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1
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Kumar A, Das SK, Emdad L, Fisher PB. Applications of tissue-specific and cancer-selective gene promoters for cancer diagnosis and therapy. Adv Cancer Res 2023; 160:253-315. [PMID: 37704290 DOI: 10.1016/bs.acr.2023.03.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023]
Abstract
Current treatment of solid tumors with standard of care chemotherapies, radiation therapy and/or immunotherapies are often limited by severe adverse toxic effects, resulting in a narrow therapeutic index. Cancer gene therapy represents a targeted approach that in principle could significantly reduce undesirable side effects in normal tissues while significantly inhibiting tumor growth and progression. To be effective, this strategy requires a clear understanding of the molecular biology of cancer development and evolution and developing biological vectors that can serve as vehicles to target cancer cells. The advent and fine tuning of omics technologies that permit the collective and spatial recognition of genes (genomics), mRNAs (transcriptomics), proteins (proteomics), metabolites (metabolomics), epiomics (epigenomics, epitranscriptomics, and epiproteomics), and their interactomics in defined complex biological samples provide a roadmap for identifying crucial targets of relevance to the cancer paradigm. Combining these strategies with identified genetic elements that control target gene expression uncovers significant opportunities for developing guided gene-based therapeutics for cancer. The purpose of this review is to overview the current state and potential limitations in developing gene promoter-directed targeted expression of key genes and highlights their potential applications in cancer gene therapy.
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Affiliation(s)
- Amit Kumar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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2
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Emran TB, Shahriar A, Mahmud AR, Rahman T, Abir MH, Siddiquee MFR, Ahmed H, Rahman N, Nainu F, Wahyudin E, Mitra S, Dhama K, Habiballah MM, Haque S, Islam A, Hassan MM. Multidrug Resistance in Cancer: Understanding Molecular Mechanisms, Immunoprevention and Therapeutic Approaches. Front Oncol 2022; 12:891652. [PMID: 35814435 PMCID: PMC9262248 DOI: 10.3389/fonc.2022.891652] [Citation(s) in RCA: 244] [Impact Index Per Article: 81.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/10/2022] [Indexed: 12/15/2022] Open
Abstract
Cancer is one of the leading causes of death worldwide. Several treatments are available for cancer treatment, but many treatment methods are ineffective against multidrug-resistant cancer. Multidrug resistance (MDR) represents a major obstacle to effective therapeutic interventions against cancer. This review describes the known MDR mechanisms in cancer cells and discusses ongoing laboratory approaches and novel therapeutic strategies that aim to inhibit, circumvent, or reverse MDR development in various cancer types. In this review, we discuss both intrinsic and acquired drug resistance, in addition to highlighting hypoxia- and autophagy-mediated drug resistance mechanisms. Several factors, including individual genetic differences, such as mutations, altered epigenetics, enhanced drug efflux, cell death inhibition, and various other molecular and cellular mechanisms, are responsible for the development of resistance against anticancer agents. Drug resistance can also depend on cellular autophagic and hypoxic status. The expression of drug-resistant genes and the regulatory mechanisms that determine drug resistance are also discussed. Methods to circumvent MDR, including immunoprevention, the use of microparticles and nanomedicine might result in better strategies for fighting cancer.
