Gene Therapy and Molecular Biology最新文献

{"title":"Adenoviral-delivered HE4-HSV-tk sensitizes ovarian cancer cells to ganciclovir.","authors":"Jennifer W Rawlinson,&nbsp;Kiara Vaden,&nbsp;Joseph Hunsaker,&nbsp;David F Miller,&nbsp;Kenneth P Nephew","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Ovarian cancer (OC) is most often contained within the peritoneal cavity, making it an ideal disease for adenoviral-delivered gene therapies. In effort to develop a safe and effective gene therapy for OC, we created a replication deficient adenovirus bearing the herpes simplex thymidine kinase (HSV-tk) gene under direction of the tumor specific promoter human epididymis protein 4 (HE4). The purpose of this study was to investigate the ability of our adenoviral construct to transduce OC cells <i>in vitro</i> and mediate transgene expression of HSV-tk, thereby sensitizing OC to the pro-drug ganciclovir. Cisplatin-sensitive (CS) and -resistant (CR) A2780 OC cells, infected with virus for 6 hours at 100, 500, and 1000 multiplicity of infection followed by ganciclovir treatment every other day for 5 days, were assayed for cell viability. Adenoviral-mediated transgene expression increased with increasing amounts of virus and peaked at 48 hours after transduction in both A2780-CS and -CR. Unexpectedly, ganciclovir alone was slightly toxic to both A2780 cell lines (IC₅₀ of 234.9 μg/mL and 257.2 μg/mL in A2780-CS and -CR, respectively). Transduction with ADV-HE4-HSV-tk followed by ganciclovir treatment increased (P<0.05) cell killing up to ten-fold, lowering the IC₅₀ to 23.9 μg/mL and 32.6 μg/mL in A2780-CS and -CR, respectively, at 1000 multiplicity of infection. The results support the potential use of this approach as a gene therapy for OC, a disease that accounts for more deaths than any other cancer of the female reproductive system.</p>","PeriodicalId":12503,"journal":{"name":"Gene Therapy and Molecular Biology","volume":"15 ","pages":"120-130"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440683/pdf/nihms-658307.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33332442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin is not a ligand for peroxisome proliferator-activated receptor-γ","authors":"Venkata R Narala,&nbsp;Monica R Smith,&nbsp;Ravi K Adapala,&nbsp;Rajesh Ranga,&nbsp;Kalpana Panati,&nbsp;Bethany B Moore,&nbsp;Todd Leff,&nbsp;Vudem D Reddy,&nbsp;Anand K Kondapi,&nbsp;Raju C Reddy","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Curcumin, a compound found in the spice turmeric, has been shown to possess a number of beneficial biological activities exerted through a variety of different mechanisms. Some curcumin effects have been reported to involve activation of the nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ), but the concept that curcumin might be a PPAR-γ ligand remains controversial. Results reported here demonstrate that, in contrast to the PPAR-γ ligands ciglitazone and rosiglitazone, curcumin is inactive in five different reporter or DNA-binding assays, does not displace [(3)H]rosiglitazone from the PPAR-γ ligand-binding site, and does not induce PPAR-γ-dependent differentiation of preadipocytes, while its ability to inhibit fibroblast-to-myofibroblast differentiation is not affected by any of four PPAR-γ antagonists. These multiple lines of evidence conclusively demonstrate that curcumin is not a PPAR-γ ligand and indicate the need for further investigation of the mechanisms through which the compound acts.</p>","PeriodicalId":12503,"journal":{"name":"Gene Therapy and Molecular Biology","volume":" ","pages":"20-25"},"PeriodicalIF":0.0,"publicationDate":"2009-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717748/pdf/nihms108812.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40002094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perspectives in vector development for systemic cancer gene therapy.","authors":"Arash Hatefi,&nbsp;Brenda F Canine","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Gene therapy is perceived as a revolutionary technology with the promise to cure almost any disease, provided that we understand its genetic basis. However, enthusiasm has rapidly abated as multiple clinical trials have failed to show efficacy. The limiting factor seems to be the lack of a suitable delivery system to carry the therapeutic genes to the target tissue safely and efficiently. Therefore, advancements in cancer gene therapy in general depend on the development of novel vectors with maximum therapeutic efficacy at the target site and minimal toxicity to normal tissues. This mini-review highlights both the major fortes and the unique challenges associated with the state-of-the-art gene carriers currently being used in cancer gene therapy.