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Amanzadeh Jajin E, Oraee-Yazdani S, Zali A, Tavanaei R. Efficacy and safety of gene therapy approaches for malignant gliomas: A systematic review and meta-analysis: ConNRNRNRNR22.5NRNR1011.413.511.9NRNRNR. Curr Probl Cancer 2025; 55:101183. [PMID: 39854884 DOI: 10.1016/j.currproblcancer.2025.101183] [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: 03/04/2024] [Revised: 09/17/2024] [Accepted: 01/08/2025] [Indexed: 01/27/2025]
Abstract
BACKGROUND Malignant gliomas are the most aggressive brain tumors with no certain therapeutic methods. Nowadays, novel treatment methods are introduced for gliomas among which gene therapy is known as a promising and robust method. In this method, genes with key roles in the prevention of cell cycle or induction of cell suicide are transferred to the tumor site using vectors. Viral vectors are the most popular transfer methods, while the liposomes are also used for gene therapy. METHODS This meta-analysis and systematic review was performed based on PRISMA guidelines. We performed a comprehensive search in databases including PubMed, Embase, and clinicaltrial.gov. After processing and filtering the articles, phase 1 clinical trials were chosen for the evaluation of the efficacy and safety of gene therapy for malignant gliomas. RESULTS The obtained results showed that gene therapy increases overall survival (OS) and progression-free survival (PFS) in two years of follow-up. Subgroup analysis also showed that cytokines exhibit the highest effectiveness compared to suicide genes and oncolytic genes. It was found that gene therapy is more efficient for recurrent gliomas than primary gliomas. The subgroup analysis for vectors revealed that Adenovirus is the most effective for increasing the OS in malignant glioma patients. CONCLUSION Gene therapy is an immunotherapy method for malignant gliomas following the standard treatment approach. Considering the effectiveness of gene therapy on the survival of patients, it is hoped that solving related issues with gene therapy will help to increase the OS rate in this malignant disease.
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Affiliation(s)
- Elnaz Amanzadeh Jajin
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Saeed Oraee-Yazdani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Zali
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roozbeh Tavanaei
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Shi Y, Zhang J, Li Y, Feng C, Shao C, Shi Y, Fang J. Engineered mesenchymal stem/stromal cells against cancer. Cell Death Dis 2025; 16:113. [PMID: 39971901 PMCID: PMC11839947 DOI: 10.1038/s41419-025-07443-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 01/03/2025] [Accepted: 02/11/2025] [Indexed: 02/21/2025]
Abstract
Mesenchymal stem/stromal cells (MSCs) have garnered attention for their potential in cancer therapy due to their ability to home to tumor sites. Engineered MSCs have been developed to deliver therapeutic proteins, microRNAs, prodrugs, chemotherapy drugs, and oncolytic viruses directly to the tumor microenvironment, with the goal of enhancing therapeutic efficacy while minimizing off-target effects. Despite promising results in preclinical studies and clinical trials, challenges such as variability in delivery efficiency and safety concerns persist. Ongoing research aims to optimize MSC-based cancer eradication and immunotherapy, enhancing their specificity and efficacy in cancer treatment. This review focuses on advancements in engineering MSCs for tumor-targeted therapy.
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Affiliation(s)
- Yuzhu Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Jia Zhang
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
- Department of Basic Medical Sciences, Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Yanan Li
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Chao Feng
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
- Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome "Tor Vergata", Rome, 00133, Italy
| | - Changshun Shao
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200025, China.
| | - Jiankai Fang
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
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Pallasch FB, Freytag V, Kriegs M, Gatzemeier D, Mair T, Voss H, Riecken K, Dawood M, Fehse B, Efferth T, Schlüter H, Schumacher U. The Histogenetic Origin of Malignant Cells Predicts Their Susceptibility towards Synthetic Lethality Utilizing the TK.007 System. Cancers (Basel) 2024; 16:2278. [PMID: 38927982 PMCID: PMC11202008 DOI: 10.3390/cancers16122278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 06/04/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Remarkable differences exist in the outcome of systemic cancer therapies. Lymphomas and leukemias generally respond well to systemic chemotherapies, while solid cancers often fail. We engineered different human cancer cells lines to uniformly express a modified herpes simplex virus thymidine kinase TK.007 as a suicide gene when ganciclovir (GCV) is applied, thus in theory achieving a similar response in all cell lines. METHODS Fifteen different cell lines were engineered to express the TK.007 gene. XTT-cell proliferation assays were performed and the IC50-values were calculated. Functional kinome profiling, mRNA sequencing, and bottom-up proteomics analysis with Ingenuity pathway analysis were performed. RESULTS GCV potency varied among cell lines, with lymphoma and leukemia cells showing higher susceptibility than solid cancer cells. Functional kinome profiling implies a contribution of the SRC family kinases and decreased overall kinase activity. mRNA sequencing highlighted alterations in the MAPK pathways and bottom-up proteomics showed differences in apoptotic and epithelial junction signaling proteins. CONCLUSIONS The histogenetic origin of cells influenced the susceptibility of human malignant cells towards cytotoxic agents with leukemias and lymphomas being more sensitive than solid cancer cells.
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Affiliation(s)
- Fabian Bernhard Pallasch
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (U.S.)
- Department of Diagnostic and Interventional Radiology, Faculty of Medicine, Medical Center—University of Freiburg, 79106 Freiburg Im Breisgau, Germany
| | - Vera Freytag
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (U.S.)
| | - Malte Kriegs
- Department of Radiotherapy and Radiation Oncology, Hubertus Wald Tumorzentrum–University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
- UCCH Kinomics Core Facility, Hubertus Wald Tumorzentrum–University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Dennis Gatzemeier
- Section Mass Spectrometric and Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Thomas Mair
- Section Mass Spectrometric and Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Hannah Voss
- Section Mass Spectrometric and Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Kristoffer Riecken
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Mona Dawood
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
| | - Boris Fehse
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
| | - Hartmut Schlüter
- Section Mass Spectrometric and Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Udo Schumacher
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (U.S.)
- Department of Medicine, Medical School Berlin, Mecklenburgische Strasse 57, 14197 Berlin, Germany
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Role of Extracellular Vesicles in Compromising Cellular Resilience to Environmental Stressors. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9912281. [PMID: 34337063 PMCID: PMC8321721 DOI: 10.1155/2021/9912281] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/16/2021] [Accepted: 07/07/2021] [Indexed: 12/17/2022]
Abstract
Extracellular vesicles (EVs), like exosomes, are nanosized membrane-enveloped vesicles containing different bioactive cargo, such as proteins, lipids, mRNA, miRNA, and other small regulatory RNAs. Cell-derived EVs, including EVs originating from stem cells, may capture components from damaged cells or cells impacted by therapeutic treatments. Interestingly, EVs derived from stem cells can be preconditioned to produce and secrete EVs with different therapeutic properties, particularly with respect to heat-shock proteins and other molecular cargo contents. This behavior is consistent with stem cells that also respond differently to various microenvironments. Heat-shock proteins play roles in cellular protection and mediate cellular resistance to radiotherapy, chemotherapy, and heat shock. This review highlights the possible roles EVs play in mediating cellular plasticity and survival when exposed to different physical and chemical stressors, with a special focus on the respiratory distress due to the air pollution.
