shiratori T, Shimizu T, Miyazaki S, Okazumi S, Nabeya Y, Shuto K, Hayashi H, Tanizawa T, Nakatani Y, Nakasa H, Kitada M, Ochiai T. Phase I/II adenoviral p53 gene therapy for chemoradiation resistant advanced esophageal squamous cell carcinoma. Cancer Sci 2006; 97:554-61. [PMID: 16734736 PMCID: PMC11158125 DOI: 10.1111/j.1349-7006.2006.00206.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
We investigated the feasibility, safety, biological activity and therapeutic efficacy of adenovirus-mediated p53 gene transfer in patients with chemoradiation resistant advanced esophageal carcinoma. Eligible patients were not surgical candidates and had measurable, advanced squamous cell carcinoma of the esophagus that was resistant to chemoradiation therapy. On a 28-day cycle, intratumoral injections of Ad5CMV-p53 (INGN 201; ADVEXIN) were administered on days 1 and 3 at four dose levels (10 x 10(11) particles to 25 x 10(11) particles) and treated for up to five cycles. Ten patients received a total of 26 cycles with no dose-limiting toxicity. Administration of multiple courses was feasible and well-tolerated. Local tumor responses revealed stable disease in nine cases and progressive disease in one case. The overall responses were stable in six and progressive in four cases. Using polymerase chain reaction (PCR) analyses, gene transfer and p53 specific transgene expression were detected in tumor biopsy tissue from all patients. mRNA levels of p53, p21 and MDM2 increased in all but one case. Three patients showed absence of disease upon repeat biopsies. Substantial improvement in swallowing was observed in one patient with stenotic lesions. Intratumoral injection of Ad5CMV-p53 is safe, feasible and biologically active when administered in multiple doses to patients with esophageal cancer. Observations from this study indicate that this treatment results in local antitumor effects in chemoradiation resistant esophageal squamous cell carcinoma.
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Affiliation(s)
- Hideaki Shimada
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chiba, 260-8670, Japan.
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22
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Kuboshima M, Shimada H, Liu TL, Nomura F, Takiguchi M, Hiwasa T, Ochiai T. Presence of serum tripartite motif-containing 21 antibodies in patients with esophageal squamous cell carcinoma. Cancer Sci 2006; 97:380-6. [PMID: 16630135 PMCID: PMC11158984 DOI: 10.1111/j.1349-7006.2006.00192.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
SEREX has been applied to esophageal SCC, and the TRIM21 gene was identified as a novel SEREX antigen of esophageal SCC. The presence of s-TRIM21-Abs was confirmed by Western blotting using bacterially expressed TRIM21 gene product and was evaluated for clinicopathological significance in patients with esophageal SCC. s-TRIM21-Abs were detected in 18 (20%) of 91 patients with esophageal SCC but not in 42 healthy donors. The presence of s-TRIM21-Abs was partly associated with tumor size (P = 0.063) and poor survival (P = 0.067). To measure serum antibody levels, ELISA using purified recombinant TRIM21 protein was developed. The levels of s-TRIM21-Abs were significantly higher in patients with esophageal SCC than in healthy donors (P = 0.013). s-TRIM21-Abs may be a useful tumor marker to diagnose and predict disease progression in patients with esophageal SCC.
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Affiliation(s)
- Mari Kuboshima
- Department of Frontier Surgery, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
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23
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Sato F, Abraham JM, Yin J, Kan T, Ito T, Mori Y, Hamilton JP, Jin Z, Cheng Y, Paun B, Berki AT, Wang S, Shimada Y, Meltzer SJ. Polo-like kinase and survivin are esophageal tumor-specific promoters. Biochem Biophys Res Commun 2006; 342:465-71. [PMID: 16487489 DOI: 10.1016/j.bbrc.2006.01.177] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2006] [Accepted: 01/31/2006] [Indexed: 01/14/2023]
Abstract
For developing successful cancer gene therapy strategies, tumor-specific gene delivery is essential. In this study, we used esophageal cancer (EC) cells to identify and evaluate esophageal tumor-specific gene promoters. Four genes (polo-like kinase-1/PLK, survivin/BIRC5, karyopherin alpha 2/KPNA2, and pituitary tumor transforming gene protein 1/PTTG1) were identified by a microarray analysis as highly expressed in EC cell lines vs. five normal organ tissues (liver, lung, kidney, brain, and heart). By quantitative RT-PCR, the average mRNA expression levels of these four genes in 20 primary ECs were 2.7-fold (PLK), 6.1-fold (survivin), 2.6-fold (KPNA2), and 2.4-fold (PTTG1) higher than that of each gene in 24 different normal organs. By dual luciferase assay, the promoter activity of PLK and survivin in EC cell lines was 18.9-fold and 28.5-fold higher, respectively, than in normal lung and renal cells. The promoters of PLK and survivin could be useful tools for developing EC-specific gene therapy vectors.