</p>","PeriodicalId":12503,"journal":{"name":"Gene Therapy and Molecular Biology","volume":"13 A","pages":"15-19"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691591/pdf/nihms108033.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28299779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of caspase-3 by Survivin prevents Wee1 Kinase degradation and promotes cell survival by maintaining phosphorylation of p34Cdc2.","authors":"Javier Rivera Guzman,&nbsp;Seiji Fukuda,&nbsp;Louis M Pelus","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The anti-apoptotic protein Survivin and the cyclin-dependent kinase p34Cdc2 regulate cell cycle progression and apoptosis. p34Cdc2 activation is required for its pro-apoptotic activity and phosphorylation of p34Cdc2 at Tyrosine-15 (Tyr15) maintains p34Cdc2 in an inactive state. In BaF3 IL-3-dependent murine hematopoietic cells, over-expression of wild-type (wt)-Survivin increased Tyrosine phosphorylation of p34Cdc2, while over-expression of dominant-negative (dn) T34A-Survivin decreased Tyr15 phosphorylation. The increased phospho-Tyr15 levels associated with ectopic wt-Survivin directly correlated with enhanced BaF3 cell survival upon growth factor withdrawal, while conversely, low phospho-Tyr15 levels and decreased survival were seen in BaF3 cells expressing ectopic dn-Survivin. Tyrosine-15 phosphorylation of p34Cdc2 is mediated by the Wee1 Kinase, a known target of caspase-3. In BaF3 cells over-expressing wt-Survivin, 2-fold higher levels of Wee1 protein were detected compared to cells expressing vector or dn-Survivin. Treatment of control vector-transduced BaF3 cells with the selective caspase-3 inhibitor Ac-DEVD-CHO increased p34Cdc2-Tyr15 phosphorylation and Wee1 protein levels. In a similar fashion, over-expression of wt-Survivin maintained high levels of phospho-Tyr15-p34Cdc2 and Wee1 protein. Since Survivin requires Hsp90 for stability, we treated cells with the Hsp90 inhibitors AICAR and 17-AAG to further link Survivin to blocking p34Cdc2 activation. Treatment of BaF3 cells expressing ectopic wt-Survivin with AICAR or 17-AAG significantly reduced p34Cdc2-Tyr15 phosphorylation compared to vehicle-treated controls. These results suggest that Survivin protects the p34Cdc2-Tyr15-targeting kinase Wee1 from degradation by blocking caspase-3 activation leading to inhibition of the pro-apoptotic function of p34Cdc2 and enhanced cell survival.</p>","PeriodicalId":12503,"journal":{"name":"Gene Therapy and Molecular Biology","volume":"13B ","pages":"264-273"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859835/pdf/nihms168710.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28953748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maintenance of a functional higher order chromatin structure: The role of the nuclear matrix in normal and disease states.","authors":"Amelia K Linnemann,&nbsp;Stephen A Krawetz","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The ordered packaging of DNA within the nucleus of somatic cells reflects a dynamic supportive structure that facilitates stable transcription interrupted by intermittent cycles of extreme condensation. This dynamic mode of packing and unpacking chromatin is intimately linked to the ability of the genome to specifically complex with both histones and non-histone proteins. Understanding the underlying mechanism that governs the formation of higher order chromatin structures is a key to understanding how local architecture modulates transcription. In part, the formation of these structures appears to be regulated through genomic looping that is dynamically mediated by attachment to the nuclear scaffold/matrix at S/MARs, i.e., Scaffold/Matrix Attachment Regions. Although the mechanism guiding the formation and use of these higher-ordered structures remains unknown, S/MARs continue to reveal a multitude of roles in development and the pathogenesis of disease.</p>","PeriodicalId":12503,"journal":{"name":"Gene Therapy and Molecular Biology","volume":"13 1","pages":"231-243"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952954/pdf/nihms-241643.