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Affiliation(s)
- Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Asif Shahriar
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, United States
| | - Aar Rafi Mahmud
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Tangail, Bangladesh
| | - Tanjilur Rahman
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chittagong, Bangladesh
| | - Mehedy Hasan Abir
- Faculty of Food Science and Technology, Chattogram Veterinary and Animal Sciences University, Chattogram, Bangladesh
| | | | - Hossain Ahmed
- Department of Biotechnology and Genetic Engineering, University of Development Alternative, Dhaka, Bangladesh
| | - Nova Rahman
- Department of Biochemistry and Molecular Biology, Jahangirnagar University, Dhaka, Bangladesh
| | - Firzan Nainu
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
| | - Elly Wahyudin
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
| | - Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, India
| | - Mahmoud M. Habiballah
- Medical Laboratory Technology Department, Jazan University, Jazan, Saudi Arabia
- SMIRES for Consultation in Specialized Medical Laboratories, Jazan University, Jazan, Saudi Arabia
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
- Bursa Uludağ University Faculty of Medicine, Bursa, Turkey
| | | | - Mohammad Mahmudul Hassan
- Queensland Alliance for One Health Sciences, School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia
- Department of Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, Chattogram Veterinary and Animal Sciences University, Chattogram, Bangladesh
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3
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Curiel TJ. Immunotherapy: a useful strategy to help combat multidrug resistance. Drug Resist Updat 2012; 15:106-13. [PMID: 22483359 DOI: 10.1016/j.drup.2012.03.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2011] [Revised: 01/24/2012] [Accepted: 03/13/2012] [Indexed: 12/22/2022]
Abstract
Multidrug resistance (MDR) renders cancer cells relatively invulnerable to treatment with many standard cytotoxic anti-cancer agents. Cancer immunotherapy could be an important adjunct for other strategies to treat MDR positive cancers, as resistance to immunotherapy generally is unrelated to mechanisms of resistance to cytotoxic agents. Immunotherapy to combat MDR positive tumors could use any of the following strategies: direct immune attack against MDR positive cells, using MDR as an immune target to deliver cytotoxic agents, capitalization on other immune properties of MDR positive cells, or conditional immunotoxins expressed under MDR control. Additional insights into the immunogenic potential of some cytotoxic agents can also be brought to bear on these strategies. This review will highlight key concepts in cancer immunotherapy and illustrate immune principles and strategies that have been or could be used to help destroy MDR positive tumor cells, either alone or in rational combinations.
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Affiliation(s)
- Tyler J Curiel
- University of Texas Health Science Center, Cancer Therapy and Research Center, STRF Adult Cancer Program MC 8252, 8403 Floyd Curl Drive, San Antonio, TX 78229-3904, United States.
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4
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Yi Y, Noh MJ, Lee KH. Current advances in retroviral gene therapy. Curr Gene Ther 2011; 11:218-28. [PMID: 21453283 PMCID: PMC3182074 DOI: 10.2174/156652311795684740] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2011] [Accepted: 03/15/2011] [Indexed: 12/25/2022]
Abstract
There have been major changes since the incidents of leukemia development in X-SCID patients after the treatments using retroviral gene therapy. Due to the risk of oncogenesis caused by retroviral insertional activation of host genes, most of the efforts focused on the lentiviral therapies. However, a relative clonal dominance was detected in a patient with β-thalassemia Major, two years after the subject received genetically modified hematopoietic stem cells using lentiviral vectors. This disappointing result of the recent clinical trial using lentiviral vector tells us that the current and most advanced vector systems does not have enough safety. In this review, various safety features that have been tried for the retroviral gene therapy are introduced and the possible new ways of improvements are discussed. Additional feature of chromatin insulators, co-transduction of a suicidal gene under the control of an inducible promoter, conditional expression of the transgene only in appropriate target cells, targeted transduction, cell type-specific expression, targeted local administration, splitting of the viral genome, and site specific insertion of retroviral vector are discussed here.
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5
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Walther W, Stein U. Heat-responsive gene expression for gene therapy. Adv Drug Deliv Rev 2009; 61:641-9. [PMID: 19394378 DOI: 10.1016/j.addr.2009.02.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2008] [Accepted: 02/05/2009] [Indexed: 11/28/2022]
Abstract
Therapy-inducible vectors are useful for conditional expression of therapeutic genes in gene therapy, which is based on the control of gene expression by conventional treatment modalities. By this approach, combination of chemotherapy, radiation or hyperthermia with gene therapy can result in considerable, additive or synergistic improvement of therapeutic efficacy. This concept has been successfully tested in particular for gene therapy of cancer. The identification of efficient heat-responsive gene promoters provided the rationale for heat-regulated gene therapy. The objective of this review is to provide insights into the cellular mechanisms of heat-shock response, as prerequisite for therapeutic actions of hyperthermia and into the field of heat-responsive gene therapy. Furthermore, the major strategies of heat-responsive gene therapy systems in particular for cancer treatment are summarized. The developments for heat-responsive vector systems for in vitro and in vivo approaches are discussed. This review will provide an overview for this gene therapy strategy and its potential for multimodal therapeutic concepts in the clinic.
