Gene delivery to glioma cells in rat brain by grafting of a retrovirus packaging cell line

Short, M. Priscilla; Choi, B. C.; Lee, J. K.; Malick, Amy; Breakefield, X. O.; Martuza, R. L.

doi:10.1002/jnr.490270322

Cited by 182 publications

(68 citation statements)

References 43 publications

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“…[10][11][12] Therefore, the success of the combined gene/chemotherapeutic approach heavily depends on the so-called bystander effect, 1 ie the killing of nontransfected bystander tumor cells by drug metabolites formed in nearby tk gene-transfected cells. Indeed, complete tumor eradication has been demonstrated even when as few as 10% of the tumor cell inoculum is transfected with the herpes tk gene.…”

Section: Correspondence: J Balzarini Rega Institute For Medical Resementioning

confidence: 99%

Bystander effect of purine nucleoside analogues in HSV-1tk suicide gene therapy is superior to that of pyrimidine nucleoside analogues

1999

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Introduction of the herpes simplex virus type 1 thymidine ganciclovir, were endowed with a pronounced bystander kinase gene into tumor cells, followed by the administration killer effect. Lobucavir (Cyclobut-G), a ganciclovir anaof the antiherpes nucleoside analogue ganciclovir has logue, displayed a two-to three-fold more pronounced been demonstrated to be effective in eliminating solid bystander killer effect than ganciclovir, eliminating, at a tumors in animals. The success of this combination treatconcentration of 10 M, 75% and 90% of a cell population ment largely depends on the bystander effect, ie the killing that contained 5% and 10% tk gene-transfected cells, of nontransfected tumor cells by activated drug carried respectively. These findings were corroborated by autoover from the nearby herpes thymidine kinase (tk) generadiographic analysis that showed that 2′-3 H-BVDU metabtransfected cells. We evaluated the in vitro bystander effect olites formed in the herpes tk gene-transfected tumor cells of several antiherpes purine and pyrimidine nucleoside were much less efficiently incorporated in the DNA of analogues, using a colorimetric assay. All pyrimidine bystander cells than 8-3 H-GCV. This indicates that, under nucleoside analogues, including (E)-5-(2-bromovinyl)-2′-the same experimental conditions, BVDU metabolites deoxyuridine (BVDU), showed low, if any, bystander killing are less prone to pass the gap junctions than GCV effect. In contrast, purine nucleoside analogues, such as metabolites.

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Section: Correspondence: J Balzarini Rega Institute For Medical Resementioning

confidence: 99%

Bystander effect of purine nucleoside analogues in HSV-1tk suicide gene therapy is superior to that of pyrimidine nucleoside analogues

1999

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“…Gene therapymediated delivery of antitumor agents after injection of retroviral-producer cells has been shown to generate prolonged local expression of these inhibitors, resulting in subsequent inhibition of tumor growth. [14][15][16][17][18] Actively dividing tumor cells can serve as the target for in vivo retroviral vector-mediated gene transfer, resulting in enforced expression of the transgene of interest. We chose to deliver TIMP-3 via an in vivo gene transfer approach, utilizing replication-deficient retroviral-producer cells, in order to study the effects on tumor growth in a murine model of neuroblastoma.…”

mentioning

confidence: 99%

Retroviral vector-producer cell-mediated in vivo gene transfer of TIMP-3 restricts angiogenesis and neuroblastoma growth in mice

Spurbeck

Vanin

et al. 2003

Cancer Gene Ther

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Destruction and remodeling of the extracellular matrix occurs during the formation of new blood vessels that are required for tumor growth. We sought to determine whether gene-therapy mediated in vivo delivery of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), using retroviral vector-producer cells, could suppress angiogenesis and subsequent tumor growth in a murine neuroblastoma model. Tumor volume 28 days after coinjection of tumor cells with producer cells generating TIMP-3-encoding retroviral vectors was 21% that of controls, as was the mean tumor vascular index, a measure of blood vessel maturity. When tumors were allowed to reach a mean volume of 0.05 cm 3 before treatment, their size 2 weeks later was 47% relative to controls; larger tumors were not significantly affected. When producer cells were injected at surgical sites following excision of subcutaneous tumors, local recurrence 14 days later was only 22% in TIMP-3 producer cell treated mice as compared to 71% in controls. Unsuccessful transduction of melanoma cells in situ, another tumor of neural crest origin, resulted in unimpaired tumor growth, despite the fact that these tumors are susceptible to TIMP-3 overexpression, demonstrating the importance of tumor cell transduction in this approach. Thus, retroviral vector-producer cell-mediated in vivo gene transfer of TIMP-3 to tumor cells can significantly restrict tumor-induced angiogenesis and tumor growth. This approach may be an effective adjuvant in the treatment of neuroblastoma and other solid tumors refractory to traditional therapy, although it appears to be most effective in smaller tumors or in the setting of minimal residual disease, and the tumor cells must be susceptible to retroviral vector-mediated transduction.

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“…Although inoculation of C6 or 9L glioma tumors with fibroblasts producing retroviral vectors results in transduction of no more than 10% of tumor cells (1,2), curative gene therapy has been demonstrated in some animal models after retroviral transfer of the herpes simplex virus thymidine kinase gene (HSV-tk) to tumor cells (3)(4)(5)(6)(7). Transduced cells become sensitive to ganciclovir (GCV), a guanine analog that causes premature chain termination when incorporated into replicating DNA, thereby disrupting cellular proliferation (8,9).…”

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confidence: 99%

The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro.

Fick

Barker

Dazin

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

187

103

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Herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) viral-directed enzyme prodrug gene therapy causes potent, tumor-selective cytotoxicity in animal models in which HSV-tk gene transduction is limited to a minority of tumor cells. The passage of toxic molecules from HSV-tk+ cells to neighboring HSV-tk-cells during GCV therapy is one mechanism that may account for this "bystander" cytotoxicity. To investigate whether gap junction-mediated intercellular coupling could mediate this bystander effect, we used a flow cytometry assay to quantitate the extent of heterocellular coupling between HSV-tk+ murine fibroblasts and both rodent and human tumor cell lines. Bystander tumor cytotoxicity during GCV treatment in a coculture assay was highly correlated (P < 0.001) with the extent of gap junctionmediated coupling. These (HSV-tk) to tumor cells (3-7). Transduced cells become sensitive to ganciclovir (GCV), a guanine analog that causes premature chain termination when incorporated into replicating DNA, thereby disrupting cellular proliferation (8, 9). The death of tumor cells not transduced with the HSV-tk transgene is called the "bystander effect" (3).Bystander cell killing occurs in cocultures of HSV-tk+ and unmodified HSV-tk-tumor cells when as few as 3% of cells express HSV-tk (10). Bystander killing in the HSV-tk/GCV system requires direct contact between HSV-tk+ cells and bystander cells (11) and is not mediated by soluble factors (10, 12). Toxic GCV metabolites transferred through gap junctions linking neighboring cells has been proposed as one possible mechanism of bystander killing (11,13 11071The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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Gene delivery to glioma cells in rat brain by grafting of a retrovirus packaging cell line

Cited by 182 publications

References 43 publications

Bystander effect of purine nucleoside analogues in HSV-1tk suicide gene therapy is superior to that of pyrimidine nucleoside analogues

Bystander effect of purine nucleoside analogues in HSV-1tk suicide gene therapy is superior to that of pyrimidine nucleoside analogues

Retroviral vector-producer cell-mediated in vivo gene transfer of TIMP-3 restricts angiogenesis and neuroblastoma growth in mice

The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro.

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