Radiosensitization and Anti-tumour Effects of Cytosine Deaminase and Thymidine Kinase Fusion Suicide Gene in Human Adenoid Cystic Carcinoma Cells

Sy, Ho; Ds, Zhang; Jq, Han; Zhang, N; Sz, Zhang; Wl, Mu; Fc, Wei

doi:10.1177/147323000903700224

Cited by 6 publications

(4 citation statements)

References 32 publications

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“…Single suicide gene therapy has various limitations, drug resistance being the most common. The high incidence of tumor gene mutation is the foundation of drug resistance (20). Since different types of tumor cells have differences in sensitivity to different enzyme/prodrug systems, and tumor in vivo often exists in the form of a variety of clonogenic tumor cells, making it difficult to achieve radical tumor eradication by application of a single enzyme/prodrug system.…”

Section: Discussionmentioning

confidence: 99%

A preliminary study on the construction of double suicide gene delivery vectors by mesenchymal stem cells and the in vitro inhibitory effects on SKOV3 cells

et al. 2013

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The aim of the present study was to investigate the efficacy of using human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) as gene delivery vectors in the treatment of ovarian cancer. Lentivectors overexpressing cytosine deaminase (CD) and herpes simplex virus thymidine kinase (HSV-tk) (pGC-FU-CD-TK) were constructed, and confirmed by enzyme digestion, DNA sequence and western blotting. Quantitative PCR (PCR) was used to verify the overexpression of the fusion gene (CD and HSV-tk). SKOV3 cells were co-cultured with MSCs/tk+CD+ at a 1:1 ratio, and were then treated with the prodrugs (GCV) and/or 5-fluorocytosine (5-FC) at different concentrations, and the cytotoxic effects were evaluated using MTT assay and flow cytometry. DNA sequencing demonstrated that the sequence of HSV-tk and CD genes were consistent with the objective sequence and western blotting verified that the constructed lentivector could produce the HSV-tk/CD gene. The packed titer was 2.00e+8 TU/ml. The pGC-FU-CD-TK could be stably transferred to hUCB‑MSCs, and the infection efficiency was almost 80%. RT-PCR demonstrated that the expression levels of the HSV-tk/CD fusion gene in MSCs/tk+CD+ group was 75 times that in the negative control (P<0.05). Compared with GCV or 5-FC alone, the growth inhibition rate (GIR) was significantly higher in the combined treatment (F=85.35, P<0.05). The reconstructed MSCs/tk+CD+ vectors were capable of slowing down the growth of human SKOV3 cells in the presence of prodrugs in vitro. The use of combination chemotherapy exhibited a more significant inhibitory effect than using a single prodrug.

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Section: Discussionmentioning

confidence: 99%

A preliminary study on the construction of double suicide gene delivery vectors by mesenchymal stem cells and the in vitro inhibitory effects on SKOV3 cells

et al. 2013

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“…Enzyme-prodrug therapy has been shown previously to enhance tumor cell sensitivity to radiation therapy (Huang et al, 2009; Robson et al, 2005). In a mouse model of human glioma, Kaliberov et al (Kaliberov et al, 2007) observed higher survival rates with a combination therapy as opposed to treatment with either cytosine deaminase/5-FC or radiation alone.…”

Section: 0 Results and Discussionmentioning

confidence: 99%

Magnetic nanoparticle hyperthermia induced cytosine deaminase expression in microencapsulated E. coli for enzyme–prodrug therapy

Nemani

Ennis

Griswold

et al. 2015

Journal of Biotechnology

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Engineered bacterial cells that are designed to express therapeutic enzymes under the transcriptional control of remotely inducible promoters can mediate the de novo conversion of non-toxic prodrugs to their cytotoxic forms. In situ cellular expression of enzymes provides increased stability and control of enzyme activity as compared to isolated enzymes. We have engineered Escherichia coli (E. coli), designed to express cytosine deaminase at elevated temperatures, under the transcriptional control of thermo-regulatory λpL-cI857 promoter cassette which provides a thermal switch to trigger enzyme synthesis. Enhanced cytosine deaminase expression was observed in cultures incubated at 42 °C as compared to 30 °C, and enzyme expression was further substantiated by spectrophotometric assays indicating enhanced conversion of 5-fluorocytosine to 5-fluorouracil. The engineered cells were subsequently co-encapsulated with magnetic iron oxide nanoparticles in immunoprotective alginate microcapsules, and cytosine deaminase expression was triggered remotely by alternating magnetic field-induced hyperthermia. The combination of 5-fluorocytosine with AMF-activated microcapsules demonstrated tumor cell cytotoxicity comparable to direct treatment with 5-fluorouracil chemotherapy. Such enzyme-prodrug therapy, based on engineered and immunoisolated E. coli, may ultimately yield an improved therapeutic index relative to monotherapy, as AMF mediated hyperthermia might be expected to pre-sensitize tumors to chemotherapy under appropriate conditions.

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“…Kong et al [24] have exploited adenovirus-mediated TK/CD double suicide genes, which are more effective in killing breast cancer cells in vitro . Huang et al [25] have excised TK/CD suicide gene therapy with combination of radiotherapy to enhance radio-sensitivity of tumor. Liao et al [26] have found that radiation can enhance therapeutic efficacy of hTERTp-mediated gene therapy.…”

Section: Discussionmentioning

confidence: 99%

Targeted gene therapy of nasopharyngeal cancer in vitro and in vivo by enhanced thymidine kinase expression driven by human TERT promoter and CMV enhancer

Shen

Wen

Qian

et al. 2010

J Exp Clin Cancer Res

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Background/AimTo explore the therapeutic effects of thymidine kinase (TK) expressed by enhanced vector pGL3-basic- hTERTp-TK-EGFP-CMV driven by human telomerase reverse transcriptase promoter (hTERTp) as well as cytomegalovirus immediate early promoter enhancer (CMV).Materials/MethodsEnhanced TK-EGFP expression was confirmed by fluorescent microscopy, real time PCR and telomerase activity. Its effects were examined by survival of tumor cells NPC 5-8F and MCF-7, index of xenograft implanted in nude mice and histology.ResultsCompared with non-enhanced vector pGL3-basic-TK-hTERTp-EGFP, TK expressed by the enhanced vector significantly decreased NPC 5-8F and MCF-7 cell survival rates after ganciclovir (GCV) treatment (p < 0.001) and tumor progress in nude mice with NPC xenograft and treated with GCV, without obvious toxicity to mouse liver and kidney.ConclusionThe enhanced TK expression vector driven by hTERTp with CMV enhancer has brighter clinical potentials in nasopharyngeal carcinoma therapy than the non-enhanced vector.

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Radiosensitization and Anti-tumour Effects of Cytosine Deaminase and Thymidine Kinase Fusion Suicide Gene in Human Adenoid Cystic Carcinoma Cells

Abstract: Herpes simplex virus thymidine kinase (HSV-TK) and

Cited by 6 publications

References 32 publications

A preliminary study on the construction of double suicide gene delivery vectors by mesenchymal stem cells and the in vitro inhibitory effects on SKOV3 cells

A preliminary study on the construction of double suicide gene delivery vectors by mesenchymal stem cells and the in vitro inhibitory effects on SKOV3 cells

Magnetic nanoparticle hyperthermia induced cytosine deaminase expression in microencapsulated E. coli for enzyme–prodrug therapy

Targeted gene therapy of nasopharyngeal cancer in vitro and in vivo by enhanced thymidine kinase expression driven by human TERT promoter and CMV enhancer

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