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

Degrève, Bart; Clercq, Erik De; Balzarini, Jan

doi:10.1038/sj.gt.3300806

Cited by 49 publications

(37 citation statements)

References 30 publications

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“…By restricting HSVtk activity, it is possible to limit the potent bystander effect of ganciclovir activation, thereby enhancing this promising strategy in therapeutic areas where it has already shown efficacy, but with toxicity. For example, therapy of solid tumors, many of which have been successfully treated with HSVtk and ganciclovir 31,32 could be more optimally treated with the use of our anti-hexon antibody adenoviral vector delivery system. HSVtk with co-administration of ganciclovir has also been demonstrated to inhibit the development of experimental arterial restenosis effectively following angioplasty.…”

Section: Discussionmentioning

confidence: 99%

Localized adenovirus gene delivery using antiviral IgG complexation

et al. 2001

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Gene therapy with viral vectors has progressed to clinical trials. However, the localization of viral vector delivery to diseased target sites remains a challenge. We tested the hypothesis that an adenoviral vector could be successfully delivered by complexation with a specific antibody that is bound to a biodegradable matrix designed for achieving localized gene transduction. We report the first successful delivery system based upon antibody immobilization of virions in a type I collagen-avidin gel using a polyclonal biotinylated IgG specific for the adenovirus hexon. In vitro stability studies demonstrated retention of viral vector activity with antibody-complexed adenovirus collagen gel preparations, in comparison to loss of vector activity from collagen gels prepared with nonspecific biotinylated IgG. Cell culture investigations using this antibody-controlled release system for adenoviral vector transduction of rat aortic smooth muscle cells (A10) demonstrated a significantly more localized reporter expression (␤-galactosidase) compared with non-antibody-complexed controls. Herpes simplex thymidine kinase (HSVtk) adenoviral vectors were immobilized on avidin-collagen gels via this antibody-com-

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Section: Discussionmentioning

confidence: 99%

Localized adenovirus gene delivery using antiviral IgG complexation

et al. 2001

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“…Moreover, substituting GCV by BVDU in association with HSVtk significantly alters the bystander effect. This striking observation, also made by Degre Áve et al 60 on osteosarcoma cells expressing HSVtk, cannot be related to a greater or less potent inhibitory effect of the prodrugs on the transduced tumor cell proliferation. Therefore, differences in the drug uptake by the nucleoside transporters are excluded.…”

Section: Discussionmentioning

confidence: 50%

“…62 Furthermore, autoradiographic analysis shows that 3 H-BVDU metabolites formed in HSVtk -expressing tumor cells are incorporated in the DNA of bystander cells less efficiently than 3 H -GCV metabolites. 60 However, this last observation could also be assigned to a more rapid degradation of the 5 H -triphosphate form of pyrimidine nucleotide over purine nucleotide analogues in bystander cells, as reported by Rubsam et al 63 in human glioblastoma cells. Thus, the possible connexin channel selectivity between purine and pyrimidine nucleotides and a more rapid degradation of the triphosphate pyrimidine analogues are factors to take into account when choosing the prodrug to use in tk gene strategy.…”

Section: Discussionmentioning

confidence: 80%

The role of cellular- and prodrug-associated factors in the bystander effect induced by the Varicella zoster and Herpes simplex viral thymidine kinases in suicide gene therapy