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Affiliation(s)
- Fumiaki Sato
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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24
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Nakashima K, Shimada H, Ochiai T, Kuboshima M, Kuroiwa N, Okazumi S, Matsubara H, Nomura F, Takiguchi M, Hiwasa T. Serological identification of TROP2 by recombinant cDNA expression cloning using sera of patients with esophageal squamous cell carcinoma. Int J Cancer 2004; 112:1029-35. [PMID: 15386348 DOI: 10.1002/ijc.20517] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
We applied serological analysis of recombinant cDNA expression libraries (SEREX) to cases of esophageal squamous cell carcinoma (SCC) to identify tumor antigens. One of the clones identified was TROP2, which is known as calcium signal transducer. To evaluate the clinical significance of serum anti-TROP2 antibodies (s-TROP2-Abs) in patients with esophageal SCC, the presence of s-TROP2-Abs was analyzed by Western blotting using bacterially expressed TROP2 protein. We found that 23 of 75 (31%) patients were positive for s-TROP2-Abs. Positivity in terms of s-TROP2-Abs showed a significant association with tumor size but not with other clinicopathological features. The protein expression levels of TROP2 were much higher in esophageal SCC cell lines as compared to those in normal esophageal mucosa and its immortalized cells although the mRNA expression levels were not necessarily elevated in malignant cell lines and tissues. Immunohistochemical studies showed that the expression of TROP2 protein in esophageal SCC specimens was noticeably higher than that found in mild hyperplasia of esophageal mucosae. Thus, s-TROP2-Abs seemed useful in the diagnosis of SCC and may be a candidate for serum tumor markers.
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MESH Headings
- Aged
- Antigens, Neoplasm/analysis
- Antigens, Neoplasm/immunology
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/immunology
- Blotting, Western
- Carcinoma, Squamous Cell/chemistry
- Carcinoma, Squamous Cell/diagnosis
- Cell Adhesion Molecules/analysis
- Cell Adhesion Molecules/immunology
- Cell Line, Tumor
- Cloning, Molecular/methods
- DNA, Complementary/analysis
- DNA, Neoplasm/analysis
- Epithelial Cell Adhesion Molecule
- Esophageal Neoplasms/chemistry
- Esophageal Neoplasms/diagnosis
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Immunohistochemistry
- Male
- Middle Aged
- Recombinant Proteins/analysis
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Affiliation(s)
- Kazue Nakashima
- Department of Academic Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan
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25
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Wu QM, Yu JP, Tong Q, Wang XH, Xie GJ. Inhibition of adenovirus-mediated p27kip1 gene on growth of esophageal carcinoma cell strain. World J Gastroenterol 2003; 9:2404-8. [PMID: 14606065 PMCID: PMC4656510 DOI: 10.3748/wjg.v9.i11.2404] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the inhibition of p27kip1 gene on the growth of esophageal carcinoma cell strain (EC9706).
METHODS: Recombinant adenovirus Ad-p27kip1 was constructed and transfected into esophageal carcinoma cell EC-9706, and its effect on p27kip1 expression, the growth of esophageal carcinoma cell, DNA replication, protein synthesis, cell multiplication and apoptosis were explored by means of cell growth count, 3H-TdR, 3H-Leucine incorporation, flow cytometry, DNA fragment analysis and TUNEL.
RESULTS: Recombinant adenovirus Ad-p27kip1 was successfully constructed with a virus titer of 1.24 × 1012 pfu/mL. p27kip protein expression increased markedly after EC-9706 transfection, while incorporation quantity of 3H-TdR and 3H-Leucine decreased significantly. The growth of esophageal carcinoma cell was inhibited obviously. Testing of flow cytometry displayed a typical apoptosis peak, and DNA gel electrophoresis showed a typical apoptosis ladder. TUNEL showed the apoptosis rate of Ad-p27kip1 group and control group to be 37.3% and 1.26% (P < 0.001) respectively.
CONCLUSION: Ad-p27kip1 can inhibit the growth and multiplication of esophageal carcinoma cells and induce apoptosis. Therefore, enhanced p27kip1 expression may be a new way to treat esophageal carcinoma.
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Affiliation(s)
- Qing-Ming Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Hubei Province, China.
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26
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Zhang WG, Wu QM, Tong Q, Yu JP. Inhibitory effect of p27kip1 mediated by adenovirus on model of esophageal carcinoma in nude mice. Shijie Huaren Xiaohua Zazhi 2003; 11:512-516. [DOI: 10.11569/wcjd.v11.i5.512] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the inhibitory effect of p27kip1 mediated by adenovirus vector on esophageal carcinoma in vivo.
METHODS Eca109 cells were injected into the subcutaneous tissue of nude mice to establish tumors. The transplanted tumors were reproduced among the nude mice contionually after original grafts grew well. The model of esophageal carcinoma in nude mice was established by transplanting the tumor tissue mass into the subcutaneous tissue of nude mice .The successful constructed recombinant adenoviral vector carrying p27kip1 gene and LacZ recombinant adenovirus were directly injected into the esophageal tumors in nude mice respectively. Compared with control group, the growth curves of tumor were drawed and the growth inhibition rates of tumor were calculated.
RESULTS The growth of tumors in gene therapy group with p27kip1 was obviously suppressed, which had a significant difference compared with control group (P < 0.001). The growth inhibition rate of tumor reached 64.1%.
CONCLUSION p27kip1 gene therapy mediated by adenovirus vector has significant inhibitory effect on esophageal carcinoma in vivo.
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Affiliation(s)
- Wei-Guo Zhang
- Department of Gastroenterology, the Affiliated Taihe Hospital, Yunyang Medical College, Shiyan 442000, Hubei Province, China
| | - Qing-Ming Wu
- Department of Gastroenterology, the Affiliated Taihe Hospital, Yunyang Medical College, Shiyan 442000, Hubei Province, China
| | - Qiang Tong
- Department of Gastroenterology, the Affiliated Taihe Hospital, Yunyang Medical College, Shiyan 442000, Hubei Province, China
| | - Jie-Ping Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
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Abstract
Despite improvement of surgical treatment and application of multimodality therapies to advanced esophageal cancer, the prognosis is extremely poor for patients with unresectable tumors. Based on the genetic background of esophageal cancer, we have developed various gene therapy strategies against human esophageal cancer. In this article, we review molecular events of esophageal cancer and p53 gene therapy approaches for its treatment. First, we analyzed p53 genetic alterations and angiogenesis in esophageal cancer. Second, we tested a p53 recombinant adenoviral vector (Ad5CMV-p53). Significant growth suppression was observed following infection with Ad5CMV-p53 in human esophageal cancer cell lines. This observation suggests that Ad5CMV-p53 may be a potentially effective therapeutic agent for locally advanced esophageal cancer. Promising avenues for investigation include double gene therapy and adjuvant use of gene therapy with radiation therapy. Third, based on recent reports of clinical trials of p53 gene therapy for lung cancer and head and neck cancer, we developed a clinical protocol for p53 gene therapy for unresectable advanced esophageal cancer. This clinical trial was planned to evaluate vector tolerability and efficacy. Up to December 1, 2001, four patients were enrolled in this phase I/II trial. No serious adverse events related to Ad5CMV-p53 have occurred so far in these patients, and the trial has been safely conducted.
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Affiliation(s)
- Hideaki Shimada
- Department of Academic Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
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Shimada H, Liu TL, Ochiai T, Shimizu T, Haupt Y, Hamada H, Abe T, Oka M, Takiguchi M, Hiwasa T. Facilitation of adenoviral wild-type p53-induced apoptotic cell death by overexpression of p33(ING1) in T.Tn human esophageal carcinoma cells. Oncogene 2002; 21:1208-16. [PMID: 11850840 DOI: 10.1038/sj.onc.1205176] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2001] [Revised: 10/31/2001] [Accepted: 11/08/2001] [Indexed: 12/21/2022]
Abstract
To investigate the effect of p33(ING1) on wild-type p53 gene therapy, T.Tn human esophageal carcinoma cells were stably transfected with p33(ING1) cDNA. Infection with Ad-p53 (recombinant adenovirus containing wild-type p53) into p33-transfected cells reduced cell viability, while infection with empty vector had little effect. This reduced viability was shown to be due to apoptotic cell death by the TUNEL (terminal deoxynucleotidyl transferase-mediated nick end-labeling) assay. Following infection with Ad-p53, levels of p53 were similar in p33-expressing cells and in the parental line. However, levels of p21 and Mdm2 were elevated in p33-transfected cells. Nonetheless, this enhanced expression of Mdm2 appeared to be ineffective in downregulating p53. Transient transfection with mutant Mdm2 prior to Ad-p53 infection provided a significant protection as compared with cells transfected with wild-type Mdm2. These results imply a synergistic effect between p33 and p53 in the induction of apoptosis of human esophageal carcinoma cells. A role for Mdm2 in this synergism is suggested.
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Affiliation(s)
- Hideaki Shimada
- Department of Academic Surgery, Chiba University, Graduate School of Medicine, Inohana 1-8-1, Chuo-ku, Chiba 260-8670, Japan
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