Retinoids augment the bystander effect in vitro and in vivo in herpes simplex virus thymidine kinase/ganciclovir-mediated gene therapy

Park, J Y; Elshami, Ashraf A.; Amin, Kunjlata M.; Rizk, Nahla; Kaiser, Larry R.; Albelda, Steven Μ.

doi:10.1038/sj.gt.3300477

Cited by 53 publications

(33 citation statements)

References 5 publications

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“…By upregulating connexin-43 expression and thus enhancing gap junctional intercellular coupling (GJIC), retinoic acid was able to increase bystander cell killing. 20 In this respect, it should be noted that GJIC is often down-regulated in tumors. 21 Another approach may be based on the identification of new nucleoside analogues that possess superior bystander killing capabilities.…”

Section: Correspondence: J Balzarini Rega Institute For Medical Resementioning

confidence: 99%

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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%

“…The procedure to evaluate the bystander effect of the compounds was modified from Park et al 20 as follows. OstTK − cells were mixed with HSV-1 tk-GFP gene-transfected cells in percentages ranging from 0 to 100% (0, 0.2, 1, 5, 10, 25, 50, 75, 90 and 100%) transfected cells.…”

Section: Bystander Effectmentioning

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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“…Recently, enhancement of the bystander effect on killing of mouse mesothelioma cells by GCV in vivo by treating mice with retinoic acids was correlated with increased Cx43 expression and GJIC capacity in vitro. 30 It thus appears that induction of GJIC can provide a useful increase in the bystander effect and compensate for the low number of tumor cells that incorporate the HSVtk gene when classical viral vectors are used. Since low communication capacity seems to be a common feature of the cancer cell phenotype, 31 it is crucial to make such cells communicate more in situ either by directly injecting GJIC enhancers or by introducing functional connexin genes into the tumor cells.…”

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

confidence: 99%

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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“…[27][28][29] Therefore, pharmacological strategies aiming at upregulating the level of connexins have been proposed in order to increase the BE. [30][31][32][33][34][35] The delivery of connexin genes together with TK has also been evaluated, and it has been shown that the BE could be induced in gap junction deficient cancer cells. 26,36 A very different type of BE that is independent of the level of connexins has been recently reported.…”

Section: Introductionmentioning

confidence: 99%

Direct evidence for the absence of intercellular trafficking of VP22 fused to GFP or to the herpes simplex virus thymidine kinase

et al. 2004

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The treatment of solid tumors by retroviral delivery of the herpes simplex virus thymidine kinase (TK) followed by ganciclovir (GCV) treatment has so far shown only limited success in patients. One major drawback in this approach is the lack of efficient in vivo gene delivery to cancer cells. Although, the transduction of every single tumor cell is not a requirement since the bystander effect (BE) mediated by gap junctions allows the diffusion of the toxic GCV metabolites from TK-expressing cells toward untransduced cells. To render the TK/GCV approach more potent, and independent of the level of gap junctions, we have tested the efficiency of a TK mutant (TK30) fused to VP22, a herpes simplex protein that seems to be capable of intercellular trafficking. We failed to detect an increase in the BE with cells expressing VP22 fused to TK30 versus cells containing TK30 alone, and this result forced us to reinvestigate the trafficking properties of VP22. Using very sensitive Western blot and fluorescence assays, we were not able to detect the spread of VP22 fused either to TK30 or GFP. These results indicate that VP22 cannot be used as a cargo to translocate TK30 or GFP.

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Retinoids augment the bystander effect in vitro and in vivo in herpes simplex virus thymidine kinase/ganciclovir-mediated gene therapy

Cited by 53 publications

References 5 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

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

Direct evidence for the absence of intercellular trafficking of VP22 fused to GFP or to the herpes simplex virus thymidine kinase

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