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Affiliation(s)
- Wolfgang Walther
- Max-Delbrück-Center for Molecular Medicine, Charité, University Medicine Berlin, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
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6
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Death ligands designed to kill: development and application of targeted cancer therapeutics based on proapoptotic TNF family ligands. Results Probl Cell Differ 2009; 49:241-73. [PMID: 19142623 DOI: 10.1007/400_2008_22] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The identification of molecular markers associated with cancer development or progression, opened a new era in the development of therapeutics. The successful introduction of a few low molecular weight chemicals and recombinant protein therapeutics with targeted actions into clinical practice have raised great expectations to broadly improve cancer therapy with respect to both overall clinical responses and tolerability. Targeting the apoptotic machinery of malignant cells is an attractive concept to combat cancer, which is currently exploited for the proapoptotic members of the TNF ligand family at various stages of preclinical and clinical development. This review summarizes recent progress in this rapidly progressing field of "biologic" therapies targeting the death receptors of TNF, CD95L, and TRAIL by means of its cognate protein ligands, receptor specific antibodies, and gene therapeutic approaches. Preclinical data on newly derived variants and fusion proteins based on these death ligands, designed to act in a tumor restricted manner, thereby preventing a systemic, potentially harmful action, will also be discussed.
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7
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Gillet JP, Macadangdang B, Fathke RL, Gottesman MM, Kimchi-Sarfaty C. The development of gene therapy: from monogenic recessive disorders to complex diseases such as cancer. Methods Mol Biol 2009; 542:5-54. [PMID: 19565894 DOI: 10.1007/978-1-59745-561-9_1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
During the last 4 decades, gene therapy has moved from preclinical to clinical studies for many diseases ranging from monogenic recessive disorders such as hemophilia to more complex diseases such as cancer, cardiovascular disorders, and human immunodeficiency virus (HIV). To date, more than 1,340 gene therapy clinical trials have been completed, are ongoing, or have been approved in 28 countries, using more than 100 genes. Most of those clinical trials (66.5%) were aimed at the treatment of cancer. Early hype, failures, and tragic events have now largely been replaced by the necessary stepwise progress needed to realize clinical benefits. We now understand better the strengths and weaknesses of various gene transfer vectors; this facilitates the choice of appropriate vectors for individual diseases. Continuous advances in our understanding of tumor biology have allowed the development of elegant, more efficient, and less toxic treatment strategies. In this introductory chapter, we review the history of gene therapy since the early 1960s and present in detail two major recurring themes in gene therapy: (1) the development of vector and delivery systems and (2) the design of strategies to fight or cure particular diseases. The field of cancer gene therapy experienced an "awkward adolescence." Although this field has certainly not yet reached maturity, it still holds the potential of alleviating the suffering of many individuals with cancer.
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Affiliation(s)
- Jean-Pierre Gillet
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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8
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Cai W, Kerner ZJ, Hong H, Sun J. Targeted Cancer Therapy with Tumor Necrosis Factor-Alpha. BIOCHEMISTRY INSIGHTS 2008. [DOI: 10.4137/bci.s901] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Tumor necrosis factor-alpha (TNF-α), a member of the TNF superfamily, was the first cytokine to be evaluated for cancer biotherapy. However, the clinical use of TNF-α is severely limited by its toxicity. Currently, TNF-α is administered only through locoregional drug delivery systems such as isolated limb perfusion and isolated hepatic perfusion. To reduce the systemic toxicity of TNF-α, various strategies have been explored over the last several decades. This review summarizes current state-of-the-art targeted cancer therapy using TNF-α. Passive targeting, cell-based therapy, gene therapy with inducible or tissue-specific promoters, targeted polymer-DNA complexes, tumor pre-targeting, antibody-TNF-α conjugate, scFv/TNF-α fusion proteins, and peptide/TNF-α fusion proteins have all been investigated to combat cancer. Many of these agents are already in advanced clinical trials. Molecular imaging, which can significantly speed up the drug development process, and nanomedicine, which can integrate both imaging and therapeutic components, has the potential to revolutionize future cancer patient management. Cooperative efforts from scientists within multiple disciplines, as well as close partnerships among many organizations/entities, are needed to quickly translate novel TNF-α-based therapeutics into clinical investigation.
