Mechanism of ‘bystander effect’ killing in the herpes simplex thymidine kinase gene therapy model of cancer treatment

Ishii-Morita, H; Agbaria, Riad; Mullen, CA; Hirano, Hiroyuki; Koeplin, DA; Ram, Zvi; Oldfield, E H; Johns, D. G.; Blaese, R. Michael

doi:10.1038/sj.gt.3300379

Cited by 123 publications

(70 citation statements)

References 4 publications

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“…A recent report stated that only cell lines able to transfer phosphorylated GCV molecules from cell-to-cell exhibited a long-term bystander effect. 27 However, this study did not clearly demonstrate the involvement of connexins, and is not easily comparable with ours since it was performed on immune-competent mice or by injecting xenogeneic mixtures of cells into nude mice. The number of injected tumorigenic cells was also five to 10 times lower than the number we injected.…”

Section: Figure 4 Hsv-tk and Cx43 Mrna Expression In Tumors Ofcontrasting

confidence: 70%

Long-term connexin-mediated bystander effect in highly tumorigenic human cells in vivo in herpes simplex virus thymidine kinase/ganciclovir gene therapy

et al. 1998

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Section: Figure 4 Hsv-tk and Cx43 Mrna Expression In Tumors Ofcontrasting

confidence: 70%

Long-term connexin-mediated bystander effect in highly tumorigenic human cells in vivo in herpes simplex virus thymidine kinase/ganciclovir gene therapy

et al. 1998

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“…18,27,28 Indeed, the bystander factor is likely to be phosphorylated GCV that enters tk Ϫ cells through cellular junctions. 17 Uptake of phosphorylated GCV released from apoptotic cells may also contribute to the bystander effect. 29 Our studies demonstrated a more pronounced level of tumor regression when both HSVtk-and IL-2-expressing MNNG cells were present (37 of 37 cured in mixture experiments).…”

Section: Discussionmentioning

confidence: 99%

“…15 HSVtk-transduced cells are also toxic to neighboring nontransduced malignant cells through a bystander effect, 16 which appears to involve transfer of phosphorylated GCV through gap junctions. [17][18][19] The efficacy of HSVtk gene therapy is diminished in animals unable to mount an adequate T-cell response and may be improved by strengthening the immune response to tumor-specific antigens. 20 -22 These observations suggest the use of cytokines to enhance the natural immune response as a potential cancer therapy.…”

mentioning

confidence: 99%

Bystander-mediated regression of osteosarcoma via retroviral transfer of the herpes simplex virus thymidine kinase and human interleukin-2 genes

2000

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Current treatment of osteosarcoma produces disappointing outcomes, and innovative therapies must be investigated. We have used retroviral vectors to transfer the herpes simplex virus thymidine kinase (HSVtk) and interleukin-2 genes to human osteosarcoma cells. Each gene was stably transduced and expressed; the HSVtk gene effectively conferred ganciclovir (GCV) susceptibility to transduced cells. A strong bystander effect was observed in vitro, whereby nontransduced tumor cells in proximity to transduced cells acquired susceptibility to GCV killing. Human osteosarcoma cells were used to develop a series of experiments in athymic nude mice to treat experimental osteosarcoma. Subcutaneously implanted mixtures of tumor cells and HSVtk vector producer cells developed into tumors that completely regressed upon administration of GCV. Subcutaneously implanted mixtures of transduced and wild-type cells showed a potent bystander effect upon administration of GCV, with complete tumor ablation when as little as 10% of the cells were HSVtk ϩ . A significant (P Ͻ .05) antitumoral response was seen against primary tumors composed of unmodified cells when a secondary tumor of transduced cells was implanted at a distance of 1 cm, suggesting a diffusible bystander factor. The presence of interleukin-2-transduced cells improved the efficacy of treatment. A significant (P Ͻ .03) antitumoral response was seen in the treatment of established osteosarcomas by the injection of HSVtk vector producer cells.

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“…[23][24][25] This effect increases the therapeutic capacity of this approach; however, a limitation to this system is that the level of intercellular communication varies in different tumors, and may even be blocked in the later stages of carcinogenesis. 24,26,27 We consider, as we will discuss in more detail presently, that the procedure we put forward in this paper shows improvements with respect to the transfer of HSV-tk, because it affects neighboring cells that need not to be joined by gap junctions, thus increasing its range of therapeutic activity.…”

Section: Discussionmentioning

confidence: 99%

Lentiviral transfer of an inducible transgene expressing a soluble form of Gas1 causes glioma cell arrest, apoptosis and inhibits tumor growth

et al. 2010

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Gliomas are the most frequent primary tumors of the central nervous system, and their clinical prognosis remains very poor. Because of the characteristics of gliomas, gene therapy appears as a potentially relevant strategy for their treatment. However, the inability of viral vectors to transfer the therapeutic genes to a significantly high number of tumor cells, due to their limited diffusion and distribution, remains a critical obstacle for their application treating gliomas. We have demonstrated that the overexpression of growth arrest specific1 (Gas1) induces cell arrest and apoptosis and eliminates glioma cells in vitro and when implanted in mice. To improve the therapeutic range of Gas1, we generated lentiviral vectors coding for a soluble form of Gas1. Here, we show that cells infected with this virus produce the mutant protein, that acting both in autocrine and paracrine manners, causes death of infected and neighbor cells, thus importantly enhancing the effect of Gas1. Furthermore, the administration of this vector, or cells expressing it, inhibit the growth of tumors inoculated in mice. We present a gene therapy strategy that increases the effect of the therapeutic molecule by eliminating not just the infected cells that express Gas1, but neighbor non-infected cells.

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Mechanism of ‘bystander effect’ killing in the herpes simplex thymidine kinase gene therapy model of cancer treatment

Cited by 123 publications

References 4 publications

Long-term connexin-mediated bystander effect in highly tumorigenic human cells in vivo in herpes simplex virus thymidine kinase/ganciclovir gene therapy

Long-term connexin-mediated bystander effect in highly tumorigenic human cells in vivo in herpes simplex virus thymidine kinase/ganciclovir gene therapy

Bystander-mediated regression of osteosarcoma via retroviral transfer of the herpes simplex virus thymidine kinase and human interleukin-2 genes

Lentiviral transfer of an inducible transgene expressing a soluble form of Gas1 causes glioma cell arrest, apoptosis and inhibits tumor growth

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