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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2001-03, Vol.61 (5), p.1805-1809
• Main Authors: KURIYAMA, Nagato, KURIYAMA, Hiroko, JULIN, Carol M, LAMBORN, Kathleen R, ISRAEL, Mark A
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animals; Antineoplastic agents; Biological and medical sciences; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Chemotherapy; Collagenases - metabolism; Collagenases - pharmacology; Endopeptidases - metabolism; Endopeptidases - pharmacology; Extracellular Matrix Proteins - metabolism; Female; Ganciclovir - pharmacology; Genetic Therapy - methods; Genetic Vectors - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma - therapy; Humans; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Pharmacology. Drug treatments; Rats; Rats, Inbred F344; Simplexvirus - enzymology; Simplexvirus - genetics; Thymidine Kinase - genetics; Thymidine Kinase - metabolism; Trypsin - metabolism; Trypsin - pharmacology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445

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.