Herpes simplex virus thymidine kinase-mediated suicide gene therapy for hepatocellular carcinoma using HIV-1-derived lentiviral vectors

Gerolami, René; Uch, Rathviro; Faivre, J; García, Stéphane; Hardwigsen, Jean; Cardoso, Jorge; Mathieu, Sylvie; Bagnis, Claude; Bréchot, Christian; Mannoni, P

doi:10.1016/j.jhep.2003.10.019

Cited by 27 publications

(21 citation statements)

References 33 publications

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“…This would be consistent with recent observations showing strong antitumoral efficacy in the absence of normal liver toxicity following direct intratumoral injection of a lentiviral vector containing the HSV-tk gene and GCV treatment. 16 However, this study and our current observations are in contrast with the severe liver dysfunction and mortality that arose following systemically administered hepatotropic adenoviral vectors expressing HSV-tk and GCV treatment. 41 These data further confirm that the L nanoparticles may have an improved biosafety profile compared to adenoviral vectors for hepatic gene delivery.…”

Section: Discussioncontrasting

confidence: 74%

“…11,12 HCC is also a target of the HSV-tk/GCV system. [13][14][15][16] However, non-specific expression of suicide genes in nontarget cells may cause undesirable adverse effects, such as bone marrow suppression, 17 and for such therapeutic genes to exert their function in a target-specific manner, it is important to specifically deliver them into the target cells or tissues while obviating inadvertent gene transfer into non-target cells.…”

Section: Introductionmentioning

confidence: 99%

“…[13][14][15][16] These vectors do not have target selectivity which reflects the broad tropism of the viruses from which they are derived. Consequently, many vectors wind up transducing non-target cells which reduces the overall efficacy of the gene therapy approach.…”

Section: Introductionmentioning

confidence: 99%

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Gene therapy of liver tumors with human liver-specific nanoparticles

et al. 2006

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The development of safe and efficient liver-specific gene delivery approaches offers new perspectives for the treatment of liver disease, in particular, liver cancer. We evaluated the therapeutic potential of hepatotropic nanoparticles for gene therapy of liver tumor. These nanoparticles do not contain a viral genome and display the hepatitis B virus L antigen, which is essential to confer hepatic specificity. It has not been shown whether a therapeutic effect could be obtained using L nanoparticles in a human liver tumor xenograft model. Rats bearing human hepatic (NuE) and non-hepatic tumors were injected with L nanoparticles containing a green fluorescent protein (GFP) expression plasmid. GFP expression was observed only in NuE-derived tumors but not in the nonhepatic tumor. The potential for treatment of liver tumors was analyzed using L nanoparticles containing the herpes simplex virus thymidine kinase gene, in conjunction with ganciclovir pro-drug administration. The growth of NuE-derived tumors in L particleinjected rats was significantly suppressed, but not of the non-hepatic tumor control. In summary, this is the first demonstration that nanoparticles could be used for delivery of therapeutic genes with anti-tumor activity into human liver tumors. This intravenous delivery system may be one of the major advantages as compared to many other viral vector systems.

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Section: Discussioncontrasting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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Gene therapy of liver tumors with human liver-specific nanoparticles

et al. 2006

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“…Moreover, a single injection of 10 7 TU of LV-tSMAC was sufficient to prolong the survival of tumor-bearing mice. Herewith, we confirm the feasibility of delivering LVs to tumor cells in situ to induce tumor cell death, a strategy that was previously explored by others, delivering among others suicide genes (29,30).…”

