Gene therapy of hepatoma: bystander effects and non-apoptotic cell death induced by thymidine kinase and ganciclovir

Kaneko, Yoshiyasu; Tsukamoto, Ayumi

doi:10.1016/0304-3835(95)03919-n

Cited by 46 publications

(27 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, cell death in cultures that do show or not a bystander effect proceeds through a similar mechanism, suggesting that apoptotic vesicle transfer is unlikely to be the major factor involved in the toxicity transfer. These results agree with other reports on HSVtk / GCV system demonstrating that a bystander effect can be induced in hepatocarcinoma cells without any evidence of apoptotic cell death 48 and that the transfer of phosphorylated GCV occurs before the appearance of apoptotic degeneration. 49,50 The results presented here show that one of the major factors that differentiate 9L cells from MDA -MB -435 cells is the presence of functional GJIC, thus giving support, at least in part, to the idea that the extent of the bystander effect and the level of gap junctions by which toxic prodrug metabolites can be transferred are correlated.…”

Section: Discussionsupporting

confidence: 93%

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 93%

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

View full text Add to dashboard Cite

show abstract

“…6 This indicates that p53-mediated apoptosis may be significantly involved in the induction of HSV-tk/GCV-induced cell death. 23,40 However, it cannot be excluded that the HSV-tk/GCV system also induces to some extent nonapoptotic cell death in human HCC cells that has been previously described for rat hepatoma cells and murine melanoma cells 2,28 or by an irreversible G2-M arrest. 43 Because cellular p53 accumulation induces Fas-mediated apoptosis by transcriptional activation of the Fas gene 44 and by cell-surface trafficking of Fas, 45 we analyzed Fas expression on the cell surface of p53-positive HepG2 and p53-negative Hep3B cells, as well as the induction of FasL following treatment with HSV-tk/GCV and PNP/fludarabine, respectively.…”

Section: Discussionmentioning

confidence: 95%

“…Tumor therapy based on the expression of suicide genes has become an attractive therapeutic strategy for human malignancies such as hepatocellular carcinoma (HCC), [1][2][3][4][5][6] which is a malignant tumor with increasing incidence. 7,8 HCC is highly resistant to chemotherapeutic agents and radiotherapy, 9 which may be caused by molecular changes occurring during oncogenesis such as overexpression of the multidrug resistance gene 10 and loss or mutations of tumor suppressor genes.…”

mentioning

confidence: 99%

Mechanisms of cell death induced by suicide genes encoding purine nucleoside phosphorylase and thymidine kinase in human hepatocellular carcinoma cells in vitro

Krohne

Shankara²,

Geißler

et al. 2001

Hepatology

View full text Add to dashboard Cite

“…6 Studies with colorectal carcinoma, glioma and melanoma cells 7 have concluded that the GCV killing of HSVtk-transduced tumor cells, as well as the 'bystander' effect is manifested by apoptosis, such as fragmentation of chromatin DNA revealed by the electrophoretic 'laddering pattern', 8 although another study using the same parameter on rat hepatoma cells reached the opposite conclusion. 9 In our previous study, kinetic analysis with additional indicators showed that apoptosis could indeed be induced by the HSVtk/GCV strategy but was slow in occurrence and preceded sequentially by p53 elevation and cell cycle S-phase retardation as well as G2 arrest, which might vary in different tumors. 7 Transduction with the bcl-2 gene was reported to confer resistance to the HSVtk/GCV induction of apoptosis and the bystander effect.…”

Section: Introductionmentioning

confidence: 92%

Involvement of Fas (CD95/APO-1) and Fas ligand in apoptosis induced by ganciclovir treatment of tumor cells transduced with herpes simplex virus thymidine kinase

Wei

Chao²,

Shih

et al. 1999

Gene Ther

View full text Add to dashboard Cite

Transduction of cancer cells with herpes simplex virus thy-HSVtk-transduced tumor cells after the cell cycle arrest midine kinase gene (HSVtk) followed by prodrug gancicloand before apoptosis. Increased expression of FasL could vir (GCV) treatment has been shown to induce apoptosis. also be observed in vivo in HSVtk-transduced tumors In this study, four murine tumors including B16F10 melainduced to regress by GCV treatment. Enzyme measurenoma, NG4TL4 sarcoma, H6 hepatoma and 1MEA 7R.1 ments using specific substrate showed that the caspase-3 hepatoma were found to vary in sensitivity to this gene activation followed kinetically the FasL expression. More therapy strategy in vitro but, at effective doses of GCV, the than half of the HSVtk/GCV-induced cell death could be HSVtk-transduced cells of all four tumors showed similar abrogated by addition to the cell culture medium of a spekinetics of early rise in p53 protein levels, then cell cycle cific antisense oligonucleotide to block FasL synthesis, a S-/G2-phase arrest and finally signs of apoptosis. Immunorecombinant Fas/Fc chimeric protein to compete with Fas blot analyses revealed that Fas (CD95/APO-1), Fas ligand receptor for FasL binding, or cell-permeable specific tetra-(FasL) and two downstream mediators, RIP and caspase-3 peptide inhibitors of caspase-3 or caspase-8. (CPP32, YAMA, Apopain) were increased in GCV-treated

show abstract

Gene therapy of hepatoma: bystander effects and non-apoptotic cell death induced by thymidine kinase and ganciclovir

Cited by 46 publications

References 14 publications

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

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

Mechanisms of cell death induced by suicide genes encoding purine nucleoside phosphorylase and thymidine kinase in human hepatocellular carcinoma cells in vitro

Involvement of Fas (CD95/APO-1) and Fas ligand in apoptosis induced by ganciclovir treatment of tumor cells transduced with herpes simplex virus thymidine kinase

Contact Info

Product

Resources

About