Reduced growth in response to ganciclovir treatment of subcutaneous xenografts expressing HSV-tk in the vascular compartment.
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.
Mavria
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Section for Cell and Molecular Biology, Institute of Cancer Research, London, UK.
Porter
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D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000628:therapy; D003110:Colonic Neoplasms / Q000628:therapy; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology*; D014161:Transduction, Genetic / Q000379:methods; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D011505:Protein-Tyrosine Kinases; D015774:Ganciclovir