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Affiliation(s)
- Weibo Cai
- Departments of Radiology and Medical Physics, School of Medicine and Public Health, University of Wisconsin–-Madison, Madison, Wisconsin, U.S.A
- University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin, U.S.A
| | - Zachary J. Kerner
- Departments of Radiology and Medical Physics, School of Medicine and Public Health, University of Wisconsin–-Madison, Madison, Wisconsin, U.S.A
| | - Hao Hong
- Departments of Radiology and Medical Physics, School of Medicine and Public Health, University of Wisconsin–-Madison, Madison, Wisconsin, U.S.A
| | - Jiangtao Sun
- Departments of Radiology and Medical Physics, School of Medicine and Public Health, University of Wisconsin–-Madison, Madison, Wisconsin, U.S.A
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9
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Tang QS, Zhang DS, Cong XM, Wan ML, Jin LQ. Using thermal energy produced by irradiation of Mn–Zn ferrite magnetic nanoparticles (MZF-NPs) for heat-inducible gene expression. Biomaterials 2008; 29:2673-9. [DOI: 10.1016/j.biomaterials.2008.01.038] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2007] [Accepted: 01/25/2008] [Indexed: 11/30/2022]
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10
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Wang X, Ji C, Ma D, Zhao J, Hou M, Yu H, Zang S. Antitumor effects of cytosine deaminase and thymidine kinase fusion suicide gene under the control of mdr1 promoter in mdr1 positive leukemia cells. Leuk Lymphoma 2007; 48:1600-9. [PMID: 17701592 DOI: 10.1080/10428190701474340] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The multidrug resistance (mdr) mediated by P-glycoprotein (P-gp), the mdr1 gene product, is one of the major obstacles in leukemia treatment. The present study was designed to explore a suicide gene therapy approach targeting mdr1 for reversal of P-gp-mediated mdr in the mdr positive K562/A02 cells. To study targeted killing effects of cytosine deaminase (CD)-thymidine kinase (TK) fusion suicide gene on multi-drug resistant leukemia, the CD-TK fusion suicide gene expression vector driven by mdr1 promoter was constructed and transferred into K562 and K562/A02 cells using lipofectintrade mark 2000. RT-PCR was used to demonstrate that there were CD and TK genes expression in K562/A02 cells, but not in K562 cells. MTT analysis showed that, compared with that in K562/CDTK, the survival rate of K562/A02-CDTK cells decreased and at the same time the apoptotic rate increased after treatment with GCV and 5-FC (P < 0.05). In vivo studies showed that the tumor volume in the prodrug treated K562/A02-CDTK groups was significantly less than that in the NS-control and K562-CDTK groups (P < 0.05). These findings show that the CD and TK fusion suicide gene expression driven by mdr1 promoter is effective in killing multidrug resistant K562/A02 cells.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Animals
- Antiviral Agents/therapeutic use
- Artificial Gene Fusion
- Cell Proliferation
- Cytosine Deaminase/genetics
- Cytosine Deaminase/metabolism
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Flow Cytometry
- Ganciclovir/pharmacology
- Genetic Therapy
- Genetic Vectors
- Humans
- K562 Cells
- Leukemia, Lymphoid/enzymology
- Leukemia, Lymphoid/genetics
- Leukemia, Lymphoid/therapy
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Promoter Regions, Genetic/genetics
- Recombinant Fusion Proteins/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Thymidine Kinase/genetics
- Thymidine Kinase/metabolism
- Transfection
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Affiliation(s)
- Xiangling Wang
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, Shandong Province, People's Republic of China
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11
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Walther W, Arlt F, Fichtner I, Aumann J, Stein U, Schlag PM. Heat-inducible in vivo gene therapy of colon carcinoma by human mdr1 promoter-regulated tumor necrosis factor-alpha expression. Mol Cancer Ther 2007; 6:236-43. [PMID: 17237282 DOI: 10.1158/1535-7163.mct-06-0070] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The promoter of the human multidrug resistance gene (mdr1) harbors defined heat-responsive elements, which could be exploited for construction of heat-inducible expression vectors. To analyze the hyperthermia inducibility of the mdr1 promoter in vitro and in vivo, we used the pcDNA3-mdrp-hTNF vector construct for heat-induced tumor necrosis factor alpha (TNF-alpha) expression in transfected HCT116 human colon carcinoma cells at mRNA level by quantitative real-time reverse transcription-PCR and at protein level by TNF-alpha ELISA. For the in vitro studies, the pcDNA3-mdrp-hTNF-transfected tumor cells were treated with hyperthermia at 43 degrees C for 2 h. In the animal studies, stably transfected or in vivo jet-injected tumor-bearing Ncr:nu/nu mice were treated for 60 min at 42 degrees C to induce TNF-alpha expression. Both the in vitro and in vivo experiments show that hyperthermia activates the mdr1 promoter in a temperature- and time-dependent manner, leading to an up to 4-fold increase in mdr1 promoter-driven TNF-alpha expression at mRNA and an up to 3-fold increase at protein level. The in vivo heat-induced TNF-alpha expression combined with Adriamycin (8 mg/kg) treatment leads to the inhibition of tumor growth in the animals. These experiments support the idea that heat-induced mdr1 promoter-driven expression of therapeutic genes is efficient and feasible for combined cancer gene therapy approaches.
