Long-term tumor-free survival from treatment with the GFP–TRAIL fusion gene expressed from the hTERT promoter in breast cancer cells

Lin, Tong; Huang, Xuefeng; Gu, Jian; Zhang, Youmin; Roth, Jack A.; Xiong, Momiao; Curley, Steven A.; Yu, Yinhua; Hunt, Kelly K.; Fang, Bingliang

doi:10.1038/sj.onc.1205926

Cited by 107 publications

(57 citation statements)

References 16 publications

(14 reference statements)

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“…30,31 For cancer gene therapy applications, strong cytotoxicity, exhibited by DR4 overexpression, required targeting. For this purpose, we used the promoter of the hTERT gene, which has been shown to be selectively active in cancer cells, [32][33][34][35] to drive DR4 expression. The main disadvantage of the majority of the currently available tumor-specific promoters, including hTERT, is relative low promoter strength.…”

Section: Discussionmentioning

confidence: 99%

Death receptor 4 (DR4) efficiently kills breast cancer cells irrespective of their sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

Kazhdan

Marciniak

2004

Cancer Gene Ther

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and 2 South Texas Veterans Health Care System, Texas, USA.Breast cancer cells are generally resistant to induction of apoptosis by treatment with tumor necrosis factor-related apoptosisinducing ligand (TRAIL). In this study, we demonstrate that both TRAIL-sensitive and TRAIL-resistant breast cancer cell lines can be efficiently killed by overexpression of the TRAIL receptor, death receptor 4 (DR4). The extent of cell death depended on the strength of the promoter driving DR4 expression. When driven by the strong CMV promoter, expression of DR4 killed over 90% of cells in five out of six cell lines tested in the absence of exogenous TRAIL. When driven by the relatively weak tumor-specific hTERT promoter, DR4 was less effective alone, but sensitized cells to killing by TRAIL. The extent of TRAIL sensitization depended on the magnitude of hTERT promoter activity. MCF-7 cells were relatively resistant to the action of DR4. We compared expression of the genes involved in transduction and execution of the death receptor-initiated apoptotic stimuli between MCF-7 and DR4-sensitive cell lines. We confirmed that in the panel of cell lines, MCF-7 was the only line deficient in expression of caspase 3. Bcl-2 and FLIP proteins, implicated in suppression of TRAIL-induced apoptosis, were expressed at a higher level.

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Section: Discussionmentioning

confidence: 99%

Death receptor 4 (DR4) efficiently kills breast cancer cells irrespective of their sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

Kazhdan

Marciniak

2004

Cancer Gene Ther

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“…35,36 These vectors have not been uniformly successful against tumors established in animal models. 25,27,[37][38][39] Lack of efficacy has generally been blamed on the acquired resistance of many tumor isolates to FasL-or TRAIL-mediated apoptosis.…”

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confidence: 99%

Enhanced apoptosis of glioma cell lines is achieved by co-delivering FasL-GFP and TRAIL with a complex Ad5 vector

Rubinchik

Woraratanadharm

et al. 2003

Cancer Gene Ther

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Brain tumors (BTs) are among the most malignant forms of human cancer. Unfortunately, current treatments are often ineffective and produce severe side effects. Cytotoxic gene therapy is an alternative treatment strategy, with the potential advantages of reduced toxicity to normal brain tissue. Apoptosis-inducing ''death ligands'' Fas ligand and TNF-related apoptosis-inducing ligand (TRAIL) are genes with substantial cytotoxic activity in susceptible tumor cells. Here, we compared the effectiveness of Ad vectormediated delivery of Fas ligand-green fluorescent protein (FasL-GFP) fusion protein, human TRAIL, and both genes simultaneously. We examined a panel of 13 cell lines (eight derived from primary isolates) for susceptibility to Ad5-based vector infection and for sensitivity to FasL-and TRAIL-mediated apoptosis. All cell lines were efficiently transduced, but, as expected, varied in their sensitivity to ligand-induced apoptosis. Generally, sensitivity to FasL-GFP correlated with cell surface FasR levels, but no such correlation was seen for TRAIL and its functional receptors, DR4 and DR5. The vector expressing both FasL-GFP and TRAIL was more effective than either of the single-gene vectors at comparable transduction levels, and it was effective against a broader range of cell lines. In five cell lines, coexpression resulted in apoptosis levels greater than those predicted for strictly additive activity of the two death ligands. We believe that Ad vector-mediated delivery of multiple death ligands may be developed as a potential BT therapy, either alone or in conjunction with surgical resection of the primary tumor.

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“…10 For cancer therapy, the telomerase or hTERT promoter has been one of the most widely examined. The hTERT promoter shows tumorspecific activity when used to drive expression of a number of transgenes such as the tumor necrosis factor-related apoptosisinducing ligand, 43,44 the herpes simplex virus thymidine kinase 45 or the bacterial nitroreductase genes. 46 Neuroendocrine or neuronal carcinoma-specific promoters have been tested and some examples are the rat calcitonin promoter for treatment of medullary thyroid carcinoma, 47,48 the gastrin releasing peptide promoter for treatment of SCLC 49 and the midkine promoter for treatment of neuroblastoma.…”

Section: Discussionmentioning

confidence: 99%

Modifications to the INSM1 promoter to preserve specificity and activity for use in adenoviral gene therapy of neuroendocrine carcinomas

et al. 2012

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The INSM1 gene encodes a transcriptional repressor that is exclusively expressed in neuronal and neuroendocrine tissue during embryonic development that is re-activated in neuroendocrine tumors. Using the 1.7 kbp INSM1 promoter, an adenoviral HSV thymidine kinase gene therapy was tested for the treatment of neuroendocrine tumors. An unforeseen interference on the INSM1 promoter specificity from the adenoviral genome was observed. Attempts were made to protect the INSM1 promoter from the influence of essential adenoviral sequences and to further enhance the tissue specificity of the INSM1 promoter region. Using the chicken b-globin HS4 insulator sequence, we eliminated off-target tissue expression from the Ad-INSM1 promoter-luciferase2 constructs in vivo. In addition, inclusion of two copies of the mouse nicotinic acetylcholine receptor (n(AchR)) neuronal-restrictive silencer element (NRSE) reduced nonspecific activation of the INSM1 promoter both in vitro and in vivo. Further, inclusion of both the HS4 insulator with the n(AchR) 2 Â NRSE modification showed a two log increase in luciferase activity measured from the NCI-H1155 xenograft tumors compared with the original adenovirus construct. The alterations increase the therapeutic potential of adenoviral INSM1 promoter-driven suicide gene therapy for the treatment of a variety of neuroendocrine tumors.

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Long-term tumor-free survival from treatment with the GFP–TRAIL fusion gene expressed from the hTERT promoter in breast cancer cells

Cited by 107 publications

References 16 publications

Death receptor 4 (DR4) efficiently kills breast cancer cells irrespective of their sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

Death receptor 4 (DR4) efficiently kills breast cancer cells irrespective of their sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

Enhanced apoptosis of glioma cell lines is achieved by co-delivering FasL-GFP and TRAIL with a complex Ad5 vector

Modifications to the INSM1 promoter to preserve specificity and activity for use in adenoviral gene therapy of neuroendocrine carcinomas

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