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Tamura R, Miyoshi H, Yoshida K, Okano H, Toda M. Recent progress in the research of suicide gene therapy for malignant glioma. Neurosurg Rev 2019; 44:29-49. [PMID: 31781985 DOI: 10.1007/s10143-019-01203-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 10/14/2019] [Accepted: 10/28/2019] [Indexed: 12/15/2022]
Abstract
Malignant glioma, which is characterized by diffuse infiltration into the normal brain parenchyma, is the most aggressive primary brain tumor with dismal prognosis. Over the past 40 years, the median survival has only slightly improved. Therefore, new therapeutic modalities must be developed. In the 1990s, suicide gene therapy began attracting attention for the treatment of malignant glioma. Some clinical trials used a viral vector for suicide gene transduction; however, it was found that viral vectors cannot cover the large invaded area of glioma cells. Interest in this therapy was recently revived because some types of stem cells possess a tumor-tropic migratory capacity, which can be used as cellular delivery vehicles. Immortalized, clonal neural stem cell (NSC) line has been used for patients with recurrent high-grade glioma, which showed safety and efficacy. Embryonic and induced pluripotent stem cells may be considered as sources of NSC because NSC is difficult to harvest, and ethical issues have been raised. Mesenchymal stem cells are alternative candidates for cellular vehicle and are easily harvested from the bone marrow. In addition, a new type of nonlytic, amphotropic retroviral replicating vector encoding suicide gene has shown efficacy in patients with recurrent high-grade glioma in a clinical trial. This replicating viral capacity is another possible candidate as delivery vehicle to tackle gliomas. Herein, we review the concept of suicide gene therapy, as well as recent progress in preclinical and clinical studies in this field.
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Affiliation(s)
- Ryota Tamura
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroyuki Miyoshi
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Kazunari Yoshida
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Masahiro Toda
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
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Malekshah OM, Chen X, Nomani A, Sarkar S, Hatefi A. Enzyme/Prodrug Systems for Cancer Gene Therapy. ACTA ACUST UNITED AC 2016; 2:299-308. [PMID: 28042530 DOI: 10.1007/s40495-016-0073-y] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The use of enzyme/prodrug system has gained attention because it could help improve the efficacy and safety of conventional cancer chemotherapies. In this approach, cancer cells are first transfected with a gene that can express an enzyme with ability to convert a non-toxic prodrug into its active cytotoxic form. As a result, the activated prodrug could kill the transfected cancer cells. Despite the significant progress of different suicide gene therapy protocols in preclinical studies and early clinical trials, none has reached the clinic due to several shortcomings. These include slow prodrug-drug conversion rate, low transfection/transduction efficiency of the vectors and nonspecific toxicity/immunogenicity related to the delivery systems, plasmid DNA, enzymes and/or prodrugs. This mini review aims at providing an overview of the most widely used enzyme/prodrug systems with emphasis on reporting the results of the recent preclinical and clinical studies.
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Affiliation(s)
- Obeid M Malekshah
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States
| | - Xuguang Chen
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States
| | - Alireza Nomani
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States
| | - Siddik Sarkar
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States
| | - Arash Hatefi
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, United States
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Wilson TA, Karajannis MA, Harter DH. Glioblastoma multiforme: State of the art and future therapeutics. Surg Neurol Int 2014; 5:64. [PMID: 24991467 PMCID: PMC4078454 DOI: 10.4103/2152-7806.132138] [Citation(s) in RCA: 187] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Accepted: 03/13/2014] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is the most common and lethal primary malignancy of the central nervous system (CNS). Despite the proven benefit of surgical resection and aggressive treatment with chemo- and radiotherapy, the prognosis remains very poor. Recent advances of our understanding of the biology and pathophysiology of GBM have allowed the development of a wide array of novel therapeutic approaches, which have been developed. These novel approaches include molecularly targeted therapies, immunotherapies, and gene therapy. METHODS We offer a brief review of the current standard of care, and a survey of novel therapeutic approaches for treatment of GBM. RESULTS Despite promising results in preclinical trials, many of these therapies have demonstrated limited therapeutic efficacy in human clinical trials. Thus, although survival of patients with GBM continues to slowly improve, treatment of GBM remains extremely challenging. CONCLUSION Continued research and development of targeted therapies, based on a detailed understanding of molecular pathogenesis can reasonably be expected to yield improved outcomes for patients with GBM.
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Affiliation(s)
- Taylor A Wilson
- Department of Neurosurgery, Division of Oncology, New York University School of Medicine, NY, USA
| | - Matthias A Karajannis
- Department of Pediatrics, Division of Oncology, New York University School of Medicine, NY, USA
| | - David H Harter
- Department of Neurosurgery, Division of Oncology, New York University School of Medicine, NY, USA
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VanderVeen N, Paran C, Appelhans A, Krasinkiewicz J, Lemons R, Appelman H, Doherty R, Palmer D, Ng P, Lowenstein PR, Castro MG. Marmosets as a preclinical model for testing "off-label" use of doxycycline to turn on Flt3L expression from high-capacity adenovirus vectors. Mol Ther Methods Clin Dev 2014; 1:10. [PMID: 25068145 PMCID: PMC4111110 DOI: 10.1038/mtm.2013.10] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 11/24/2013] [Indexed: 12/17/2022]
Abstract
We developed a combined conditional cytotoxic, i.e., herpes simplex type 1-thymidine kinase (TK), plus immune-stimulatory, i.e., fms-like tyrosine kinase ligand-3-mediated gene therapy for glioblastoma multiforme (GBM). Therapeutic transgenes were encoded within high-capacity adenoviral vectors (HC-Ad); TK was expressed constitutively, while Flt3L was under the control of the TetOn regulatable promoter. We previously assessed efficacy and safety in intracranial GBM rodent models. But, since this approach involves expression of a cytokine within the brain, we chose the nonhuman primate, i.e., Callithrix jaccus (marmoset) as it has been established that its immune response shares similarities with man. We characterized the safety, cell-type specific expression, and doxycycline (DOX)-inducibility of HC-Ad-TetOn-Flt3L delivered within the striatum. We used allometrically scaled DOX doses delivered orally, twice daily for one month, mimicking the route and duration of DOX administration planned for the GBM trial. Flt3L was effectively expressed within astrocytes, microglia, oligodendrocytes, and neurons. No evidence of brain or systemic toxicities due to the treatment was encountered. Our data indicate that DOX doses equivalent to those used in humans to treat infections can be safely used "off-label" to turn "on" therapeutic gene expression from HC-Ad-TetOn-Flt3L; providing evidence for the safety of this approach in the clinic.
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Affiliation(s)
- Nathan VanderVeen
- Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
- Department of Cell and Developmental Biology, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
| | - Christopher Paran
- Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
- Department of Cell and Developmental Biology, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
| | - Ashley Appelhans
- Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
- Department of Cell and Developmental Biology, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
| | - Johnny Krasinkiewicz
- Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
- Department of Cell and Developmental Biology, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
| | - Rosemary Lemons
- Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
- Department of Cell and Developmental Biology, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
| | - Henry Appelman
- Department of Pathology, The University of Michigan School of Medicine, University Hospital, Ann Arbor, Michigan, USA
| | - Robert Doherty
- Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
- Department of Cell and Developmental Biology, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
| | - Donna Palmer
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Philip Ng
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Pedro R Lowenstein
- Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
- Department of Cell and Developmental Biology, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
| | - Maria G Castro
- Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
- Department of Cell and Developmental Biology, The University of Michigan School of Medicine, Ann Arbor, Michigan, USA
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Affiliation(s)
- Thierry VandenDriessche
- Department of Gene Therapy and Regenerative Medicine, Free University of Brussels, B-1090 Brussels, Belgium.
