The bystander effect in the HSVtk/ganciclovir system and its relationship to gap junctional communication

Abstract

The bystander effect (BSE) is an interesting and important communication. We confirmed that mixtures of tumor cells property of the herpes thymidine kinase/ganciclovir resistant to the BSE did not show dye transfer from cell to (hTK/GCV) system of gene therapy for cancer. With the cell while bystander-sensitive tumor cells did. Dieldrin, a BSE, not only are the hTK expressing cells killed upon gandrug known to decrease GJ communication, diminished ciclovir (GCV) exposure but also neighboring wild-type dye transfer and also inhibited the BSE. Forskolin, an uptumor cells. On testing a large number of tumor cell lines regulator of cAMP did increase GJ, but directly inhibited in vitro, a wide range of sensitivity to bystander killing was hTK and therefore its effect on BSE could not be deterfound. Since transfer of toxic GCV metabolites from hTKmined. We conclude that these observations further supmodified to wild-type tumor cells via gap junctions (GJ) port the concept that functional GJ play an important role seemed to be a likely mechanism of the BSE, we tested in the BSE and further suggest that pharmacological GJ function in these various tumors with a dye transfer manipulation of GJ may influence the outcome of cancer technique and pharmacological agents known to affect GJ therapy with hTK/GCV.

Herpes simplex virus thymidine kinase/ganciclovir system in multicellular tumor spheroids

“…27 Gap junctions, cellular channels built up by proteins called connexins, are of special interest because they allow the transfer of toxic GCV metabolites from HSVtk-transfected tumor cells to the wild-type tumor cells, thus contributing to cell death. 27,28 Most tumors and cancer cell lines have lost their ability to communicate through gap junctions.…”

“…27 Gap junctions, cellular channels built up by proteins called connexins, are of special interest because they allow the transfer of toxic GCV metabolites from HSVtk-transfected tumor cells to the wild-type tumor cells, thus contributing to cell death. 27,28 Most tumors and cancer cell lines have lost their ability to communicate through gap junctions. 29,30 Since in MCS, the expression of connexins is usually downregulated with respect to monolayers, 31 we investigated the expression of connexin-43 (Cx43), a major gap junction-forming connexin protein in these 2D-and 3D-cultured tumor cells.…”

GCV phosphates are transferred between HeLa cells despite lack of bystander cytotoxicity

“…22 In HSV-TK/ GCV therapy, bystander cytotoxicity has been effective at killing cocultures of HSV-TK-expressing and HSV-TKnon-expressing cells in vitro and at reducing tumor size in vivo. 10,11,[29][30][31][32][33][34][35][36] HSV-TK expression in as few as 10% of tumor cells in vivo resulted in tumor regression or a significant reduction in tumor growth when GCV was administered. Bystander cytotoxicity has been attributed to the transfer of phosphorylated GCV metabolites from HSV-TK-expressing cells to non-HSV-TK-expressing bystander cells, presumably via protein channels known as gap junctions.…”

Lentiviral transfer of an inducible transgene expressing a soluble form of Gas1 causes glioma cell arrest, apoptosis and inhibits tumor growth

“…Interestingly, the effects of this type of vectors are amplified by the bystander effect, caused by the passage of the toxic metabolites to cells connected by gap junctions. [23][24][25] This effect increases the therapeutic capacity of this approach; however, a limitation to this system is that the level of intercellular communication varies in different tumors, and may even be blocked in the later stages of carcinogenesis. 24,26,27 We consider, as we will discuss in more detail presently, that the procedure we put forward in this paper shows improvements with respect to the transfer of HSV-tk, because it affects neighboring cells that need not to be joined by gap junctions, thus increasing its range of therapeutic activity.…”