Gemcitabine-Based Chemogene Therapy for Pancreatic Cancer Using Ad-dCK::UMK GDEPT and TS/RR siRNA Strategies

Rejiba, Soukaïna; Bigand, Christelle; Parmentier, Céline; Hajri, Amor

doi:10.1593/neo.81686

Cited by 71 publications

(68 citation statements)

References 39 publications

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“…Exceptions were PANC-1 and SK-BR-3 cell lines that showed high gemcitabine resistance. The obtained result was comparable with IC 50 values found in the literature 13,14 for standard drugs in 2D assay, taking in account the differences in assay setup (number of cells per well, source and formulation of tested standard drugs, washout period, etc.) higher IC 50 value for MIA-PA-Ca-2 and a lower IC 50 value for MDA-MB-231 and T47D.…”

Section: Differences In Drug Responses Between 2d and 3d Culture Modelssupporting

confidence: 88%

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Antitumor activity of amidino-substituted benzimidazole and benzimidazo[1,2-a]quinoline derivatives tested in 2D and 3D cell culture systems

Brajša¹,

Vujasinović²,

Jelić³

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Due to a poor clinical predictive power of 2D cell cultures, standard tool for in vitro assays in drug discovery process, there is increasing interest in developing 3D in vitro cell cultures, biologically relevant assay feasible for the development of robust preclinical anti-cancer drug screening platforms. Herein, we tested amidino-substituted benzimidazoles and benzimidazo[1,2-a]quinolines as a small platform for comparison of antitumor activity in 2D and 3D cell culture systems and correlation with structure-activity relationship. 3D cell culture method was applied on a human cancer breast (SK-BR-3, MDA-MB-231, T-47D) and pancreatic cancer cells (MIA PaCa-2, PANC-1). Results obtained in 2D and 3D models were highly comparable, but in some cases we have observed significant disagreement indicating that some prominent compounds can be discarded in early phase of researching because of compounds with false positive result. To confirm which of cell culture systems is more accurate, in vivo profiling is needed. Keywords

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Section: Differences In Drug Responses Between 2d and 3d Culture Modelssupporting

confidence: 88%

“…IR spectra were recorded on a Perkin-Elmer Spectrum 1 spectrophotometer, with KBr disks. 1 H and 13 C NMR spectra were recorded on Bruker Avance DPX 300 and Bruker Avance DRX 500 spectrometers using TMS as an internal standard in DMSO-d 6 . Mass spectra were recorded on Agilent 1100 series LC/MSD Trap SL.…”

Section: General Methodsmentioning

confidence: 99%

Antitumor activity of amidino-substituted benzimidazole and benzimidazo[1,2-a]quinoline derivatives tested in 2D and 3D cell culture systems

Brajša¹,

Vujasinović²,

Jelić³

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Chemogene therapy is effective due to the sensitizing of tumor cells to apoptosis by overexpression of a pro-apoptotic protein, followed by the administration of lower doses of chemotherapeutic drugs, therefore reducing systemic toxicity (21,22). Choi et al (23) found that the combination of adenoviral-mediated IFN-β gene therapy and 5-FU resulted in tumor regression, apoptosis, and improved survival in an established liver metastasis model of colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

EBP50 gene transfection promotes 5-fluorouracil-induced apoptosis in gastric cancer cells through Bax- and Bcl-2-triggered mitochondrial pathways

Dong

et al. 2012

Mol Med Report

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Abstract. 5-Fluorouracil (5-FU) plays an important role in the chemotherapy of advanced gastric cancer. However, genetic factors that affect therapeutic efficacy of 5-FU warrant further investigation. In the present study, using stable transfection of the ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) gene, we explored the genetic influences on 5-FU-induced apoptosis of human gastric cancer cells. Stable overexpression of the EBP50 gene was determined by reverse transcription polymerase chain reaction (RT-PCR) assay and western blot analysis. After treatment with 5-FU, cell growth activities in vitro were investigated by MTT assay. Cell apoptosis was evaluated by Hoechst 33258 staining and flow cytometry of Annexin V-FITC/PI staining. Compared with the BGC823 or BGC823/neo cells, EBP50 mRNA and protein levels in the BGC823/EBP50 cells (EBP50-transfected BGC823 cells) were markedly higher. Chemosensitivity and apoptosis rates of the BGC823/EBP50 cells were higher compared to the BGC823 and BGC823/neo cells following treatment with 5-FU. Stable overexpression of extrinsic EBP50 distinctly increases the 5-FU-induced apoptosis of gastric cancer cells, and is a novel strategy by which to improve the chemosensitivity of gastric cancer to 5-FU.