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29353675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunoresistant human glioma cell clones selected with alloreactive cytotoxic T lymphocytes: downregulation of multiple proapoptotic factors.","authors":"German G Gomez, Michelle J Hickey, Richard Tritz, Carol A Kruse","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We previously reported the cellular, functional and cytogenetic characterization of immunoresistant (IR) 13-06-IR29 and 13-06-IR30 human glioma cell clones isolated after immunoselection with alloreactive cytotoxic T lymphocytes (aCTL). Relative to the 13-06-MG parental cells, both clones resisted aCTL lysis at multiple effector to target ratios; the resistant phenotype was maintained for 13-41 cell doublings after cloning and when selective pressure was removed; cross-resistance to other inducers of apoptosis/cell death was also observed (Gomez et al, 2006; Gomez and Kruse, 2007). In this study we further characterize the IR clones for factors that may contribute to the resistance. Data obtained by in-vitro quantitative morphologic and 7-amino actinomycin D flow cytometric assays revealed reduced apoptotic cell death when IR clones were coincubated with aCTL, relative to the parental cells. Since changes in apoptosis were observed, we examined the expression patterns of apoptosis-related genes in several extracts of parental cells and IR clones using pathway-specific cDNA microarray analysis. In general, the apoptotic factors were downregulated in the IR clones. From three separate extracts analyzed separately on microarrays, three factors, ATM, caspases 3 and 8, were statistically downregulated in both IR clones. Immunoblotting of the proteins confirmed the findings. Therefore, a possible mechanism for immunoresistance in gliomas may be achieved by the downregulation of one or more genes in the apoptotic pathway.</p>","PeriodicalId":12503,"journal":{"name":"Gene Therapy and Molecular Biology","volume":"12 1","pages":"101-110"},"PeriodicalIF":0.0,"publicationDate":"2008-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597650/pdf/nihms-66860.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27886534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decreased risk of bladder cancer in men treated with quinazoline-based α1-adrenoceptor antagonists.","authors":"Frances M Martin, Andrew M Harris, Randall G Rowland, William Conner, Matthew Lane, Erik Durbin, Andre T Baron, Natasha Kyprianou","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Previous studies documented that human bladder cancer cells are sensitive to the apoptotic effects of quinazoline-derived α1-adrenoreceptor antagonists and bladder tumors exhibit reduced tissue vascularity in response to terazosin. More recent evidence suggests that exposure to quinazoline α1-adrenorecptor antagonists leads to a significant reduction in prostate cancer incidence. This retrospective observational cohort study was conducted to determine whether male patients treated with quinazoline α1-adrenoceptor antagonists for either benign prostate hyperplasia (BPH) or hypertension have a decreased risk of developing bladder cancer. Review of the medical records of all male patients enrolled at the Lexington Veterans Administration (VA) Medical Center identified men exposed to quinazoline-based α1-adrenoceptor antagonists (Jan 1, 1998-Dec 31, 2002) for either hypertension and/or benign prostate obstructive symptoms. The whole group of 27,138 male patients was linked to the Markey Cancer Center's Kentucky Cancer Registry (KCR), part of the NCI's Surveillance, Epidemiology, and End Results (SEER) Program, to identify all incident bladder cancer cases diagnosed in this population. Measures of disease incidence, relative risk, and attributable risk were calculated to compare the risk of developing bladder cancer for α1-blocker-exposed versus unexposed men. A two-by-two contingency table of α1-antagonist exposure versus bladder cancer diagnoses was constructed and the relative risk was calculated. Our analysis revealed a cumulative bladder cancer incidence of 0.24% among the α1-blocker-exposed men compared to 0.42% in the unexposed group. Thus, there was a risk difference of -0.0018, which indicates that 1.8 fewer bladder cancer cases developed per 1000 exposed men. Alternatively stated, 556 men would need to be treated with quinazoline α1-blockers to prevent one case of bladder cancer. Exposure to quinazoline α1-blockers thus may have prevented 7 to 8 bladder cancer cases among the 4173 treated men during the study period. The data yield an unadjusted risk ratio of 0.57 (95% CI: 0.30, 1.08) and therefore, men treated with α1-adrenoreceptor antagonists have a 43% lower relative risk of developing bladder cancer than unexposed men (p=0.083). Our inability to determine person-years at risk of developing bladder cancer for each unexposed control patient, was a limitation for calculating an incidence ratio and rate difference. These results offer an initial indication that exposure to doxazosin and terazosin decreases the incidence of bladder cancer. This is the first epidemiological evidence that the anti-tumor action of quinazoline-based α1-antagonists may potentially translate into a protective effect from bladder cancer development.