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

journal_name

Gene Ther

journal_title

Gene therapy

authors

Touraine RL,Ishii-Morita H,Ramsey WJ,Blaese RM

doi

10.1038/sj.gt.3300784

keywords:

subject

Has Abstract

pub_date

1998-12-01 00:00:00

pages

1705-11

issue

12

eissn

0969-7128

issn

1476-5462

journal_volume

5

pub_type

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