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Westphal M, Ylä-Herttuala S, Martin J, Warnke P, Menei P, Eckland D, Kinley J, Kay R, Ram Z. Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14:823-33. [PMID: 23850491 DOI: 10.1016/s1470-2045(13)70274-2] [Citation(s) in RCA: 173] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Besides the use of temozolomide and radiotherapy for patients with favourable methylation status, little progress has been made in the treatment of adult glioblastoma. Local control of the disease by complete removal increases time to progression and survival. We assessed the efficacy and safety of a locally applied adenovirus-mediated gene therapy with a prodrug converting enzyme (herpes-simplex-virus thymidine kinase; sitimagene ceradenovec) followed by intravenous ganciclovir in patients with newly diagnosed resectable glioblastoma. METHODS For this international, open-label, randomised, parallel group multicentre phase 3 clinical trial, we recruited patients from 38 sites in Europe. Patients were eligible if they were aged 18-70 years, had newly diagnosed supratentorial glioblastoma multiforme amenable to complete resection, and had a Karnofsky score of 70 or more at screening. We used a computer-generated randomisation sequence to allocate patients in a one-to-one ratio (with block sizes of four) to receive either surgical resection of the tumour and intraoperative perilesional injection of sitimagene ceradenovec (1 × 10(12) viral particles) followed by ganciclovir (postoperatively, 5 mg/kg intravenously twice a day) in addition to standard care or resection and standard care alone. Temozolomide, not being standard in all participating countries at the time of the study, was allowed at the discretion of the treating physician. The primary endpoint was a composite of time to death or re-intervention, adjusted for temozolamide use, assessed by intention-to-treat (ITT) analysis. This trial is registered with EudraCT, number 2004-000464-28. FINDINGS Between Nov 3, 2005, and April 16, 2007, 250 patients were recruited and randomly allocated: 124 to the experimental group and 126 to the standard care group, of whom 119 and 117 patients, respectively, were included in the ITT analyses. Median time to death or re-intervention was longer in the experimental group (308 days, 95% CI 283-373) than in the control group (268 days, 210-313; hazard ratio [HR] 1·53, 95% CI 1·13-2·07; p=0·006). In a subgroup of patients with non-methylated MGMT, the HR was 1·72 (95% CI 1·15-2·56; p=0·008). However, there was no difference between groups in terms of overall survival (median 497 days, 95% CI 369-574 for the experimental group vs 452 days, 95% CI 437-558 for the control group; HR 1·18, 95% CI 0·86-1·61, p=0·31). More patients in the experimental group had one or more treatment-related adverse events those in the control group (88 [71%] vs 51 [43%]). The most common grade 3-4 adverse events were hemiparesis (eight in the experimental group vs three in the control group) and aphasia (six vs two). INTERPRETATION Our findings suggest that use of sitimagene ceradenovec and ganciclovir after resection can increase time to death or re-intervention in patients with newly diagnosed supratentorial glioblastoma multiforme, although the intervention did not improve overall survival. Locally delivered gene therapy for glioblastoma should be further developed, especially for patients who are unlikely to respond to standard chemotherapy. FUNDING Ark Therapeutics Ltd.
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Gene therapy with HSV1-sr39TK/GCV exhibits a stronger therapeutic efficacy than HSV1-TK/GCV in rat C6 glioma cells. ScientificWorldJournal 2013; 2013:951343. [PMID: 23533367 PMCID: PMC3603674 DOI: 10.1155/2013/951343] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Accepted: 01/29/2013] [Indexed: 11/18/2022] Open
Abstract
Although the combination of herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) with ganciclovir (GCV) has been shown as a promising suicide gene treatment strategy for glioma, the almost immunodepressive dose of GCV required for its adequate in vivo efficacy has hampered its further clinical application. Therefore, In order to reduce the GCV dose required, we aim to compare the therapeutic efficacy of HSV1-sr39TK, an HSV1-TK mutant with increased GCV prodrug catalytic activity, with wildtype TK in C6 glioma cells. Accordingly, rat C6 glioma cells were first transfected with pCDNA-TK and pCDNA-sr39TK, respectively, and the gene transfection efficacy was verified by immunocytochemistry and western blot analysis. Then the in vivo sensitivity of these transfected C6-TK and C6-sr39TK cells to GCV was determined by 3-(4,5)-dimethylthiahiazo-(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) colorimetric assay and Hoechst-propidium iodide (PI) staining. Finally, a subcutaneously C6 xenograft tumor model was established in the nude mice to test the in vitro efficacy of TK/GCV gene therapy. Our results showed that, as compared with wildtype TK, HSV1-sr39TK/GCV demonstrated a stronger therapeutic efficacy against C6 glioma both in vitro and in vivo, which, by reducing the required GCV dose, might warrant its future use in the treatment of glioma under clinical setting.
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Zarogoulidis P, Darwiche K, Sakkas A, Yarmus L, Huang H, Li Q, Freitag L, Zarogoulidis K, Malecki M. Suicide Gene Therapy for Cancer - Current Strategies. ACTA ACUST UNITED AC 2013; 4. [PMID: 24294541 DOI: 10.4172/2157-7412.1000139] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Current cancer treatments may create profound iatrogenic outcomes. The adverse effects of these treatments still remain, as the serious problems that practicing physicians have to cope with in clinical practice. Although, non-specific cytotoxic agents constitute an effective treatment modality against cancer cells, they also tend to kill normal, quickly dividing cells. On the other hand, therapies targeting the genome of the tumors are both under investigation, and some others are already streamlined to clinical practice. Several approaches have been investigated in order to find a treatment targeting the cancer cells, while not affecting the normal cells. Suicide gene therapy is a therapeutic strategy, in which cell suicide inducing transgenes are introduced into cancer cells. The two major suicide gene therapeutic strategies currently pursued are: cytosine deaminase/5-fluorocytosine and the herpes simplex virus/ganciclovir. The novel strategies include silencing gene expression, expression of intracellular antibodies blocking cells' vital pathways, and transgenic expression of caspases and DNases. We analyze various elements of cancer cells' suicide inducing strategies including: targets, vectors, and mechanisms. These strategies have been extensively investigated in various types of cancers, while exploring multiple delivery routes including viruses, non-viral vectors, liposomes, nanoparticles, and stem cells. We discuss various stages of streamlining of the suicide gene therapy into clinical oncology as applied to different types of cancer. Moreover, suicide gene therapy is in the center of attention as a strategy preventing cancer from developing in patients participating in the clinical trials of regenerative medicine. In oncology, these clinical trials are aimed at regenerating, with the aid of stem cells, of the patients' organs damaged by pathologic and/or iatrogenic factors. However, the stem cells carry the risk of neoplasmic transformation. We discuss cell suicide inducing strategies aimed at preventing stem cell-originated cancerogenesis.
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Affiliation(s)
- Paul Zarogoulidis
- Pulmonary Department-Oncology Unit, "G. Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece, EU ; Department of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital, University Duisburg-Essen, Essen, Germany, EU
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13
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Suicide gene therapy in cancer: where do we stand now? Cancer Lett 2012; 324:160-70. [PMID: 22634584 DOI: 10.1016/j.canlet.2012.05.023] [Citation(s) in RCA: 153] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Revised: 04/11/2012] [Accepted: 05/21/2012] [Indexed: 12/21/2022]
Abstract
Suicide gene therapy is based on the introduction into tumor cells of a viral or a bacterial gene, which allows the conversion of a non-toxic compound into a lethal drug. Although suicide gene therapy has been successfully used in a large number of in vitro and in vivo studies, its application to cancer patients has not reached the desirable clinical significance. However, recent reports on pre-clinical cancer models demonstrate the huge potential of this strategy when used in combination with new therapeutic approaches. In this review, we summarize the different suicide gene systems and gene delivery vectors addressed to cancer, with particular emphasis on recently developed systems and associated bystander effects. In addition, we review the different strategies that have been used in combination with suicide gene therapy and provide some insights into the future directions of this approach, particularly towards cancer stem cell eradication.
