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: 2.07). 12/2011; 32(4):865-85. DOI: 10.1016/j.ccm.2011.08.006
Source: PubMed


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.

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Available from: Elliot Wakeam, Apr 07, 2014
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    • "12-22 Additional investigation of cancer pathways revealed underlying mechanisms that could be utilized to block chemotherapy resistance and sensitize tumors to chemotherapy and radiotherapy. 23 A major breakthrough has been achieved with so called: ``suicide gene therapy`` modality. The introduction of a therapeutic gene encoding, enzyme capable of transforming a nontoxic pro-drug into a cell toxin enhances the cytotoxic effect for cancer cells and protects the healthy cells.15-17 "
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    ABSTRACT: Local treatment as a treatment modality is gaining increased general acceptance over time. Novel drugs and methodologies of local administration are being investigated in an effort to achieve disease local control. Suicide gene therapy is a method that has been investigated as a local treatment with simultaneously distant disease control. In our current experiment we purchased HTB-70 (melanoma cell line, derived from metastatic axillary node) and CRL-2302 (human retinal epithelium) were from ATCC LGC Standards and Ancotil(®), 2.5 g/250 ml (1 g/00ml) (5-Flucytosine) MEDA; Pharmaceuticals Ltd. UK. Adenosine Cytosine Deaminase (Ad.CD) was also used in order to convert the pro-drug 5-Flucytosine to the active 5-Fluoracil. Three different concentrations of 5-Flucytosine (5-FC) were administered (0.2ml, 0.8ml and 1.2ml). At indicated time-points (4h, 8h and 24h) cell viability and apoptosis were measured. Our concept was to investigate whether suicide gene therapy with Ad. CD-5-FC could be used with safety and efficiency as a future local treatment for melanoma located in the eye cavity. Indeed, our results indicated that in every 5-FC administration had mild cytotoxicity for the retinal cells, while increased apoptosis was observed for the melanoma cell line.
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    ABSTRACT: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a very poor prognosis. Several clinical studies such as immunotherapy, gene therapy and molecular targeting agents have been tried for treatment of malignant mesothelioma, however, there is no application for effective clinical treatment. Coffee has various biological functions such as anti-oxidant, anti-inflammatory, anti-mutagenic and anti-carcinogenic activities. The therapeutic activities of the bioactive compounds in coffee was sugested to influence intracellular signaling of MPM. Regarding to the cancer-related functions, In this study, suppression of Sp1 protein level followed by induction of MSTO-211H cell apoptosis by cafestol and kahweol were investigated in oreder to determine Sp1's potential as a significant target for human MPM therapy as well. Cells were treated separately with final concentration of cafestol and kahweol and the results were analyzed by MTS assay, DAPI staining, PI staining, luciferase assay, RT-PCR, and immunoblotting. Viability of MSTO-211H and H28 cells were decreased, and apoptotic cell death was increased in MSTO-211H as a result of cafestol and kahweol treatment. Cafestol and kahweol increased Sub-G1 population and nuclear condensation in MSTO-211H cells. Roles of Sp1 in cell proliferation and apoptosis of the MSTO-211H cells by the Sp1 inhibitor of Mithramycin A were previously confirmed. Cafestol and kahweol significantly suppressed Sp1 protein levels. Kahweol slightly attenuated Sp1 mRNA, while Cafestol did not affect in MSTO-211H cells. Cafestol and kahweol modulated the promoter activity and protein expression level of the Sp1 regulatory genes including Cyclin D1, Mcl-1, and Survivin in mesothelioma cells. Apoptosis signaling cascade was activated by cleavages of Bid, Caspase-3, and PARP with cafestol and by upregulation of Bax, and downregulation of Bcl-xl by kahweol. Sp1 can be a novel molecular target of cafestol and kahweol in human MPM.
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