Tissue-specific expression of a suicide gene for selective killing of neuroblastoma cells using a promoter region of the NCX gene

Narita, Mitsuharu; Bahar, Rumana; Hatano, Masahiko; Kang, Myeng M.; Tokuhisa, Takeshi; Goto, Shigemasa; Saisho, Hiromitsu; Sato, Shigeru; Tagawa, Masatoshi

doi:10.1038/sj.cgt.7700408

Cited by 11 publications

(12 citation statements)

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“…INSM1 expression peaks in early fetal development and is absent from normal adult tissues. Although INSM1 is silenced in normal adult tissues, it is highly reactivated in tumors of neuroendocrine origin, which display an ideal expression pattern for use in transcriptionally targeted cancer gene therapy (Narita et al, 2001;Adachi et al, 2002;Steffens et al, 2004;Arvidsson et al, 2005). Using a 1.7-kb (bp À1661 to þ 40) INSM1 promoter-driven LacZ transgenic mouse line, we convincingly demonstrated that the information required for tissue-specific expression of the INSM1 gene is present in the 5 0 -upstream regulatory region (Breslin et al, 2003).…”

Section: Discussionmentioning

confidence: 78%

“…Therefore, alternative treatment options for these forms of cancer are needed. Gene therapy approaches focused toward high-risk neuroblastoma and central nervous system tumors such as medulloblastoma have used common neuronal-specific promoters from the genes encoding midkine, tyrosine hydroxylase, neural crest homeobox (NCX), and Mash1 (Narita et al, 2001;Adachi et al, 2002;Steffens et al, 2004;Arvidsson et al, 2005). Despite promising results from these gene therapy strategies, one significant barrier is the continuous expression of these gene products, with the exception of Mash1, in normal adult neuronal cells.…”

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confidence: 99%

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INSM1Promoter-Driven Adenoviral Herpes Simplex Virus Thymidine Kinase Cancer Gene Therapy for the Treatment of Primitive Neuroectodermal Tumors

et al. 2009

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The INSM1 gene encodes a developmentally regulated zinc finger transcription factor. INSM1 expression is normally absent in adult tissues, but is reactivated in neuroendocrine tumor cells. In the present study, we analyzed the therapeutic potential of an adenoviral INSM1 promoter-driven herpes simplex virus thymidine kinase (HSV-tk) construct in primitive neuroectodermal tumors (PNETs). We constructed an adenoviral INSM1 promoter-driven HSV-tk gene for therapy in PNETs. The PNET-specific adeno-INSM1 promoter HSV-tk construct was tested both in vitro and in vivo in a nude mouse tumor model. Northern blot analysis and transient transfection of an INSM1 promoter-driven luciferase reporter gene indicated that the INSM1 promoter was active in neuroblastoma (IMR-32), retinoblastoma (Y79), and medulloblastoma (D283 Med) cells, but not in glioblastoma (U-87 MG) cells. After Ad-INSM1p-HSV-tk infection, the levels of HSV-tk protein expression were consistent with INSM1 promoter activities. Furthermore, in vitro multiplicity of infection and ganciclovir (GCV) sensitivity studies indicated that the INSM1 promoter could mediate specific expression of the HSV-tk gene and selective killing of INSM1-positive PNETs. In vivo intratumoral adenoviral delivery demonstrated that the INSM1 promoter could direct HSV-tk gene expression in a nude mouse tumor model and effectively repressed tumor growth in response to GCV treatment. Taken together, our data show that the INSM1 promoter is specific and effective for targeted cancer gene therapy in PNETs.