Section: Discussionsupporting

confidence: 82%

Proinflammatory Characteristics of SMAC/DIABLO-Induced Cell Death in Antitumor Therapy

et al. 2012

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Molecular mimetics of the caspase activator second mitochondria-derived activator of caspase (SMAC) are being investigated for use in cancer therapy, but an understanding of in vivo effects remains incomplete. In this study, we offer evidence that SMAC mimetics elicit a proinflammatory cell death in cancer cells that engages an adaptive antitumor immune response. Cancer cells of different histologic origin underwent apoptosis when transduced with lentiviral vectors encoding a cytosolic form of the SMAC mimetic LVtSMAC. Strikingly, treatment of tumor-bearing mice with LV-tSMAC resulted in the induction of apoptosis, activation of antitumor immunity, and enhanced survival. Antitumor immunity was accompanied by an increase of tumor-infiltrating lymphocytes displaying low PD-1 expression, high lytic capacity, and high levels of IFN-g when stimulated. We also noted in vivo a decrease in regulatory T cells along with in vitro activation of tumor-specific CD8 þ T cells by dendritic cells (DC) isolated from tumor draining lymph nodes. Last, tumorspecific cytotoxic T cells were also found to be activated in vivo. Mechanistic analyses showed that transduction of cancer cells with LV-tSMAC resulted in exposure of calreticulin but not release of HMGB1 or ATP. Nevertheless, DCs were activated upon engulfment of dying cancer cells. Further validation of these findings was obtained by their extension in a model of human melanoma using transcriptionally targeted LV-tSMAC. Together, our findings suggest that SMAC mimetics can elicit a proinflammatory cell death that is sufficient to activate adaptive antitumor immune responses in cancer. Cancer Res; 72(6);

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“…Ovarian cancer, 14 hepatocellular carcinoma 15 and prostate cancer 16 have been studied to demonstrate the utility in cell lines or animal tumor models originating from solid human tumors. However, lentivirus vectors have not been studied widely as gene transfer vehicles for cancerous cells for obvious reasons.…”

Section: Discussionmentioning

confidence: 99%

Lentivirus-mediated gene therapy by suppressing survivin in BALB/c nude mice bearing oral squamous cell carcinoma

Jiang¹,

Li²,

Zeng³

et al. 2006

Cancer Biology & Therapy

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Despite advances in surgery, radiotherapy, and chemotherapy, the long-term survival rates with oral squamous cell carcinoma (OSCC) have not significantly improved. Gene therapy for OSCC is currently under investigation in clinical trials. Lentivirus vector is considered to be a promising gene delivery tool, but their value in cancer gene therapy has not been studied thoroughly. Survivin is overexpressed in OSCC, making it a promising target for gene therapy. This study was conducted to determine whether lentivirus-mediated gene therapy by suppressing survivin could be exploited in the treatment of OSCC. A lentivirus vector encoding short hairpin RNA (shRNA) targeting survivin was constructed and transfected into KB cells in vitro. The results showed that survivin was persistently and markedly reduced by lentivirus-mediated RNA interference (RNAi); the growth of KB cells was decreased by 34.2% on day 5; the apoptosis rate induced by vincristine (VCR) was increased by 29.8% and caspase-3 activity was also significantly increased; the IC 50 value of adriamycin (ADM) were 0.09 µg/ml, which indicated that survivin-knockout KB cells were 2.1 times more susceptible to ADM than the control; the clonogenic survival rate at 6 Gy of X ray was 3.7%, less than 15.3% of the control. In the xenograft model, the development of tumors as well as the growth of established tumors was inhibited by transfection of lentivirus. Our study indicates that lentivirus-mediated gene therapy is an attractive strategy in the treatment of OSCC and justifies the use of lentivirus in cancer gene therapy studies.

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Herpes simplex virus thymidine kinase-mediated suicide gene therapy for hepatocellular carcinoma using HIV-1-derived lentiviral vectors

Cited by 27 publications

References 33 publications

Gene therapy of liver tumors with human liver-specific nanoparticles

Gene therapy of liver tumors with human liver-specific nanoparticles

Proinflammatory Characteristics of SMAC/DIABLO-Induced Cell Death in Antitumor Therapy

Lentivirus-mediated gene therapy by suppressing survivin in BALB/c nude mice bearing oral squamous cell carcinoma

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