Targeted killing effects of double CD and TK suicide genes controlled by survivin promoter on gastric cancer cell

Luo, Xian-Run; Li, Jiansheng; Niu, Yingjie; Li, Miao

doi:10.1007/s11033-010-0218-8

Cited by 15 publications

(10 citation statements)

References 31 publications

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“…However, the specificity of therapeutic gene expression was unsatisfied [4]. To prevent the toxicity of suicide genes in normal cells, tumor specific promoters including hTERT promoter have been utilized to drive the specific expression of 'toxic' genes in tumors of certain origins [23-25]. hTERT is transcriptionally repressed in normal human adult tissues but up-regulated in the majority of human tumors from all tissues, which prompted the investigations on the use of hTERT promoter to restrict the expression of delivered genes to cancer cells and the results were encouraging [4,26-28].…”

Section: Discussionmentioning

confidence: 99%

Gene therapy with tumor-specific promoter mediated suicide gene plus IL-12 gene enhanced tumor inhibition and prolonged host survival in a murine model of Lewis lung carcinoma

Hou

Liu

et al. 2011

J Transl Med

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BackgroundGene therapy is a promising therapeutic approach for cancer. Targeted expression of desired therapeutic proteins within the tumor is the best approach to reduce toxicity and improve survival. This study is to establish a more effective and less toxic gene therapy of cancer.MethodsCombined gene therapy strategy with recombinant adenovirus expressing horseradish peroxidase (HRP) mediated by human telomerase reverse transcriptase (hTERT) promoter (AdhTERTHRP) and murine interleukin-12 (mIL-12) under the control of Cytomegalovirus (CMV) promoter (AdCMVmIL-12) was developed and evaluated against Lewis lung carcinoma (LLC) both in vivo and in vitro. The mechanism of action and systemic toxicities were also investigated.ResultsThe combination of AdhTERTHRP/indole-3-acetic acid (IAA) treatment and AdCMVmIL-12 resulted in significant tumor growth inhibition and survival improvement compared with AdhTERTHRP/IAA alone (tumor volume, 427.4 ± 48.7 mm3 vs 581.9 ± 46.9 mm3, p = 0.005 on day 15; median overall survival (OS), 51 d vs 33 d) or AdCMVmIL-12 alone (tumor volume, 362.2 ± 33.8 mm3 vs 494.4 ± 70.2 mm3, p = 0.046 on day 12; median OS, 51 d vs 36 d). The combination treatment stimulated more CD4+ and CD8+ T lymphocyte infiltration in tumors, compared with either AdCMVmIL-12 alone (1.3-fold increase for CD4+ T cells and 1.2-fold increase for CD8+ T cells, P < 0.01) or AdhTERTHRP alone (2.1-fold increase for CD4+ T cells and 2.2-fold increase for CD8+ T cells, P < 0.01). The apoptotic cells in combination group were significantly increased in comparison with AdCMVmIL-12 alone group (2.8-fold increase, P < 0.01) or AdhTERTHRP alone group (1.6-fold increase, P < 0.01). No significant systematic toxicities were observed.ConclusionsCombination gene therapy with AdhTERTHRP/IAA and AdCMVmIL-12 could significantly inhibit tumor growth and improve host survival in LLC model, without significant systemic adverse effects.

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Section: Discussionmentioning

confidence: 99%

Gene therapy with tumor-specific promoter mediated suicide gene plus IL-12 gene enhanced tumor inhibition and prolonged host survival in a murine model of Lewis lung carcinoma

Hou

Liu

et al. 2011

J Transl Med

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“…Therefore, prior studies have been focused on developing targeting strategies (26,27). Tissue-specific promoters represent one of the primary methods of gene therapy (28,29). hSLPI is produced by cells in the respiratory tract and genital mucosa epithelium, and is highly expressed in hNSCLC (19); by contrast, it has low expression in other normal tissues, particularly in the liver (22).…”

Section: Discussionmentioning

confidence: 99%

Targeted gene therapy of the HSV-TK/hIL-12 fusion gene controlled by the hSLPI gene promoter of human non-small cell lung cancer inï¿½vitro