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14
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Hunt MA, Li D, Hay MP, Currie MJ, Robinson BA, Patterson AV, Dachs GU. Characterisation of enzyme prodrug gene therapy combinations in coated spheroids and vascular networks in vitro. J Gene Med 2012; 14:62-74. [DOI: 10.1002/jgm.1635] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Michelle A. Hunt
- Angiogenesis and Cancer Research Group, Department of Pathology; University of Otago; Christchurch; New Zealand
| | - Dan Li
- Auckland Cancer Society Research Centre; University of Auckland; Auckland; New Zealand
| | - Michael P. Hay
- Auckland Cancer Society Research Centre; University of Auckland; Auckland; New Zealand
| | - Margaret J. Currie
- Angiogenesis and Cancer Research Group, Department of Pathology; University of Otago; Christchurch; New Zealand
| | - Bridget A. Robinson
- Angiogenesis and Cancer Research Group, Department of Pathology; University of Otago; Christchurch; New Zealand
| | - Adam V. Patterson
- Auckland Cancer Society Research Centre; University of Auckland; Auckland; New Zealand
| | - Gabi U. Dachs
- Angiogenesis and Cancer Research Group, Department of Pathology; University of Otago; Christchurch; New Zealand
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15
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Duarte S, Faneca H, Lima MCPD. Folate-associated lipoplexes mediate efficient gene delivery and potent antitumoral activity in vitro and in vivo. Int J Pharm 2011; 423:365-77. [PMID: 22209825 DOI: 10.1016/j.ijpharm.2011.12.035] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Revised: 12/14/2011] [Accepted: 12/21/2011] [Indexed: 12/20/2022]
Abstract
The lack of suitable vectors for efficient nucleic acid delivery into target cells represents a major hurdle for the successful application of gene therapy. Cationic liposomes exhibit attractive features for gene delivery, but their efficacy is still unsatisfactory, particularly for in vivo applications, which justifies the drive to further improve their performance by developing novel and efficient formulations. In the present study, we generated a new formulation of lipoplexes through electrostatic association of folate (FA) to 1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine (EPOPC):cholesterol (Chol) liposomes, prepared at different lipid/DNA charge ratios, and explored their potential to mediate gene delivery. The optimal FA-lipoplex formulation was evaluated for its efficacy to mediate antitumoral activity upon application of HSV-tk suicide gene therapy, both in vitro and in an animal model of oral cancer. Our results demonstrate that FA-EPOPC:Chol/DNA lipoplexes were able to promote a great enhancement of transfection and high in vitro antitumoral activity compared to plain lipoplexes in two different cancer cell lines. Most importantly, a considerable reduction of tumor growth was achieved with the developed FA-lipoplexes as compared to that observed for control FA-lipoplexes or plain lipoplexes. Overall, our study shows that FA-EPOPC:Chol/DNA lipoplexes constitute a promising system for the successful application of suicide gene therapy aiming at treating solid tumors.
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Affiliation(s)
- Sónia Duarte
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
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16
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Ma S, Zhao L, Zhu Z, Liu Q, Xu H, Johansson M, Karlsson A, Zheng X. The multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster as a therapeutic suicide gene of breast cancer cells. J Gene Med 2011; 13:305-11. [PMID: 21674733 DOI: 10.1002/jgm.1573] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK) was investigated for its broader substrate specificity and higher catalytic rate as a suicide gene in a combined gene/chemotherapy of cancer. METHODS To evaluate the effects of nucleoside analog phosphorylation by Dm-dNK in vitro and in vivo, we generated a replication-deficient retroviral vector expressing Dm-dNK to transduce human breast cancer cells MCF7 (ER+) and MDA-MB-231 (ER-). We further determined the enzymatic activity and the sensitivity of the nontransduced and Dm-dNK-transduced 231/dNK and MCF7/dNK cells to the pyrimidine nucleoside analogs araC and araT. RESULTS The data obtained show that Dm-dNK is enzymatically active and its overexpression in the nuclei of breast cancer cells results in an increased sensitivity to the nucleoside analogs araC and araT in vitro. Furthermore, subcutaneously transplanted 231/dNK cells were significantly inhibited after araC treatment, whereas nontransduced cancer cells continued to grow and develop in vivo. CONCLUSIONS These results suggest that the Dm-dNK/nucleoside analog system could be a novel therapeutic strategy for treating breast cancer and improving anti-tumor efficacy, as well as for optimizing approaches for suicide gene therapy.
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Affiliation(s)
- Shuai Ma
- Department of Surgical Oncology, Department of General Surgery, First Affiliated Hospital, China Medical University, Shenyang
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17
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Castro MG, Candolfi M, Kroeger K, King GD, Curtin JF, Yagiz K, Mineharu Y, Assi H, Wibowo M, Ghulam Muhammad AKM, Foulad D, Puntel M, Lowenstein PR. Gene therapy and targeted toxins for glioma. Curr Gene Ther 2011; 11:155-80. [PMID: 21453286 DOI: 10.2174/156652311795684722] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2011] [Accepted: 03/08/2011] [Indexed: 12/12/2022]
Abstract
The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of 15-18 months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors.
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Affiliation(s)
- Maria G Castro
- Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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18
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Niculescu-Duvaz D, Negoita-Giras G, Niculescu-Duvaz I, Hedley D, Springer CJ. Directed Enzyme Prodrug Therapies. PRODRUGS AND TARGETED DELIVERY 2011. [DOI: 10.1002/9783527633166.ch12] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
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19
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Germano IM, Binello E. Gene therapy as an adjuvant treatment for malignant gliomas: from bench to bedside. J Neurooncol 2009; 93:79-87. [PMID: 19430884 PMCID: PMC11766529 DOI: 10.1007/s11060-009-9869-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2008] [Accepted: 03/16/2009] [Indexed: 01/02/2023]
Abstract
Malignant brain tumors, including high-grade gliomas, are among the most lethal of all cancers. Despite considerable advances, including multi-modality treatments with surgery, radiotherapy, and chemotherapy, the overall prognosis for patients with this disease remains dismal. Currently available treatments necessitate the development of more effective tumor-selective therapies. The use of gene therapy for brain tumor therapy is promising as it can be delivered in situ and selectively targets brain tumor cells while sparing the adjacent normal brain tissue. In this article, we summarize the laboratory and clinical work using viral, cell-based, and synthetic vectors, as well as other strategies focused on potentiate gene delivery. Although tangible results on patients' survival remains to be further documented, significant advances in therapeutic gene transfer strategies have been made. The enthusiasm of this progress needs to be tempered by the realistic assessment of the challenges needed to be overcome. Finally, as the field of gene delivery progresses, advances must be made in identifying genes and proteins key to the treatment of malignant gliomas. Due to the great heterogeneity of malignant glioma cells, only approaches combining different strategies may be ultimately successful in defeating this disease.
