Gene therapy for malignant mesothelioma: beyond the infant years

Most, Robbert G. van der; Robinson, Bruce; Nelson, Delia J.

doi:10.1038/sj.cgt.7700935

Cited by 25 publications

(24 citation statements)

References 94 publications

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“…42 The use of the HSVTK-GCV system in human trials to cause the death of tumoral cells has not been efficient. [43][44][45][46] A recently improved HSVTK system based on the TK30 mutant is able to increase the killing efficacy of GCV and the bystander effect on animal models of human tumor cells up to 500-fold. 47 The combination of this system with the expression of exogenous wild-type p53 seems to be optimum for clinical trials of suicide-gene therapy of tumoral cells.…”

Section: Discussionmentioning

confidence: 99%

“…48 Other gene strategies are currently in trial for human use, for example, the restitution of the tumor suppressor gene function, downregulation of oncogenic expression, stimulation of immune response, increase of drug sensitivity and modulation of the tumor angiogenesis. 43 This range of possibilities can be explored with the NT-polyplex. The therapeutic effect of the NT-polyplexmediated gene transfer can be magnified with the combined use of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…Several phase I/phase II clinical trials of gene therapy for MM have been carried out using various genes (HSVtk combined with ganciclovir, IL-2, and IFN-h) and have shown gene transduction or T-cell infiltration in tumors injected with therapeutic vectors (25). However, these trials also highlighted the need for further optimization of such treatment regimens and more potent therapeutic genes.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of Inhibition of Differentiation-1 via Activation of Activating Transcription Factor 3 and Smad Regulates REIC/Dickkopf-3–Induced Apoptosis

Kashiwakura

Ochiai

Watanabe³

et al. 2008

Cancer Research

118

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REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, has been investigated in gene therapy studies. Our previous study suggested that REIC/Dkk-3-induced apoptosis mainly resulted from phosphorylation of c-Jun-NH 2 kinase (JNK) in prostate cancer cells. However, the precise mechanisms, especially the molecular mechanisms regulating JNK phosphorylation, remain unclear. In this study, we investigated the mechanisms participating in JNK phosphorylation in the context of a refractory cancer disease, malignant mesothelioma (MM). Adenovirus-mediated overexpression of REIC/Dkk-3 induced apoptosis mainly through JNK activation in immortalized MM cells (211H cells). Interestingly, transcriptional downregulation of inhibition of differentiation-1 (Id-1) was detected in REIC/Dkk-3-overexpressed 211H cells. Moreover, restoration of Id-1 expression antagonized REIC/Dkk-3-induced JNK phosphorylation and apoptosis. Mutagenesis experiments with the 2.1-kb human Id-1 promoter revealed that activating transcription factor 3 (ATF3) and Smad interaction, with their respective binding motifs, was essential for REIC/Dkk-3-mediated suppression of Id-1 promoter activity. ATF3 activation was probably induced by endoplasmic reticulum stress. Finally, we showed strong antitumor effects from REIC/Dkk-3 gene transfer into the pleural cavity in an orthotopic MM mouse model. Relative to control tumor tissue, REIC/Dkk-3-treated tumor tissue showed downregulated expression of Id-1 mRNA, enhanced expression of phosphorylated JNK, and an increased number of apoptotic cells. In summary, we first showed that both ATF3 and Smad were crucially and synergistically involved in down-regulation of Id-1, which regulated JNK phosphorylation in REIC/Dkk-3-induced apoptosis. Thus, gene therapy with REIC/Dkk-3 may be a promising therapeutic tool for MM. [Cancer Res 2008;68(20):8333-41]

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“…Surgery, radical radiotherapy and chemotherapy are still the main lines of treatment 10 . Gene therapy, immuotherapy, photodyamic therapy or hyperthermic chemoperfusion of the pleura are still investigational 11,12 . The challenging issue in treating MPM in Egypt is the unsatisfactory treatment outcome relative to the high financial cost of surgery, chemotherapy and radiotherapy.…”

Section: Introductionmentioning

confidence: 99%