</p>","PeriodicalId":12503,"journal":{"name":"Gene Therapy and Molecular Biology","volume":"12 2","pages":"253-258"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921713/pdf/nihms124172.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29196779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of hormonal therapy resistance by cell cycle machinery.","authors":"Binoj Chandrasekharan Nair,&nbsp;Ratna K Vadlamudi","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Estrogen Receptor (ER) plays a central role in the development and progression of breast cancer. Hormonal therapy substantially improves disease-free survival of ER+ve breast tumors, however acquired resistance to endocrine therapies frequently occur. Emerging data implicate growth factor signaling pathways and their cross talk with ER as major cause of resistance. Both these pathways have been recently shown to use cell cycle machinery as downstream effectors in mediating therapy resistance. Several studies have demonstrated deregulation of cell cycle regulators and their cross talk with ER in therapy resistant tumors. The objective of this article is to review the underlying mechanisms by which tumor cells use cell cycle machinery to override hormonal therapy and to explore cell cycle machinery components as novel therapy targets for overcoming hormonal therapy resistance.</p>","PeriodicalId":12503,"journal":{"name":"Gene Therapy and Molecular Biology","volume":"12 ","pages":"395"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817953/pdf/nihms-107448.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28706708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene therapy trials for the treatment of high-grade gliomas.","authors":"Adam M Sonabend,&nbsp;Ilya V Ulasov,&nbsp;Maciej S Lesniak","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>High-grade gliomas remain relatively resistant to current therapy. Local recurrence is a common feature and the majority of patients progress despite conventional therapy. One modality-gene therapy-has shown a lot of promise in early preclinical and clinical studies aimed at advancing the treatment of this disease. In this review, we provide a comprehensive overview of clinical trials involving gene therapy in the field of neuro-oncology. The use of different delivery vehicles, including liposomes, cells, and viruses, as well genes, especially cytokines and suicide genes, are explored in detail. The unique features and advantages/disadvantages of the different vectors employed are compared based on results of human studies. We discuss both the limitations and successes encountered in these clinical trials, with an emphasis on the lessons learned and potential ways of improving current gene therapy protocols.</p>","PeriodicalId":12503,"journal":{"name":"Gene Therapy and Molecular Biology","volume":"11 A","pages":"79-92"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1913943/pdf/nihms23630.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26825694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isolation of genes controlling apoptosis through their effects on cell survival.","authors":"Gwyn T Williams,&nbsp;Jane P Hughes,&nbsp;Victoria Stoneman,&nbsp;Claire L Anderson,&nbsp;Nicola J McCarthy,&nbsp;Mirna Mourtada-Maarabouni,&nbsp;Mark Pickard,&nbsp;Vanessa L Hedge,&nbsp;Ian Trayner,&nbsp;Farzin Farzaneh","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The identification of the most suitable molecular targets for gene and drug therapy is the crucial first step in the development of new disease treatments. The rational identification of such targets depends on a detailed understanding of the pathological changes occuring at the molecular level. We have applied forward genetics approaches to the identification of the critical genes involved in the control of apoptosis in mammalian cells, since defective control of apoptosis underlies many diseases, including cancer and neurodegenerative diseases. We have identified two groups of genes by their effects on cell survival using retroviral cDNA functional expression cloning and retroviral insertional mutagenesis. The identification of these novel genes opens up new areas for apoptosis research and subsequently for the development of new gene and drug therapies.</p>","PeriodicalId":12503,"journal":{"name":"Gene Therapy and Molecular Biology","volume":"10 B","pages":"255-262"},"PeriodicalIF":0.0,"publicationDate":"2006-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828370/pdf/nihms-250.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26614393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}