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Affiliation(s)
- Isabelle M Germano
- Department of Neurosurgery, Mt. Sinai School of Medicine, New York, NY 10029, USA.
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20
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Solaroli N, Johansson M, Persoons L, Balzarini J, Karlsson A. Substrate specificity of feline and canine herpesvirus thymidine kinase. Antiviral Res 2008; 79:128-32. [DOI: 10.1016/j.antiviral.2008.03.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2007] [Revised: 02/13/2008] [Accepted: 03/13/2008] [Indexed: 11/30/2022]
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21
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The positive predictive value of O-(2-[18F]fluoroethyl)-l-tyrosine (FET) PET in the diagnosis of a glioma recurrence after multimodal treatment. J Neurooncol 2008; 88:27-35. [DOI: 10.1007/s11060-008-9526-4] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2007] [Accepted: 01/03/2008] [Indexed: 11/25/2022]
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22
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Faneca H, Faustino A, Pedroso de Lima MC. Synergistic antitumoral effect of vinblastine and HSV-Tk/GCV gene therapy mediated by albumin-associated cationic liposomes. J Control Release 2007; 126:175-84. [PMID: 18201792 DOI: 10.1016/j.jconrel.2007.12.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2007] [Revised: 11/30/2007] [Accepted: 12/03/2007] [Indexed: 10/22/2022]
Abstract
Despite recent advances in conventional therapeutic approaches for cancer, the frequently observed acquired drug resistance and toxic side effects have limited their clinical application. The main goal of this work was to investigate the combined antitumoral effect of vinblastine with HSV-Tk/GCV "suicide" gene therapy mediated by human serum albumin (HSA)-associated lipoplexes, in mammary adenocarcinoma cells (TSA cells). Our results show that, among the different lipoplex formulations tested, HSA-associated complexes prepared from EPOPC:Chol liposomes, at the (4/1) (+/-) charge ratio, was the most efficient to mediate gene delivery, even in the presence of serum. The simultaneous addition of vinblastine and HSA-EPOPC:Chol/DNA (+/-) (4/1) lipoplexes to TSA cells improved transgene expression more than 10 times. When combined with the HSV-Tk/GCV "suicide" gene therapy mediated by HSA-EPOPC:Chol/DNA (+/-) (4/1) lipoplexes, vinblastine induced a great enhancement in the antitumoral activity in TSA cells. Most importantly, this combined strategy resulted in a significant synergistic effect, thus allowing the use of a much lower dose of the drug to achieve the same therapeutic effect. Overall, our results indicate that this approach has the potential to overcome some major limitations of conventional chemotherapy, and may therefore constitute a promising strategy for future applications in antitumoral therapy.
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Affiliation(s)
- H Faneca
- Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal
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23
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Hedley D, Ogilvie L, Springer C. Carboxypeptidase-G2-based gene-directed enzyme-prodrug therapy: a new weapon in the GDEPT armoury. Nat Rev Cancer 2007; 7:870-9. [PMID: 17943135 DOI: 10.1038/nrc2247] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Gene-directed enzyme-prodrug therapy (GDEPT) aims to improve the therapeutic ratio (benefit versus toxic side-effects) of cancer chemotherapy. A gene encoding a 'suicide' enzyme is introduced into the tumour to convert a subsequently administered non-toxic prodrug into an active drug selectively in the tumour, but not in normal tissues. Significant effects can now be achieved in vitro and in targeted experimental models, and GDEPT therapies are entering the clinic. Our group has developed a GDEPT system that uses the bacterial enzyme carboxypeptidase G2 to convert nitrogen mustard prodrugs into potent DNA crosslinking agents, and a clinical trial of this system is pending.
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Affiliation(s)
- Douglas Hedley
- Institute of Cancer Research Haddow Laboratories, 15, Cotswold Road, Sutton, Surrey, UK
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24
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Portsmouth D, Hlavaty J, Renner M. Suicide genes for cancer therapy. Mol Aspects Med 2007; 28:4-41. [PMID: 17306358 DOI: 10.1016/j.mam.2006.12.001] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2006] [Accepted: 12/18/2006] [Indexed: 12/31/2022]
Abstract
The principle of using suicide genes for gene directed enzyme prodrug therapy (GDEPT) of cancer has gained increasing significance during the 20 years since its inception. The astute application of suitable GDEPT systems should permit tumour ablation in the absence of off-target toxicity commonly associated with classical chemotherapy, a hypothesis which is supported by encouraging results in a multitude of pre-clinical animal models. This review provides a clear explanation of the rationale behind the GDEPT principle, outlining the advantages and limitations of different GDEPT strategies with respect to the roles of the bystander effect, the immune system and the selectivity of the activated prodrug in contributing to their therapeutic efficacy. An in-depth analysis of the most widely used suicide gene/prodrug combinations is presented, including details of the latest advances in enzyme and prodrug optimisation and results from the most recent clinical trials.
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Affiliation(s)
- Daniel Portsmouth
- Research Institute for Virology and Biomedicine, University of Veterinary Medicine, Vienna, Austria
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25
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Faneca H, Cabrita AS, Simões S, Pedroso de Lima MC. Evaluation of the antitumoral effect mediated by IL-12 and HSV-tk genes when delivered by a novel lipid-based system. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2007; 1768:1093-102. [PMID: 17296164 DOI: 10.1016/j.bbamem.2006.12.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2006] [Revised: 11/30/2006] [Accepted: 12/05/2006] [Indexed: 11/28/2022]
Abstract
In the present work, we used a novel albumin-associated lipoplex formulation, containing the cationic lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine (EPOPC) and cholesterol (Chol), to evaluate the antitumoral efficacy of two gene therapy strategies: immuno-gene therapy, mediated by IL-12 gene expression, and "suicide" gene therapy, mediated by HSV-tk gene expression followed by ganciclovir (GCV) treatment. Our data show that, in an animal model bearing a subcutaneous TSA (mouse mammary adenocarcinoma) tumor, intratumoral administration of the albumin-associated complexes containing the plasmid encoding IL-12 results in a strong antitumoral effect, as demonstrated by the smaller tumor size, the higher T-lymphocyte tumor infiltration and the more extensive tumor necrotic and hemorrhagic areas, as compared to that observed in animals treated with control complexes. On the other hand, the application of the "suicide" gene therapy strategy results in a significant antitumoral activity, which is similar to that achieved with the immuno-gene therapy strategy, although involving different antineoplastic mechanisms. For the tested model, albumin-associated complexes were shown to efficiently mediate intratumoral delivery of therapeutic genes, thus leading to a significant antitumoral effect. This finding is particularly relevant since TSA tumors are characterized for being poorly immunogenic, aggressive and exhibiting high proliferation capacity.
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Affiliation(s)
- H Faneca
- Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal
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26
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Barzon L, Zanusso M, Colombo F, Palù G. Clinical trials of gene therapy, virotherapy, and immunotherapy for malignant gliomas. Cancer Gene Ther 2006; 13:539-54. [PMID: 16410822 DOI: 10.1038/sj.cgt.7700930] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Despite advances in surgical and adjuvant therapy, the prognosis for malignant gliomas remains dismal. This gloomy scenario has been recently brightened by the increasing understanding of the genetic and biological mechanisms at the basis of brain tumor development. These findings are being translated into innovative therapeutic approaches, including gene therapy, virotherapy, and vaccination, some of which have already been experimented in clinical trials. The advantages and disadvantages of all these different therapeutic modalities for malignant gliomas will be critically discussed, providing perspective for future investigations.
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Affiliation(s)
- L Barzon
- Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Padova, and Division of Neurosurgery, San Bortolo Hospital, Vicenza, Italy.
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27
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King GD, Curtin JF, Candolfi M, Kroeger K, Lowenstein PR, Castro MG. Gene therapy and targeted toxins for glioma. Curr Gene Ther 2006; 5:535-57. [PMID: 16457645 PMCID: PMC1629033 DOI: 10.2174/156652305774964631] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted, this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors.
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Affiliation(s)
- Gwendalyn D King
- Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
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28
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Gentry BG, Im M, Boucher PD, Ruch RJ, Shewach DS. GCV phosphates are transferred between HeLa cells despite lack of bystander cytotoxicity. Gene Ther 2005; 12:1033-41. [PMID: 15789060 DOI: 10.1038/sj.gt.3302487] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The role of gap junctional intercellular communication (GJIC) in bystander killing with herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) was evaluated in U251 cells expressing a dominant-negative connexin 43 cDNA (DN14), and in HeLa cells, reportedly devoid of connexin protein. These cell lines both exhibited 0% GJIC when assayed by Lucifer Yellow fluorescent dye microinjection. Bystander cytotoxicity was still apparent in 50:50 cocultures of DN14 and HSV-TK-expressing U251 cells, but not in 50:50 cocultures of HeLa cells. However, the sensitivity of HeLa HSV-TK-expressing cells to GCV decreased nearly 100-fold (IC90=109 microM) when cocultured with bystander cells compared to results in 100% cultures of HSV-TK-expressing cells (IC90=1.2 microM). A more sensitive flow cytometry technique to measure GJIC over 24 h revealed that the DN14 and HeLa cells exhibited detectable levels of communication (29 and 23%, respectively). Transfer of phosphorylated GCV to HeLa bystander cells occurred within 4 h after drug addition, and GCV triphosphate (GCVTP) accumulated to 213+/-84 pmol/10(6) cells after 24 h. In addition, GCVTP levels were decreased in HSV-TK-expressing cells in coculture (867+/-33 pmol/10(6) cells) compared to 100% cultures of HSV-TK-expressing cells (1773+/-188 pmol/10(6) cells). The half-life of GCVTP in the HSV-TK-expressing cells was approximately four times that measured in the bystander cells (12.3 and 3.1 h, respectively). These data suggest that the lack of bystander cytotoxicity in HeLa cocultures is due to low transfer of phosphorylated GCV and a rapid half-life of GCVTP in the bystander cells. Thus, GCV phosphate transfer to non-HSV-TK-expressing bystander cells may mediate either bystander cell killing or sparing of HSV-TK-positive cells, depending upon the cell specific drug metabolism.
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Affiliation(s)
- B G Gentry
- Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0504, USA
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29
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Rachinger W, Goetz C, Pöpperl G, Gildehaus FJ, Kreth FW, Holtmannspötter M, Herms J, Koch W, Tatsch K, Tonn JC. Positron Emission Tomography with O-(2-[18F]fluoroethyl)-l-tyrosine versus Magnetic Resonance Imaging in the Diagnosis of Recurrent Gliomas. Neurosurgery 2005; 57:505-11; discussion 505-11. [PMID: 16145529 DOI: 10.1227/01.neu.0000171642.49553.b0] [Citation(s) in RCA: 190] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
ABSTRACT
OBJECTIVE:
New treatment modalities are available for patients with glioma, which may lead to unspecific changes in posttherapeutic magnetic resonance imaging (MRI) findings. Differentiation between tumor- and therapy-associated contrast enhancement on MRI scans after treatment may be difficult. The aim of this study was to analyze the diagnostic value of O-(2-[18F]fluoroethyl)-l-tyrosine (FET)-positron emission tomography (PET) and MRI in the detection of tumor recurrence in patients with glioma after radiotherapy, radiosurgery, or multimodal treatment.
METHODS:
The study included 36 patients with gliomas and neuroradiological diagnosis of tumor recurrence and 9 patients who had undergone radioimmunotherapy. Patients were consecutively treated between September 2001 and May 2003. A contemporary FET-PET investigation was performed in all patients. A tissue diagnosis was made for comparative analysis in all patients with progressive neuroradiological or clinical findings (32 of 45 patients). In patients with transient neuroradiological or clinical deterioration (13 of 45 patients), clinical follow-up was used to support or contradict the imaging-based diagnosis.
RESULTS:
Tumor recurrence was documented in 31 of 45 patients, and 14 of 45 patients were tumor free. FET-PET and MRI revealed a correct diagnosis in 44 and 36 patients, respectively. The difference was statistically significant (P < 0.01). Concordant findings after MRI and FET-PET were documented in 37 patients and discordant findings in 8 patients. The difference was statistically significant (P < 0.01). Specificity of FET-PET was 92.9%, and sensitivity was 100% (in patients suspected of having recurrent tumor as revealed by MRI). Sensitivity of MRI was 93.5%, and specificity was 50% (P < 0.05).
CONCLUSION:
For patients with gliomas undergoing multimodal treatment or various forms of irradiation, conventional follow-up with MRI is insufficient to distinguish between benign side effects of therapy and tumor recurrence. FET-PET is a powerful tool to improve the differential diagnosis in these patients.
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Affiliation(s)
- Walter Rachinger
- Department of Neurosurgery, University of Munich, Munich, Germany.
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30
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Dachs GU, Tupper J, Tozer GM. From bench to bedside for gene-directed enzyme prodrug therapy of cancer. Anticancer Drugs 2005; 16:349-59. [PMID: 15746571 DOI: 10.1097/00001813-200504000-00001] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Gene therapy of cancer offers the possibility of a targeted treatment that destroys tumors and metastases, but not normal tissues. In gene-directed enzyme prodrug therapy (GDEPT), or suicide gene therapy, the gene encoding an enzyme is delivered to tumor cells, followed by administration of a prodrug, which is converted locally to a cytotoxin by the enzyme. The producer cells as well as surrounding bystanders are subsequently killed. Promising results have meant that suicide gene therapy has reached multicenter phase III clinical trials. This review will discuss the development, efficiency, mode of action and pharmacokinetics of seven GDEPT systems in vitro and in vivo. We will review the latest data of those systems in clinical trials (herpes simplex virus thymidine kinase/gancyclovir, bacterial cytosine deaminase/5-fluorocytosine, bacterial nitroreductase/CB1954 and cytochrome P450/cyclophosphamide), as well as the development of more recent and experimental systems which are not yet in clinical trials (P450 reductase/tirapazamine, carboxypeptidase/CMDA, horseradish peroxidase/indole-3-acetic acid or paracetamol and others).
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Affiliation(s)
- Gabi U Dachs
- Angiogenesis Research Group, Department of Pathology, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch, New Zealand.