Hao

Song

et al. 2018

Oncol Lett

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Abstract. The incidence of lung cancer and lung cancer-associated mortality have markedly increased worldwide, and gene-targeted therapy has emerged as a promising treatment strategy. The present study aimed to explore the targeted antitumor effect of the herpes simplex virus-thymidine kinase/human interleukin-12 (HSV-TK/hIL-12) fusion gene regulated by the human secretory leukocyte protease inhibitor (hSLPI) promoter of human non-small cell lung cancer (hNSCLC). There were four recombinant eukaryotic expression vectors: pcDNA3.1-CMV-TK, pcDNA3.1-CMV-TK/hIL-12, pcDNA3.1-phSLP-TK and pcDNA3.1-phSLP-TK/hIL-12. These were constructed and transfected into the A549, SPC-A1 and HepG2 cell lines in vitro. The expression of the HSV-TK/hIL-12 fusion gene was detected with reverse transcription-polymerase chain reaction (RT-PCR), and the content of hIL-12 was measured using an ELISA. The antitumor effect of the fusion gene on the A549, SPC-A1 and HepG2 cell lines was determined using an MTT assay. Analysis of the experimental data demonstrated that genes regulated by the cytomegalovirus promoter were expressed at the same level in three different tumor cell lines. Genes regulated by the hSLPI promoter were expressed in the A549 and SPC-A1 cell lines, but not in the HepG2 cell line. Coincidentally, the hIL-12 expression levels were similar to those observed in previous RT-PCR findings. In the Pcmv-TK/Pcmv-TK-hIL-12 group for all three cell lines, as well as in the PSLPI-TK/PSLPI-TK-hIL-12 group for the A549 and SPC-A1 cell lines, the cell survival rate declined significantly and the fusion gene transfection group indicated a lower cell survival rate, when compared with single gene transfection group. The present study indicated that the fusion gene regulated by the hSLPI promoter had a targeted antitumor effect on hNSCLC, and that the combined suicide gene and immune gene therapy had a stronger antitumor effect, compared with single gene therapy.

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“…The survivin promoter was superior to other promoters, additionally it exhibited very low activities in major organs [40]. It mediated genes targeted therapy that had been detected in breast cancer [26], lung cancer [41][42] , gastric cancer [43] and glioma [40].…”

Section: Discussionmentioning

confidence: 99%

Suppression of hepatoma tumor growth by systemic administration of the phytotoxin gelonin driven by the survivin promoter

Wang

Zhou²,

Li³

et al. 2013

neo

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Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide. However, there is currently no effective therapy strategy in the clinical practice. Recombinant phytotoxin gelonin fused to other factors have been used to treat different cancers. But there have been no reports of gelonin gene therapy. In this study, we have constructed a recombinant plasmid which contained a tumor-specific survivin promoter to drive phytotoxin gelonin (pSur-Gel). And the cytotoxicity effects of pSur-Gel in HCC were also validated both in vitro and in vivo. The expression level of survivin was detetected in different liver cancer cell lines and nomal liver cell lines by western blot analysis, and a survivin promoter-driven green fluorescent protein (GFP) expression vectors (pSur-GFP) was also tested in liver cancer cell line HepG2 and normal liver cell line LO2. Moreover, phytotoxin gelonin expression experiment and cytotoxicity experiment of pSur-Gel was performed in HepG2 cells and LO2 cells in vitro. Furthermore, anti-tumor effect of pSur-Gel against HepG2 xenografts and toxicity of this gene were evaluated in the mice model. Finally, LDH release assay, apoptosis assay and immunoblot analyse LC3 conversion (LC3-I to LC3-II) were tested. We found that the expression of survivin protein was higher in liver cancer cell lines compared with the normal liver cells. Further study showed that the pSur-GFP and pSur-Gel was expressed specially in liver cancer cell other than in normal liver cells. pSur-Gel plasmid could effectively inhibit the proliferation of liver cancer cells (*P<0.05), and significantly repress the growth of HepG2 xenografts via intravenous in vivo (*P<0.05). Otherwise, compared to cytomegalovirus promoter-driven gelonin expression vectors (pCMV-Gel), no significantly systemic toxicity or organ injuries had been observed in pSur-Gel treated mice. Further studies revealed that the phytotoxin gelonin induced cell death might be mediated by apoptosis and the damage of cell membrane. Taken together, treating hepatocellular carcinoma with the pSur-Gel may be a novel and interesting cancer gene therapy protocol and is worthy of further development for future clinical trials.

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Targeted killing effects of double CD and TK suicide genes controlled by survivin promoter on gastric cancer cell

Cited by 15 publications

References 31 publications

Gene therapy with tumor-specific promoter mediated suicide gene plus IL-12 gene enhanced tumor inhibition and prolonged host survival in a murine model of Lewis lung carcinoma

Gene therapy with tumor-specific promoter mediated suicide gene plus IL-12 gene enhanced tumor inhibition and prolonged host survival in a murine model of Lewis lung carcinoma

Targeted gene therapy of the HSV-TK/hIL-12 fusion gene controlled by the hSLPI gene promoter of human non-small cell lung cancer inï¿½vitro

Suppression of hepatoma tumor growth by systemic administration of the phytotoxin gelonin driven by the survivin promoter

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