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Affiliation(s)
- Wolfgang Walther
- Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13092 Berlin, Germany.
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12
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van Gaal EVB, Hennink WE, Crommelin DJA, Mastrobattista E. Plasmid engineering for controlled and sustained gene expression for nonviral gene therapy. Pharm Res 2006; 23:1053-74. [PMID: 16715361 DOI: 10.1007/s11095-006-0164-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2005] [Accepted: 01/03/2006] [Indexed: 01/18/2023]
Abstract
Gene therapy requires the introduction of genetic material in diseased cells with the aim of treating or ultimately curing a disease. Since the start of gene therapy clinical trials in 1990, gene therapy has proven to be possible, but studies to date have highlighted the difficulty of achieving efficient, specific, and long-term transgene expression. Efforts to improve gene therapy strategies over the past years were mainly aimed at solving the problem of delivery, without paying much attention to the optimization of the expression cassette. With the current understanding of the eukaryotic transcription machinery and advanced molecular biology techniques at our disposition, it has now become possible to create custom-made transgene expression cassettes optimized for gene therapy applications. In this review, we will discuss several strategies that have been explored to improve the level and duration of transgene expression, to increase control over expression, or to restrict transgene expression to specific cell types or tissues. Although still in its infancy, such strategies will eventually lead to improvement of nonviral gene therapy and expansion of the range of possible therapeutic applications.
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Affiliation(s)
- Ethlinn V B van Gaal
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O Box 80082, 3508 TB, Utrecht, The Netherlands
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13
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Mezhir JJ, Schmidt H, Yamini B, Senzer NN, Posner MC, Kufe DW, Weichselbaum RR. Chemoinducible gene therapy. Anticancer Drugs 2005; 16:1053-8. [PMID: 16222146 DOI: 10.1097/00001813-200511000-00003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Chemo-inducible cancer gene therapy is a potential new treatment for solid tumors that may in part enhance the anti-tumor effects of chemotherapy while minimizing toxicity. This approach combines viral vectors expressing cytotoxic transgenes that can be transcriptionally activated by DNA-damaging agents. The development of chemo-inducible gene therapy has numerous implications for the treatment of both localized and metastatic disease in patients with solid tumors.
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Affiliation(s)
- James J Mezhir
- Department of Surgery, University of Chicago Hospitals, Chicago, Illinois 60637, USA
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14
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Ding L, Chen XP, Zhang ZW, Guan J, Zhang WG, Wang HP, Wang ZH, Li CL. Synergistic effect of bromocriptine and tumor necrosis factor-α on reversing hepatocellular carcinoma multidrug resistance in nude mouse MDR1 model of liver neoplasm. World J Gastroenterol 2005; 11:5621-6. [PMID: 16237754 PMCID: PMC4481477 DOI: 10.3748/wjg.v11.i36.5621] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [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 effect of bromocriptine (BCT) and tumor necrosis factor-α (TNF-α ) on hepatocellular carcinoma (HCC) multidrug resistance (MDR) in nude mouse MDR model of liver neoplasm.