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31
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Parney IF, Kunwar S, McDermott M, Berger M, Prados M, Cha S, Croteau D, Puri RK, Chang SM. Neuroradiographic changes following convection-enhanced delivery of the recombinant cytotoxin interleukin 13-PE38QQR for recurrent malignant glioma. J Neurosurg 2005; 102:267-75. [PMID: 15739554 DOI: 10.3171/jns.2005.102.2.0267] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECT Convection-enhanced delivery (CED) is a novel method for delivering therapeutic agents to infiltrative brain tumor cells. For agents administered by CED, changes on magnetic resonance (MR) imaging directly resulting from catheter placement, infusion, and the therapeutic compound may confound any interpretation of tumor progression. As part of an ongoing multiinstitutional Phase I study, 14 patients with recurrent malignant glioma underwent CED of interleukin (IL) 13-PE38QQR, a recombinant cytotoxin consisting of human IL-13 conjugated with a truncated Pseudomonas exotoxin. Serial neuroradiographic changes were assessed in this cohort of patients. METHODS Patients were treated in two groups: Group 1 patients received IL13-PE38QQR before and after tumor resection; Group 2 patients received infusion only after tumor resection. Preoperative and postinfusion MR images were obtained prospectively at specified regular intervals. Changes were noted along catheter tracks on postresection MR images obtained in all patients. A simple grading system was developed to describe these changes. When MR imaging changes appeared to be related to IL1 3-PE38QQR, patients were followed up without instituting new antitumor therapy. CONCLUSIONS As CED of therapeutic agents becomes more common, clinicians and investigators must become aware of associated neuroimaging changes that should be incorporated into toxicity assessment. We have developed a simple grading system to facilitate communication about these changes among investigators. Biological imaging modalities that could possibly distinguish these changes from recurrent tumor should be evaluated. In this study the authors demonstrate the challenges in determining efficacy when surrogate end points such as time to tumor progression as defined by new or progressive contrast enhancement on MR imaging are used with this treatment modality.
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Affiliation(s)
- Ian F Parney
- Department of Neurological Surgery, Brain Tumor Research Center, University of California at San Francisco, California 94143-0350, USA
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Yaghoubi SS, Barrio JR, Namavari M, Satyamurthy N, Phelps ME, Herschman HR, Gambhir SS. Imaging progress of herpes simplex virus type 1 thymidine kinase suicide gene therapy in living subjects with positron emission tomography. Cancer Gene Ther 2004; 12:329-39. [PMID: 15592447 DOI: 10.1038/sj.cgt.7700795] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Molecular imaging of a suicide transgene's expression will aid the development of efficient and precise targeting strategies, and imaging for cancer cell viability may assess therapeutic efficacy. We used the PET reporter probe, 9-(4-[18F]fluoro-3-(hydroxymethyl)butyl)guanine ([18F]FHBG) to monitor the expression of a mutant Herpes Simplex Virus 1 thymidine kinase (HSV1-sr39tk) in C6 glioma tumors implanted subcutaneously in nude mice that were repetitively being treated with the pro-drug Ganciclovir (GCV). [18F]-Fluorodeoxyglucose ([18F]FDG), a metabolic tracer, was used to assess tumor cell viability and therapeutic efficacy. C6 glioma tumors stably expressing the HSV1-sr39tk gene (C6sr39) accumulated [18F]FHBG prior to GCV treatment. Significant declines in C6sr39 tumor volumes and [18F]FHBG and [18F]FDG accumulation were observed following 2 weeks of GCV treatment. However, 3 weeks after halting GCV treatment, the tumors re-grew and [18F]FDG accumulation increased significantly; in contrast, tumor [18F]FHBG concentrations remained at background levels. Therefore, [18F]FHBG can be used to detect tumors expressing HSV1-sr39tk, susceptible to regression in response to GCV exposure, and the effectiveness of GCV therapy in eradicating HSV1-sr39tk-expressing cells can be monitored by [18F]FHBG scanning. [18F]FHBG and [18F]FDG imaging data indicate that exposure of C6sr39 tumors to GCV causes the elimination of [18F]FHBG-accumulating C6sr39 cells and selects for re-growth of tumors unable to accumulate [18F]FHBG.
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Affiliation(s)
- Shahriar S Yaghoubi
- Department of Molecular & Medical Pharmacology, UCLA School of Medicine, Los Angeles, California 90095-1770, USA
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Chiocca EA, Broaddus WC, Gillies GT, Visted T, Lamfers MLM. Neurosurgical delivery of chemotherapeutics, targeted toxins, genetic and viral therapies in neuro-oncology. J Neurooncol 2004; 69:101-17. [PMID: 15527083 DOI: 10.1023/b:neon.0000041874.02554.b3] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Local delivery of biologic agents, such as gene and viruses, has been tested preclinically with encouraging success, and in some instances clinical trials have also been performed. In addition, the positive pressure infusion of various therapeutic agents is undergoing human testing and approval has already been granted for routine clinical use of biodegradable implants that diffuse a chemotherapeutic agent into peritumoral regions. Safety in glioma patients has been shown, but anticancer efficacy needs additional refinements in the technologies employed. In this review, we will describe these modalities and provide a perspective on needed improvements that should render them more successful.
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Affiliation(s)
- E Antonio Chiocca
- Molecular Neuro-Oncology Laboratories, Neurosurgery Service, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
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Ammerpohl O, Thormeyer D, Khan Z, Appelskog IB, Gojkovic Z, Almqvist PM, Ekström TJ. HDACi phenylbutyrate increases bystander killing of HSV-tk transfected glioma cells. Biochem Biophys Res Commun 2004; 324:8-14. [PMID: 15464975 DOI: 10.1016/j.bbrc.2004.09.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2004] [Indexed: 10/26/2022]
Abstract
Malignant glioma patients have a dismal prognosis with an urgent need of new treatment modalities. Previously developed gene therapies for brain tumors showed promising results in experimental animal models, but failed in clinical trials due to low transfection rates and insufficient expression of the transgene in tumor cells, as well as low bystander killing effects. We have previously shown that the histone deacetylase inhibitor 4-phenylbutyrate (4-PB) enhances gap junction communication between glioma cells in culture. In this study, we demonstrate an activation of recombinant HSV-tk gene expression, and a dramatic enhancement of gap junction-mediated bystander killing effect by administration of the HSV-tk prodrug ganciclovir together with 4-PB. These findings that 4-PB potentiates "suicide gene" expression as well as enhances gap junctional communication and bystander killing of tumor cells justify further testing of this paradigm as an adjunct to suicide gene therapy of malignant gliomas.
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Affiliation(s)
- Ole Ammerpohl
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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Zhang JH, Wan MX, Yuan JY, Pan BR. Construction and identification of recombinant vectors carrying herpes simplex virus thymidine kinase and cytokine genes expressed in gastric carcinoma cell line SGC7901. World J Gastroenterol 2004; 10:26-30. [PMID: 14695763 PMCID: PMC4717072 DOI: 10.3748/wjg.v10.i1.26] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To construct and identify the recombinant vectors carrying herpes simplex virus thymidine kinase (HSV-TK) and tumor necrosis factor alpha (TNF-α) or interleukin-2 (IL-2) genes expressed in gastric carcinoma cell line SGC7901.
METHODS: The fragments of HSV-TK, internal ribosome entry sites (IRES) and TNF-α or IL-2 genes were inserted in a TK-IRES-TNF-α or TK-IRES-IL-2 order into pEGFP-N3 and pLXSN to generate the therapeutic vectors pEGFP-TT, pEGFP-TI, pL(TT)SN and pL(TI)SN respectively, which were structurally confirmed by the digestion analysis of restriction endonuclease. The former two plasmids were used for the transient expression of recombinant proteins in the target cells while pL(TT)SN and pL(TI)SN were transfected into SGC7901 cells by lipofectamine for the stable expression of objective genes through G418 selection. The protein products expressed transiently and stably in SGC7901 cells by the constructed vectors were confirmed by fluorescent microscopy and Western blot respectively.