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“…The expression of the therapeutic gene can directly kill the cells (diphtheria toxin, [20]), or can render the cells sensitive to certain otherwise non toxic prodrugs (Gene Directed Enzyme Prodrug Therapy, GDEPT, [21]), or based on gemcitabine association with the deoxycytidine kinase::uridine monophosphate kinase fusion gene [22]. The systemic administration of conventional chemotherapies fails to reach sufficiently the pancreatic tumor cells and affects the normal cells.…”

Section: Delivering a Suicide Genementioning

confidence: 99%

Gene Therapy of Pancreatic Cancer

Dabernat¹,

Lafitte²,

Bedel³

et al. 2013

J Genet Syndr Gene Ther

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a 5-year survival rate of less than 5%. The poor prognosis of the disease is associated with late diagnosis and a high degree of drug resistance has not been overcome during the past decades. Gemcitabine-based regimens are the first line therapy for advanced pancreatic cancer but are not curative. Recent new combination chemotherapies achieved significant benefits but toxicity makes their use controversial. Novel approaches are currently being developed; in particular cancer gene therapies are undergoing preclinical and clinical validation and are the topic of the present review. We will present different ways to design gene therapy against pancreatic cancers that have been validated in preclinical studies. We also reviewed the clinical trials already published or still ongoing.Citation: Dabernat S, Lafitte M, Bedel A, de Verneuil H, Moreau-Gaudry F (2013) Gene Therapy of Pancreatic Cancer. J Genet Syndr Gene Ther 4: 138. doi:10.4172/2157-7412.1000138 Page 2 of 6Volume 4 • Issue 4 • 1000138 Suicide Gene Therapy of Cancer J Genet Syndr Gene Ther ISSN: 2157-7412 JGSGT, an open access journal gene restoration efficiency [12]. Restoring a wild type SMAD4 did not always block tumor cells [13] rendering the use of this tumor suppressor controversial [14]. Many oncogenes can be deregulated and/or mutated in pancreatic cancers. Among them, mutations in the KRAS oncogene occur in almost all pancreatic adenorcinomas [9]. Thus, it is tempting to use direct anti-KRAS strategies to inhibit tumor growth (Figure 1b), since disappointing results have been obtained with inhibition of farnesyl transferases [1]. RNAi directed against mutated KRAS showed anti-tumor activity [15], limited the aggressive phenotype of the tumor cells [16] and potentiated gemcitabine antitumor activity [17]. Preclinical studies showed encouraging results with viral delivery systems such as oncolytic adenovirus [18]. However, this strategy has not been further tested in phase I clinical trials.In fact, pancreatic adenocarcinomas present very complex genetic alterations profiles. The Pancreatic Cancer Genome project has analyzed 23,219 transcripts and identified an average of 63 somatic mutations per PDAC affecting 12 core signaling pathways and the overexpression of 500 different genes in 24 tumors [19]. These highly versatile and unpredictable molecular patterns can explain the failure of single gene/pathway targeted adjuvant therapies. It is now critical to test therapies targeting several pathways or therapies that induce specific tumor cell death. Delivering a Suicide GeneWith the suicide gene approach, a gene that encodes a protein triggering tumor cell death is delivered to the tumor cells ( Figure 1c). The expression of the therapeutic gene can directly kill the cells (diphtheria toxin, [20]), or can render the cells sensitive to certain otherwise non toxic prodrugs (Gene Directed Enzyme Prodrug Therapy, GDEPT,[21]), or based on gemcitabine association ...

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Gemcitabine-Based Chemogene Therapy for Pancreatic Cancer Using Ad-dCK::UMK GDEPT and TS/RR siRNA Strategies

Cited by 71 publications

References 39 publications

Antitumor activity of amidino-substituted benzimidazole and benzimidazo[1,2-a]quinoline derivatives tested in 2D and 3D cell culture systems

Antitumor activity of amidino-substituted benzimidazole and benzimidazo[1,2-a]quinoline derivatives tested in 2D and 3D cell culture systems

EBP50 gene transfection promotes 5-fluorouracil-induced apoptosis in gastric cancer cells through Bax- and Bcl-2-triggered mitochondrial pathways

Gene Therapy of Pancreatic Cancer

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