Gene therapy for lung neoplasms.

Division of Pulmonary, Allergy & Critical Care Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA.
Clinics in chest medicine (Impact Factor: 2.17). 12/2011; 32(4):865-85. DOI: 10.1016/j.ccm.2011.08.006
Source: PubMed

ABSTRACT Both advanced-stage lung cancer and malignant pleural mesothelioma are associated with a poor prognosis. Advances in treatment regimens for both diseases have had only a modest effect on their progressive course. Gene therapy for thoracic malignancies represents a novel therapeutic approach and has been evaluated in several clinical trials. Strategies have included induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine-based therapy, various vaccination approaches, and adoptive transfer of modified immune cells. This review considers the clinical results, limitations, and future directions of gene therapy trials for thoracic malignancies.


Available from: Elliot Wakeam, Apr 07, 2014
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gene-directed enzyme prodrug therapy (GDEPT) represents a technology to improve drug selectivity for cancer cells. It consists of delivery into tumor cells of a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. Major limitations of GDEPT that hinder its clinical application include inefficient delivery into cancer cells and poor prodrug activation by suicide enzymes. We tried to overcome these constraints through a combination of suicide gene therapy with immunomodulating therapy. Viral vectors dominate in present-day GDEPT clinical trials due to efficient transfection and production of therapeutic genes. However, safety concerns associated with severe immune and inflammatory responses as well as high cost of the production of therapeutic viruses can limit therapeutic use of virus-based therapeutics. We tried to overcome this problem by using a simple nonviral delivery system. We studied the antitumor efficacy of a PEI (polyethylenimine)-PEG (polyethylene glycol) copolymer carrying the HSVtk gene combined in one vector with granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA. The system HSVtk-GM-CSF/PEI-PEG was tested in vitro in various mouse and human cell lines, ex vivo and in vivo using mouse models. We showed that the HSVtk-GM-CSF/PEI-PEG system effectively inhibited the growth of transplanted human and mouse tumors, suppressed metastasis and increased animal lifespan. We demonstrated that appreciable tumor shrinkage and metastasis inhibition could be achieved with a simple and low toxic chemical carrier - a PEI-PEG copolymer. Our data indicate that combined suicide and cytokine gene therapy may provide a powerful approach for the treatment of solid tumors and their metastases.
    Journal of Translational Medicine 12/2015; 13(1):433. DOI:10.1186/s12967-015-0433-0 · 3.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Preclinical ResearchQuercetin, found in red onions and red apple skin can induce apoptosis insome malignant cells. However, the apoptotic effect of quercetin in hepatocellular carcinoma HepG2 cells via regulation of specificity protein 1 (Sp1) has not been studied. Here, we demonstrated that quercetin decreased cell growth and induce apoptosis in HepG2 cells via suppression of Sp1 using 3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay, 4′,6-diamidino-2-phenylindole (DAPI) staining, Annexin V, and Western blot analysis, an effect that was dose- and time-dependent manner. Treatment of HepG2 cells with quercetin reduced cell growth and induced apoptosis, followed by regulation of Sp1 and Sp1 regulatory protein. Taken together, the results suggest that quercetin can induce apoptotic cell death by regulating cell cycle and suppressing antiapoptotic proteins. Therefore, quercetin may be useful for cancer prevention. Drug Dev Res, 2014. © 2014 Wiley Periodicals, Inc.
    Drug Development Research 01/2015; DOI:10.1002/ddr.21235 · 0.73 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Since cancer is a genetic disease, the possibility of correcting defective genes would appear to be a highly promising approach to its treatment. However, the use of gene therapy has been limited by the inability to deliver a therapeutic gene to every cell in the tumor and by the heterogeneity in the enabling mutations found both between and within tumors. However, recent advances in the design of both viral (including non-replicating and oncolytic, or selectively replicating viruses) and non-viral gene delivery vehicles have allowed for more efficient and selective delivery of therapeutic genes to tumor cells leading to greater and longer term gene expression. In addition, a more realistic assessment of how genetic material most likely produce the greatest anti-tumor effect when expressed from within only a portion of cells in the tumor has resulted in the evolution of vectors that have demonstrated anti-tumor effects in the clinical setting and will likely result in approved therapies that can truly benefit the patient population. In particular, the capacity to induce a bystander effect, in a way that killing cells within the tumor which might not have been transfected directly with the genetic material be affected is an important property of most successful cancer gene therapies. As such, genes whose products induce an anti-tumor immune response within and against the tumor have been especially successful, as well as genes that can sensitize tumors to chemotherapies (such as through pro-drug conversion) or that target angiogenesis within the tumor. These can be used alone, or in combination with other therapies and many have now demonstrated potential in the clinical setting. Here, we describe the advantages and limitations of the current leading viral and non-viral gene delivery systems; assess the potential and proven capabilities of different therapeutic genes expressed from within the tumor, with special focus on immune-modulating genes and vaccines; and provide an overview of the use of oncolytic viruses as both therapies and gene expression vehicles.
    Cancer Immunology, Bench to Bedside Immunotherapy of Cancers edited by N Resaei, 01/2015: chapter Gene Therapy and Virus-Based Cancer Vaccines: pages 131-150; Publisher Springer Berlin Heidelberg., ISBN: 978-3-662-44945-5