METHODS: Human hepatocarcinoma cell line HepG2, drug resistant hepatocarcinoma cell line HepG2/adriamycin (ADM) and hepatocarcinoma cell line transfected with TNF-α gene HepG2/ADM/TNF were injected into the liver of nude mice via orthotopic implantation and MDR model of liver neoplasm in vivo was established (HepG2, ADM, TNF, BCT groups). Among these groups, BCT group and TNF group were treated with BCT through gastric canal. Each group was divided into control group and chemotherapy group. Size and weight of the tumor were measured. Furthermore, tumor histological character and growth of the nude mice were observed and their chemosensitivity was tested. MDR-associated genes and proteins (MRP, LRP) of implanted tumors were detected by immunohistochemistry, reverse transcriptase polymerase chain reaction, and apoptosis rate of hepatocarcinoma cells was detected by TUNEL assay.
RESULTS: The nude mouse model of each cell line was inoculated successfully. The tumor growth rate and weight were significantly different among groups. After chemotherapy, abdominal cavity tumor growth inhibition rate was higher in BCT group (67%) compared to ADM and TNF groups, and similar to HepG2 group (54%). MDR1 and LRPmRNA could be detected in all groups, but TNF-αwas detected only in TNF and BCT groups. Furthermore, MDR1 and LRP protein expression of tumors in TNF and BCT groups was low similar to HepG2 group. The apoptosis rate of hepatocarcinoma cells was much higher in BCT group than in other groups with TUNEL assay.
CONCLUSION: BCT and TNF-α can reverse HCC MDR in nude mouse MDR1 model of liver neoplasm.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Animals
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Apoptosis
- Bromocriptine/pharmacology
- Cell Line, Tumor
- Drug Resistance, Neoplasm/drug effects
- Drug Synergism
- Female
- Gene Expression Regulation, Neoplastic
- Genes, MDR/genetics
- Genes, MDR/physiology
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/physiopathology
- Mice
- Mice, Nude
- Neoplasm Transplantation
- RNA, Messenger/metabolism
- Tumor Necrosis Factor-alpha/pharmacology
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Affiliation(s)
- Lei Ding
- Hepatic Surgery Center, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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15
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Arima H. Polyfection as Nonviral Gene Transfer Method —Design of Novel Nonviral Vector Using α-Cyclodextrin—. YAKUGAKU ZASSHI 2004; 124:451-64. [PMID: 15235229 DOI: 10.1248/yakushi.124.451] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Due to the growing concerns over the toxicity and immunogenicity of viral DNA delivery systems, DNA delivery via nonviral routes has become more desirable and advantageous. In particular, polycation complexes with DNA (polyplex) are attractive nonviral vectors. To design novel polycationic vectors, we prepared polyamidoamine starburst dendrimer (dendrimer) conjugates with three cyclodextrins (CDE conjugates) and three generations (G2, G3, and G4) of dendrimers. Of seven CDE conjugates, an alpha-CDE conjugate (G3) with an average degree of substitution (DS) of alpha-CyD of 2.4 [alpha-CDE conjugate (G3, DS 2.4)] showed greater gene transfer activity than dendrimers and other alpha-CDE conjugates with less cytotoxicity. These results suggest the potential use of alpha-CDE conjugate (G3, DS 2.4) as a polycationic vector in vitro and in vivo. Herein, I review a recent polyfection method, with special focus on alpha-CDE conjugate (G3, DS 2.4).
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Affiliation(s)
- Hidetoshi Arima
- Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.
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16
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Abstract
The field of cancer gene therapy is in continuous expansion, and technology is quickly moving ahead as far as gene targeting and regulation of gene expression are concerned. This review focuses on the endocrine aspects of gene therapy, including the possibility to exploit hormone and hormone receptor functions for regulating therapeutic gene expression, the use of endocrine-specific genes as new therapeutic tools, the effects of viral vector delivery and transgene expression on the endocrine system, and the endocrine response to viral vector delivery. Present ethical concerns of gene therapy and the risk of germ cell transduction are also discussed, along with potential lines of innovation to improve cell and gene targeting.
