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

Duflot-Dancer, Agnès; Piccoli, C.; Rolland, Alain; Yamasaki, Hiroshi; Mesnil, Marc

doi:10.1038/sj.gt.3300734

Cited by 25 publications

(10 citation statements)

References 24 publications

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“…In fact, in cells with poor gap junctional intercellular communication (GJIC), a bystander effect by GCV was enhanced after transfection and expression of gap junction protein genes including that encoding connexin 43 (Mesnil et al, 1996). The HeLa cells used in the present study do not communicate well by gap junction, and thus the bystander effect is limited (Duflot-Dancer et al, 1998). In spite of poor GJIC, both ACV and GCV exerted dose-dependent bystander killing in HeLa cells in the present study.…”

mentioning

confidence: 56%

Contribution of a Combination of Ponicidin and Acyclovir/Ganciclovir to the Antitumor Efficacy of the Herpes Simplex Virus Thymidine Kinase Gene Therapy System

Hayashi

Sun

et al. 2002

Human Gene Therapy

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We have previously reported that ponicidin (PND), isolated from Rabdosia ternifolia, potentiates the cell-killing activity of antiherpes prodrugs acyclovir (ACV) and ganciclovir (GCV) in human cancer cells expressing herpes simplex virus thymidine kinase (HSV-TK). To extend these in vitro results to in vivo situations, HSV-TK-expressing HeLa cells were injected into nude mice. The in vivo growth of TK(+) HeLa cells was significantly inhibited by coadministration of PND and ACV, or of PND and GCV, compared with single use of ACV or GCV in spite of lower doses of 1 or 0.25 mg/mouse, respectively. These results indicate that there is a good correlation between this in vivo efficacy and previously reported in vitro efficacy. Because of the insufficiency of incorporation of genes into tumors, bystander cell killing has attracted special interest. In the present study, we determined the ability of PND to potentiate the bystander effects of ACV and GCV in both in vitro and in vivo systems. In vitro combined use of PND with ACV or GCV rendered tumor cells more sensitive to the prodrugs, demonstrating a 1.8- to 97-fold or 2.8- to 26-fold reduction in IC(50) compared with ACV or GCV only, respectively, in 1 to 20% of HSV-TK(+) cells. In the in vivo experiments using nude mice injected with 3 or 10% HSV-TK(+) cells, tumor volume was lower in mice treated with a combination of PND and ACV/GCV than in those treated with ACV or GCV only. No toxicity of PND was seen in mice even at a dose 10-fold higher than that used in the in vivo experiments. These novel strategies could provide benefit to ablative cancer gene therapy by making it feasible to use toxic GCV at lower doses and relatively nontoxic ACV.

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confidence: 56%

Contribution of a Combination of Ponicidin and Acyclovir/Ganciclovir to the Antitumor Efficacy of the Herpes Simplex Virus Thymidine Kinase Gene Therapy System

Hayashi

Sun

et al. 2002

Human Gene Therapy

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“…Indeed this dose produced cell growth inhibition equivalent to that of 3 Gy without the switch, resulting in an exceptionally high radiation dose modifying factor of approximately 4. Whilst a suicide gene is likely to elicit the greatest killing effect in the cells that are induced to express it, we expect that more extensive and widespread prodrug-mediated cell killing would be achieved under in vivo conditions where local (connexinmediated) [24][25][26] or systemic (immune system-mediated) [27][28][29] bystander effects and cytotoxicity synergies 22 will occur. The possibility that the prodrug activating protein could be expressed as a fusion protein with a cellular transporter such as VP22 30 to exploit the sustained expression of the switched vector further, might also be considered.…”

Section: Discussionmentioning

confidence: 99%

A radiation-controlled molecular switch for use in gene therapy of cancer

et al. 2000

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Ionising radiation induces the expression of a number of radiation-responsive genes and there is current interest in exploiting this to regulate the expression of exogenous therapeutic genes in gene therapy strategies for cancer. However, the radiation-responsive promoters used in these approaches are often associated with low and transient levels of therapeutic gene expression. We describe here a novel radiation-triggered molecular switching device based on promoter elements from the radiation-responsive Egr-1 gene and the cre-LoxP site-specific recombination system of the P1 bacteriophage. Using this system, a single, minimally

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“…Gap junctional communication, for instance, can be enhanced by regulating the production of connexins (Cx), membrane proteins considered to be the building blocks of gap junctions and the major factors responsible for the gap junctionmediated bystander phenomenon (Mesnil and Yamasaki, 2000). The transfer of Cx-encoding genes (Cx43, Cx32, Cx40) or chemically induced Cx-overexpression has been shown in tissue culture (in vitro) (Elshami et al, 1996;Ghoumari et al, 1998;Kunishige et al, 1998;Carystinos, et al, 1999;Andrade-Rozental et al, 2000) and in vivo (Dilber et al, 1997;Park et al, 1997;Du¯ot-Dancer et al, 1998;Touraine et al, 1998) to increase intercellular communication and the transfer of toxic agents. It is important to notice that in some human tumour cells not only expression but also correct surface localisation of Cx43 are necessary components of the bystander effect (McMasters et al, 1998), and that Cx-cotransfection appears not be applicable to all tumour systems (Cirenei et al, 1998).…”

Section: The Bystander Effectmentioning

confidence: 99%

Gene directed enzyme/prodrug therapy of cancer: Historical appraisal and future prospectives

2001

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Gene therapy of cancer is a novel approach with the potential to selectively eradicate tumour cells, whilst sparing normal tissue from damage. In particular, gene-directed enzyme prodrug therapy (GDEPT) is based on the delivery of a gene that encodes an enzyme which is non-toxic per se, but is able to convert a prodrug into a potent cytotoxin. Several GDEPT systems have been investigated so far, demonstrating effectiveness in both tissue culture and animal models. Based on these encouraging results, phase I/II clinical trials have been performed and are still ongoing. The aim of this review is to summarise the progress made in the design and application of GDEPT strategies. The most widely used enzyme/prodrug combinations already in clinical trials (e.g., herpes simplex 1 virus thymidine kinase/ganciclovir and cytosine deaminase/5-¯uorocytosine), as well as novel approaches (carboxypeptidase G2/CMDA, horseradish peroxidase/indole-3-acetic acid) are described, with a particular attention to translational research and early clinical results.

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

Cited by 25 publications

References 24 publications

Contribution of a Combination of Ponicidin and Acyclovir/Ganciclovir to the Antitumor Efficacy of the Herpes Simplex Virus Thymidine Kinase Gene Therapy System

Contribution of a Combination of Ponicidin and Acyclovir/Ganciclovir to the Antitumor Efficacy of the Herpes Simplex Virus Thymidine Kinase Gene Therapy System

A radiation-controlled molecular switch for use in gene therapy of cancer

Gene directed enzyme/prodrug therapy of cancer: Historical appraisal and future prospectives

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