RESULTS: The inserted fragments in all constructed plasmids were structurally confirmed to be consistent with that of the published data. In the transient expression, both pEGFP-TT and pEGFP-TI were shown expressed in nearly 50% of the transfected SGC7901 cells. Similarly, the G418 selected vectors PL(TT)SN and PL(TI)SN were confirmed to be successful in the stable expression of the objective proteins in the target cells.
CONCLUSION: The constructed recombinant vectors in the present study that can express the suicide gene TK in combination with cytokines genes may serve as the potential tools to perform more effective investigations in future for the gene therapy of gastric carcinoma.
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Affiliation(s)
- Jian-Hua Zhang
- Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, 28 West Xianning Road, Xi'an 710049, Shaanxi Province, China
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Zhang JH, Wan MX, Yuan JY, Pan BR. Do there exist synergistic antitumor effects by coexpression of herpes simplex virus thymidine kinase with cytokine genes on human gastric cancer cell line SGC7901? World J Gastroenterol 2004; 10:147-51. [PMID: 14695787 PMCID: PMC4717068 DOI: 10.3748/wjg.v10.i1.147] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To evaluate the synergistic antitumor effects of herpes simplex virus thymidine kinase (HSV-TK) together with tumor necrosis factor alpha (TNF-α) or interleukin-2 (IL-2) gene expression on gastric cancer cell line SGC7901.
METHODS: Recombinant vectors pL(TT)SN and pL(TI)SN, which express TK-IRES-TNF-α and TK-IRES-IL-2 genes separately, as well as the control plasmids pL(TK)SN and pLXSN were employed to transfect PA317 cells respectively to generate the viruses that can stably express the objective genes through G418 selection. The gastric cancer cells were then transfected by the retroviral serum from the package cells and maintained in culture to determine the cell growth and apoptosis. The cytotoxic effects of HSV-TK together with TNF-α or IL-2 gene expression on the transfected cancer cells were evaluated by the cell viability and bystander effects in the presence of GCV supplemented in the cultural medium.
RESULTS: Expression of recombinant proteins including TNF-α and IL-2 by stable transfectants was confirmed by Western blotting. The percentage of cell apoptosis in the SGC/0, SGC/TK-TNF-α, SGC/TK-IL-2 and SGC/TK clone was 2.3%, 12.3%, 11.1% and 10.9% respectively at 24 h post-transfection. Cell growth status among all the experimental groups as judged by cell absorbance (A) at 570nm did not exhibit any significant difference (P > 0.05); although it was noted to be slightly lower in the SGC/TT group. Cell survival rate in SGC/TI, SGC/TT and SGC/TK group was significantly decreased in a dose-dependent manner of GCV compared with that of the SGC/0 group (P < 0.05-0.01). Among all studied cells, the SGC/TT was shown most sensitive to GCV with a half lethal dose of 0.5 mg·L-1. In contrast, the survival rate of SGC/0 cells was not affected by the presence of GCV with the doses less than 10 mg·L-1. The half lethal dose of GCV for SGC/0 cells was more than 100 mg·L-1. Marked bystander effect induced by SGC/TI, SGC/TT and SGC/TK cells was confirmed by the fact that 20% of these stable transfectants could kill 50% of the co-cultured cells, in which the most prominent bystander effect was found in the circumstance of SGC/TT presence. However, no significant difference of these variables was found among SGC/TI, SGC/TT and SGC/TK cells (P > 0.05).
CONCLUSION: The synergistic antitumor effects produced by the co-expression of HSV-TK with TNF-α or IL-2 genes were not present in the transfected SGC7901 cells. The mechanism underlying these phenomena was not known.
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Affiliation(s)
- Jian-Hua Zhang
- Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, 28 West Xianning Road, Xi'an 710049, Shaanxi Province, China.
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Abstract
Gastric cancer is common in China, and its early diagnosis and treatment are difficult. In recent years great progress has been achieved in gene therapy, and a wide array of gene therapy systems for gastric cancer has been investigated. The present article deals with the general principles of gene therapy and then focuses on how these principles may be applied to gastric cancer.
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Affiliation(s)
- Chao Zhang
- Department of General Surgery, Southwest Hospital, Third Military Medical University, Gaotan Yan, Chongqing 400038, China.
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Kanzawa T, Ito H, Kondo Y, Kondo S. Current and Future Gene Therapy for Malignant Gliomas. J Biomed Biotechnol 2003; 2003:25-34. [PMID: 12686720 PMCID: PMC179758 DOI: 10.1155/s1110724303209013] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Malignant gliomas are the most common neoplasm in the central nervous system. When treated with conventional treatments including surgery, irradiation, and chemotherapy, the average life expectancy of the most malignant type, glioblastoma multiforme is usually less than 1 year. Therefore, gene therapy is expected to be an effective and possibly curative treatment. Many gene therapeutic approaches have demonstrated efficacy in experimental animal models. However, the current clinical trials are disappointing. This review focuses on current therapeutic genes/vectors/delivery systems/targeting strategies in order to introduce updated trends and hopefully indicate prospective gene therapy for malignant gliomas.
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Affiliation(s)
- Takao Kanzawa
- Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY 10029, USA
- Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Hideaki Ito
- Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY 10029, USA
- Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Yasuko Kondo
- Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY 10029, USA
- Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Seiji Kondo
- Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY 10029, USA
- Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
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Abstract
Malignant glioma formation is associated with characteristic genetic alterations, although epigenetic mechanisms may contribute in tumorigenesis. Until recently, our knowledge has mainly been based on chromosomal and molecular studies performed in the last two decades. This has increased tremendously with the advent of new technologies, in particular expression arrays for simultaneous analysis of thousands of genes. Consequently, gene therapy of gliomas may aim at molecular interference with 'gain of function' genes (oncogenes) or replacement of 'loss of function' genes (tumor suppressor genes). Such approaches require transgene expression in whole tumor cell populations (if not other mechanisms come into play) which cannot be achieved with current vector systems. Hence other strategies have been pursued which may be independent of genes actually involved in tumorigenesis. Microbial genes (e.g. herpes simplex virus thymidine kinase) may be transferred into the tumors allowing for prodrug activation (e.g. ganciclovir). Furthermore, cytokines or other immunomodulatory genes may be used for vaccination purposes which frequently involves ex vivo transfection of autologous tumor cells with such genes. These approaches proved promising in preclinical studies performed in cell culture and different inbred rodent models. A considerable number of clinical trials have been initiated based on these approaches. Although most therapeutic strategies proved safe, clinical responses fell short of expectations raised by preclinical results. This, to a large extent, has to be attributed to a lag in the development of efficient vector systems. Although much effort has been put into this area of research, neuro-oncologists are still in await of a vector system allowing for selective and efficient tumor cell transduction. This has led to increased interest in distinct but related strategies, e.g. oncolytic viruses or direct intra-tumoral delivery of anti-sense oligonucleotides.
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Affiliation(s)
- W Hamel
- Klinik für Neurochirurgie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
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Abstract
Despite advances in surgery, radiotherapy, and chemotherapy, the survival of patients with oral squamous cell carcinoma has not significantly improved over the past several decades. Treatment options for recurrent or refractory oral cancers are limited. Gene therapy for oral cancer is currently under investigation in clinical trials. The goal of cancer gene therapy is to introduce new genetic material into target cells without toxicity to non-target tissues. This review discusses the techniques used in cancer gene therapy for oral squamous cell carcinoma and summarizes the ongoing strategies that are being evaluated in clinical trials.
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Affiliation(s)
- S Xi
- Department of Otolaryngology, University of Pittsburgh School of Medicine, PA, USA
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