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Reduced growth in response to ganciclovir treatment of subcutaneous xenografts expressing HSV-tk in the vascular compartment

Gene Therapy volume 8, pages 913–920 (2001)Cite this article

Abstract

Using a recombinant retrovirus with ecotropic envelope we have achieved high efficiency of transduction of endothelial cells in the vasculature of subcutaneous xenografts arising from the co-injection of tumour cells and irradiated virus producers. We have used this experimental system to assess the efficacy of the herpes simplex virus-thymidine kinase (HSV-tk)/ganciclovir (GCV) prodrug activation system in anti-vascular therapy. Treatment of KSY-1 xenografts with HSV-tk transduction in the vascular compartment with the S-phase-dependent drug GCV resulted in extensive haemorrhagic necrosis, indicative of vascular damage. Therapeutic potential in tumours with transduced endothelial cells comprising 5% or less of the total tumour mass was similar to that of tumours with HSV-tk expression in over 46% of tumour cells. GCV treatment of animals bearing MDA-MB-361 breast carcinoma, SW620 and CACO2 colon carcinomas with HSV-tk expression in the vascular compartment also resulted in reduced tumour growth. We conclude that HSV-tk/GCV prodrug activation is an effective strategy for eradicating tumour vasculature, and that direct targeting of proliferating endothelial cells in established vasculature results in reduced tumour growth. The therapeutic potential observed with the slow-growing CACO2 colon and MDA-MB-361 breast carcinomas supports the notion that anti-vascular therapy targeted at proliferating endothelium is likely to prove efficacious in human cancers that generally grow at a lower rate than experimental tumours.

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Acknowledgements

This work was fumded by the Medical Research Council. We thank Professor CJ Marshall and Dr R Marais for advice and comments on the manuscript. We are grateful to CellGeneSys, Inc. for the plasmid pMFG-S-, and to Gene Therapy, Inc. for the plasmid pG1TK1SVNa (originally supplied to Professor M Collins and used with permission). We are also grateful to Dr F-L Cosset, University of Lyons for the packaging cell lines and to Dr RC Gallo, University of Maryland for the KS Y-1 cell line. We would also like to thank the members of BSU for animal husbandry and Sue Clinton for preparing tumour sections.

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  1. Section for Cell and Molecular Biology, Institute of Cancer Research, London, UK

    G Mavria & CD Porter

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Mavria, G., Porter, C. Reduced growth in response to ganciclovir treatment of subcutaneous xenografts expressing HSV-tk in the vascular compartment. Gene Ther 8, 913–920 (2001). https://doi.org/10.1038/sj.gt.3301483

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