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Affiliation(s)
- Luisa Barzon
- Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, I-35121 Padua, Italy
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17
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Abstract
Cancer gene therapy has been one of the most exciting areas of therapeutic research in the past decade. In this review, we discuss strategies to restrict transcription of transgenes to tumour cells. A range of promoters which are tissue-specific, tumour-specific, or inducible by exogenous agents are presented. Transcriptional targeting should prevent normal tissue toxicities associated with other cancer treatments, such as radiation and chemotherapy. In addition, the specificity of these strategies should provide improved targeting of metastatic tumours following systemic gene delivery. Rapid progress in the ability to specifically control transgenes will allow systemic gene delivery for cancer therapy to become a real possibility in the near future.
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Affiliation(s)
- Tracy Robson
- School of Biomedical Sciences, University of Ulster, Newtownabbey, Co. Antrim, BT37 0QB, Northern Ireland, UK
| | - David G. Hirst
- School of Biomedical Sciences, University of Ulster, Newtownabbey, Co. Antrim, BT37 0QB, Northern Ireland, UK
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18
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Walther W, Stein U, Schlag PM. Use of the human MDR1 promoter for heat-inducible expression of therapeutic genes. Int J Cancer 2002; 98:291-6. [PMID: 11857422 DOI: 10.1002/ijc.10174] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The promoter of the human multidrug resistance gene (mdr1) harbors stress-responsive elements, which can be induced e.g., by heat or cytostatic drugs. In previous studies the drug-responsiveness of the mdr1 promoter was successfully used for the drug-inducible expression of the human TNF-alpha gene in vitro and in vivo. Beside the drug-responsive elements of the mdr1 promoter, heat-shock responsive elements have also been identified, which could be exploited for construction of heat-inducible expression vectors. To analyze the hyperthermia-inducibility of the mdr1 promoter we used the pmdr-p-CAT and pM3mdr-p-hTNF vector constructs. Both constructs carry the mdr1 promoter fragment spanning from -207 to +153 to drive expression of the CAT-reporter or TNF-alpha gene. We tested the heat-induced CAT-reporter and TNF-alpha expression in vitro in transduced HCT15 and HCT116 human colon carcinoma cells. For the studies the transduced tumor cells were treated with hyperthermia at 41.5 degrees C or 43 degrees C for 2 hr to induce CAT or TNF-alpha expression. Cells and supernatants were harvested before hyperthermia and at certain time points (0-120 hr) after heat shock. The heat-induced CAT-reporter expression or TNF-alpha secretion was determined by specific ELISA. The experiments indicate that hyperthermia activates the mdr1 promoter in a temperature and time dependent manner. This induction leads to an 2- to 4-fold increase in CAT-reporter or 2- to 7-fold increase in TNF alpha expression in the tumor cell lines. These experiments reveal that the mdr1 promoter driven expression of therapeutic genes can be employed for combined cancer gene therapy approaches.
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19
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Abstract
Current treatment of solid tumors is limited by severe adverse effects, resulting in a narrow therapeutic index. Therefore, cancer gene therapy has emerged as a targeted approach that would significantly reduce undesired side effects in normal tissues. This approach requires a clear understanding of the molecular biology of both the malignant clone and the biological vectors that serve as vehicles to target cancer cells. In this review we discuss novel approaches for conditional gene expression in cancer cells. Targeting transgene expression to malignant tissues requires the use of specific regulatory elements including promoters based on tumor biology, tissue-specific promoters and inducible regulatory elements. We also discuss the regulation of both replication and transgene expression by conditionally-replicative viruses. These approaches have the potential to restrict the expression of transgenes exclusively to tissues of interest and thereby to increase the therapeutic index of future vectors for cancer gene therapy.