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Section: Discussionmentioning

confidence: 78%

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confidence: 99%

INSM1Promoter-Driven Adenoviral Herpes Simplex Virus Thymidine Kinase Cancer Gene Therapy for the Treatment of Primitive Neuroectodermal Tumors

et al. 2009

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“…10,28 Because of this feature, the brain will be protected from the NT-polyplex-mediated transfection of cell-death-promoting genes. In addition, NTSR1-bearing cells of healthy peripheral tissues can be protected from the deleterious effects of transgene expression using a neuroblastoma cell-specific promoter such as the NCX promoter 36 or a tumor-selective promoter such as the E2F-1 promoter to confine the therapeutic effect within the tumoral cells. 37 In this work, we used the HSVTK-GCV system because of its efficiency to cause cell death in addition to the bystander effect.…”

Section: Discussionmentioning

confidence: 99%

NT-polyplex: a new tool for therapeutic gene delivery to neuroblastoma tumors

et al. 2009

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and 4 Molecular and Steroid hormones, Neurotensin and Tumor Progression INSERM UPMC Cdr Saint-Antoine Eq 7, Paris, France Neurotensin (NT)-polyplex is a nonviral system for the targeted gene delivery to cells that express and internalize the high-affinity NT receptor (NTSR1). In hemiparkinsonian rats, we previously demonstrated the morphological and functional recovery from dopaminergic neurodegeneration using the NT-polyplex as a vehicle to transfect a neurotrophic gene. The main objective of this work was to demonstrate the feasibility of NT-polyplex to transfect reporter or therapeutic genes into neuroblastoma tumors through the blood stream or by intratumoral injection. N1E-115 cells known to express NTSR1 were allografted into athymic mice to generate the neuroblastoma tumor model. Both routes of administration allowed the NT-polyplex to reach and transfect tumoral cells. A low transgene expression was also detected in intestinal tract cells only after the injection into the blood stream. The transfection of the thymidine kinase (HSVTK) suicide gene followed by ganciclovir (GCV) treatment decreased the size and weight of neuroblastoma tumors by 30-50% and increased apoptosis compared to controls. This study shows the potential of the NTpolyplex as specific gene-transfer system for NTSR1 cancer cells.

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“…Suicide gene therapy with the herpes simplex virus thymidine kinase (HSV-TK) fragment, the most widely used strategy for the cancer therapeutic study [3] , has been shown to exert antitumor efficacy in various cancer models [4][5][6][7] . However, its efficacy seems not to be fully developed to eliminate tumor cells in some of the investigations [8][9][10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

Do there exist synergistic antitumor effects by coexpression of herpes simplex virus thymidine kinase with cytokine genes on human gastric cancer cell line SGC7901?

Zhang¹,

Wan²,

Yuan³

et al. 2004

WJG

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AIM:To evaluate the synergistic antitumor effects of herpes simplex virus thymidine kinase (HSV-TK) together with tumor necrosis factor alpha (TNF-α) or interleukin-2 (IL-2) gene expression on gastric cancer cell line SGC7901. METHODS:Recombinant vectors pL(TT)SN and pL(TI)SN, which express TK-IRES-TNF-α and TK-IRES-IL-2 genes separately, as well as the control plasmids pL(TK)SN and pLXSN were employed to transfect PA317 cells respectively to generate the viruses that can stably express the objective genes through G418 selection. The gastric cancer cells were then transfected by the retroviral serum from the package cells and maintained in culture to determine the cell growth and apoptosis. The cytotoxic effects of HSV-TK together with TNF-α or IL-2 gene expression on the transfected cancer cells were evaluated by the cell viability and bystander effects in the presence of GCV supplemented in the cultural medium.

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Tissue-specific expression of a suicide gene for selective killing of neuroblastoma cells using a promoter region of the NCX gene

Abstract: The human NCX gene, a homologue of the murine neural crest homeobox ( Ncx / Hox11L.1 ) gene whose expression is restricted to a subset of neural crest -derived tissues, was expressed in human neuroblastoma cells but not in other tumors or fibroblasts.

Cited by 11 publications

References 13 publications

INSM1Promoter-Driven Adenoviral Herpes Simplex Virus Thymidine Kinase Cancer Gene Therapy for the Treatment of Primitive Neuroectodermal Tumors

INSM1Promoter-Driven Adenoviral Herpes Simplex Virus Thymidine Kinase Cancer Gene Therapy for the Treatment of Primitive Neuroectodermal Tumors

NT-polyplex: a new tool for therapeutic gene delivery to neuroblastoma tumors

Do there exist synergistic antitumor effects by coexpression of herpes simplex virus thymidine kinase with cytokine genes on human gastric cancer cell line SGC7901?

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