Grignet-Debrus

Cool²,

Baudson³

et al. 2000

Cancer Gene Ther

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To investigate the factors influencing the bystander effect Ð a key element in the efficacy of suicide gene therapy against cancer Ð we compared the effect triggered by four extremely efficient gene / prodrug combinations, i.e., VZVtk / BVDU, the thymidine kinase of Varicella zoster virus associated with ( E ) -5 -( 2 -bromovinyl ) -2 H -deoxyuridine; VZVtk / BVaraU, the same enzyme associated with ( E ) -5 -( 2 -bromovinyl ) -1 --D -arabinofuranosyluracil; HSVtk / BVDU, the association of the Herpes simplex virus thymidine kinase with BVDU; and the classical HSVtk / GCV ( ganciclovir ) paradigm. The cells used, the human MDA -MB -435 breast cancer, and the rat 9L glioblastoma lines were equally sensitive in vitro to these four associations. In both cell types, the combinations involving pyrimidine analogues ( BVDU, BVaraU ) displayed a smaller bystander killing than the combination involving the purine analogue ( GCV ) . In addition, the bystander effect induced by all the tk / prodrug systems was reduced in MDA -MB -435 cells in comparison to 9L cells; albeit, the viral kinases were produced at a higher level in the breast cancer cells. All systems induced apoptotic death in the two cell types, but the MDA -MB -435 cells, deprived of connexin 43, were noncommunicating in striking contrast with the 9L cells. That functional gap junctions have to be increased in order to improve the breast cancer cell response to suicide gene therapy was demonstrated by transducing the Cx43 gene: this modification enhanced the bystander effect associated in vitro with GCV treatment and, by itself, decreased the tumorigenicity of the untreated cells. However, the noncommunicating MDA -MB -435 cells triggered a significant bystander effect both in vitro and in vivo with the HSVtk / GCV system, showing that communication through gap junctions is not the only mechanism involved. Cancer Gene Therapy ( 2000 ) 7, 1456 ± 1468Key words: Suicide gene therapy; viral thymidine kinases; bystander effect; connexin 43.G ene therapy is a promising approach for the treatment of human cancers. The introduction into tumoral cells of à`s uicide'' gene, whose product is able to activate a nontoxic prodrug into a toxic compound, is a powerful method to selectively kill the modified cells. The most frequently used system consists of transferring the Herpes simplex thymidine kinase gene ( HSVtk ) into tumor cells and to treat them with ganciclovir (GCV ) . This guanosine analogue is specifically monophosphorylated by the viral kinase and then converted by cellular enzymes into the triphosphate derivative, which, upon incorporation into elongating DNA, induces cell death by premature chain termination. The efficacy of the HSVtk / GCV system first described by Moolten 1 in 1986 has been demonstrated in many different types of tumoral cells in vitro and in vivo, and it is currently under clinical investigation as treatment for a wide variety of cancers.A major obstacle to successful cancer gene therapy is the poor efficiency of the gene transfer process r...

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“…A bystander effect, in conjunction with BVDU treatment, has also been suggested by other studies, although pyrimidine nucleoside analogues ( e.g., BVDU ) appear to exert a less potent bystander effect than purine nucleoside analogues (e.g., GCV ). 45,46 Our observations warrant further investigations in vivo. In preliminary experiments examining a subcutaneous 9L STK tumor model in Balb / c and NMRI nude mice, BVDU did not lead to significant tumor growth reduction (data not shown ).…”

Section: Discussionmentioning

confidence: 60%

(E)-5-(2-Bromovinyl)-2′-deoxyuridine potentiates ganciclovir-mediated cytotoxicity on herpes simplex virus-thymidine kinase–expressing cells

et al. 2001

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Tumor cells expressing the thymidine kinase gene of the herpes simplex virus ( HSV -tk ) are rendered highly susceptible to the cytotoxic effects of different antiherpes drugs. In an attempt to enhance cytotoxicity of this therapeutic approach in glioma and other tumor cell lines transduced with the HSV -tk gene, we evaluated tumor cell killing following co -administration of two different prodrugs metabolized by HSV -tk, ( E ) -5 -( 2 -bromovinyl ) -2 H -deoxyuridine ( BVDU ), and ganciclovir ( GCV ). In 8 of 12 cell lines investigated, addition of BVDU in concentrations showing no cytotoxic effect or only limited cytotoxicity could enhance GCVmediated cell killing by as much as one order of magnitude. In co -cultures consisting of HSV -tk + ( 9L STK ) and HSV -tk À ( 9L wildtype ) cells, we also observed potentiation of GCV -mediated cytotoxicity in the presence of BVDU, suggesting strongly enhanced bystander cell killing. BVDU is thought to exert its cytotoxic effect through inhibition of thymidylate synthase activity or by incorporation into replicating DNA. Both effects could be observed in all HSV -tk ± expressing cells investigated, including cell lines which did not exhibit cytotoxicity after incubation with BVDU. These findings argue against current concepts of BVDU -mediated cytotoxicity in HSV -tk ± expressing cells. Taken together, our data suggest that gene therapy utilizing prodrug activating enzymes may be rendered more effective by simultaneous treatment with two different prodrugs metabolized by the same enzyme. Cancer Gene Therapy ( 2001 ) 8, 388 ± 396

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

Cited by 49 publications

References 30 publications

Localized adenovirus gene delivery using antiviral IgG complexation

Localized adenovirus gene delivery using antiviral IgG complexation

The role of cellular- and prodrug-associated factors in the bystander effect induced by the Varicella zoster and Herpes simplex viral thymidine kinases in suicide gene therapy

(E)-5-(2-Bromovinyl)-2′-deoxyuridine potentiates ganciclovir-mediated cytotoxicity on herpes simplex virus-thymidine kinase–expressing cells

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