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Affiliation(s)
- Y S Haviv
- Division of Human Gene Therapy, Departments of Medicine, Surgery and Pathology, University of Alabama at Birmingham, 1824 6th Avenue South, Birmingham, AL 35294, USA
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20
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Kianmanesh A, Hackett NR, Lee JM, Kikuchi T, Korst RJ, Crystal RG. Intratumoral administration of low doses of an adenovirus vector encoding tumor necrosis factor alpha together with naive dendritic cells elicits significant suppression of tumor growth without toxicity. Hum Gene Ther 2001; 12:2035-49. [PMID: 11747595 DOI: 10.1089/10430340152677395] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Although tumor necrosis factor alpha (TNF-alpha) is a potent cytokine with a myriad of innate immune antitumor properties, systemic administration of TNF-alpha is associated with significant toxicity, limiting the use of the TNF-alpha protein as an antitumor therapeutic. On the basis of the knowledge that dendritic cells (DCs) play a central role in initiating antitumor adaptive immune responses, we hypothesized that intratumoral administration of low doses of an adenovirus encoding TNF-alpha (AdTNF-alpha) together with syngeneic DCs would act synergistically to suppress preexisting tumors. As a model, four different tumor cell lines, all resistant in vitro to the TNF-alpha protein, were implanted in syngeneic mice, and established tumors received intratumor AdTNF-alpha alone or in combination with DCs. At high doses (10(9) PFU), AdTNF-alpha alone suppressed tumor growth, but was associated with systemic toxicity. A 100-fold lower AdTNF-alpha concentration (10(7) PFU) or high doses of the control vector AdNull had no systemic toxicity, but also minimal suppression of tumor growth. In contrast, local administration of the low dose (10(7) PFU) of AdTNF-alpha in combination with syngeneic DCs (AdTNF-alpha + DCs) elicited marked tumor suppression without toxicity. Administration of AdTNF-alpha + DCs into tumors elicited tumor-specific cytotoxic T cells and protected animals against subsequent challenge with the same tumor, suggesting that AdTNF-alpha + DC therapy induced tumor-specific adaptive immune host responses. Consistent with this concept, studies with syngeneic knockout mice showed that MHC class I molecules on DCs as well as CD8(+) T cells were necessary for the antitumor effect of intratumor AdTNF-alpha + DCs. These data demonstrate that the combination of intratumoral administration of the TNF-alpha cDNA together with naive DCs can evoke tumor suppression without systemic toxicity, providing a new paradigm for the use of TNF-alpha as antitumor therapy.
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Affiliation(s)
- A Kianmanesh
- Division of Pulmonary and Critical Care Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA
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21
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Ito A, Shinkai M, Honda H, Kobayashi T. Heat-inducible TNF-alpha gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy. Cancer Gene Ther 2001; 8:649-54. [PMID: 11593333 DOI: 10.1038/sj.cgt.7700357] [Citation(s) in RCA: 126] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2001] [Indexed: 11/08/2022]
Abstract
Heat-induced therapeutic gene expression is highly desired for gene therapy to minimize side effects. Furthermore, if the gene expression is triggered by heat stress, combined therapeutic effects of hyperthermia and gene therapy may be possible. We combined TNF-alpha gene therapy driven by the stress-inducible promoter, gadd 153, with hyperthermia using magnetite cationic liposomes (MCLs). In nude mice, MCLs induced cell death throughout much of the tumor area on heating under an alternating magnetic field. This heat stress also resulted in a 3-fold increase in TNF-alpha gene expression driven by the gadd 153 promoter as compared with that of nonheated tumor. TNF-alpha gene expression was also observed in the peripheral area where the hyperthermic effect was not enough to cause cell death. The combined treatment strongly arrested tumor growth in nude mice over a 30-day period, suggesting potential for cancer treatment.
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Affiliation(s)
- A Ito
- Department of Biotechnology, Graduate School of Engineering, Nagoya University, Nagoya 464-8603, Japan
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22
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Casado E, Nettelbeck DM, Gomez-Navarro J, Hemminki A, Gonzalez Baron M, Siegal GP, Barnes MN, Alvarez RD, Curiel DT. Transcriptional targeting for ovarian cancer gene therapy. Gynecol Oncol 2001; 82:229-37. [PMID: 11531272 DOI: 10.1006/gyno.2001.6305] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Ovarian carcinoma is a leading cause of cancer death in women. Though advances in conventional therapies have been achieved, long-term survival rates for most patients diagnosed with ovarian cancer are still low. Therefore, novel molecular therapeutic strategies such as gene therapy are being intensively pursued. Such approaches are based on the enormous progress that has been achieved in the elucidation of the molecular foundations of ovarian cancer. In this regard transcriptional control elements (promoters) of genes frequently upregulated or specifically expressed in tumors can be applied in a heterologous context to drive expression of therapeutic genes in targeted gene therapy strategies. This review discusses transcriptional targeting strategies in ovarian cancer gene therapy and gives an overview of tumor-specific promoters (TSPs) that have been applied for this purpose.
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Affiliation(s)
- E Casado
- Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
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