VP22 enhanced intercellular trafficking of HSV thymidine kinase reduced the level of ganciclovir needed to cause suicide cell death

The Journal of Gene Medicine
C S LiuM Q Wei

Abstract

The inefficiency of herpes simplex virus thymidine kinase (TK) gene transfer and toxicity of ganciclovir (GCV) at high concentrations in vivo limits the use of this suicide gene therapy approach for the treatment of cancers in clinical settings. To overcome the problem, we have sought evidence of amplification of cytotoxicity by co-transfer of the TK gene fused with the gene encoding HSV-1 structural protein VP22 which has a remarkable ability for intercellular trafficking. The expression of the fusion proteins from the chimeric VP22-TK or VP22-EGFP genes was shown by Western blot and VP22 promoted TK or EGFP intercellular trafficking by an indirect immunofluorescent assay. The cytotoxicity was demonstrated by a colorimetric cell proliferation assay followed by an assessment of the bystander effect on admixtures of transfected with non-transfected naive cells. Our results show the expression of the VP22 fusion proteins and their spread to varying numbers of bystander cells (up to 30, observed in viable cells with VP22-EGFP as well as after methanol fixation), confirming that VP22 assisted intercellular trafficking of the fusion proteins. This VP22 promoted TK spreading resulted in killing by 2.5 microg/ml GCV of virtually all c...Continue Reading

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