Protease pretreatment increases the efficacy of adenovirus-mediated gene therapy for the treatment of an experimental glioblastoma model.

Abstract

Effective virus-mediated gene therapy for cancer will be facilitated by procedures that enhance the low level of gene transfer mediated by replication-deficient, recombinant viral vectors. We found recently that protease pretreatment of solid tumors is a useful strategy for enhancing virus-mediated gene transduction in vivo. In this study, we examined the potential of protease pretreatment to improve the efficacy of a gene therapy strategy for prodrug activation that depends on infection with a recombinant adenovirus encoding herpes simplex virus thymidine kinase (Ad-HSV-tk). Trypsin or a dissolved mixture of collagenase/dispase was inoculated into xenografts derived from the human glioblastoma multiforme-derived cell lines, U87 or U251. Ad-HSV-tk was administered 24 h after protease pretreatment, and animals were then treated for 10 days with ganciclovir (GCV). We found that protease pretreatment increased the efficacy of adenovirus mediated HSV-tk/GCV gene therapy in these experimental tumor models. Mice receiving Ad-HSV-tk/GCV after protease pretreatment demonstrated a significantly greater regression of tumors compared with those treated with Ad-HSV-tk/GCV alone. No adverse effects of protease pretreatment were observed. No signs of metastasis were seen either by histological inspection of lymph nodes or by a PCR-based analysis of selected mouse tissues to detect human tumor cells. Our findings indicate that protease pretreatment may be a useful strategy to enhance the efficacy of virus-mediated cancer gene therapy.

• Authors: N Kuriyama, H Kuriyama, C M Julin, K R Lamborn, M A Israel
• Journal: Cancer research (Cancer Res) Vol. 61 Issue 5 Pg. 1805-9 (Mar 01 2001) ISSN: 0008-5472 [Print] United States
• PMID: 11280727 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Extracellular Matrix Proteins
• Thymidine Kinase
• Endopeptidases
• Trypsin
• Collagenases
• dispase
• Ganciclovir

Topics

• Adenoviridae (genetics)
• Animals
• Brain Neoplasms (metabolism, pathology, therapy)
• Collagenases (metabolism, pharmacology)
• Endopeptidases (metabolism, pharmacology)
• Extracellular Matrix Proteins (metabolism)
• Female
• Ganciclovir (pharmacology)
• Genetic Therapy (methods)
• Genetic Vectors (genetics)
• Glioblastoma (metabolism, pathology, therapy)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Metastasis
• Rats
• Rats, Inbred F344
• Simplexvirus (enzymology, genetics)
• Thymidine Kinase (genetics, metabolism)
• Trypsin (metabolism, pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays