This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kuriyama, N. Articles by Israel, M. A. Search for Related Content PubMed PubMed Citation Articles by Kuriyama, N. Articles by Israel, M. A.

Protease Pretreatment Increases the Efficacy of Adenovirus-mediated Gene Therapy for the Treatment of an Experimental Glioblastoma Model¹

Preuss Laboratory for Molecular Neuro-Oncology, Brain Tumor Research Center, Departments of Neurological Surgery [N. K., H. K., C. M. J., K. R. L., M. A. I.] and Pediatrics [M. A. I.], University of California, San Francisco, California 94143-0520

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.

This article has been cited by other articles:

				S. Libertini, I. Iacuzzo, G. Perruolo, S. Scala, C. Ierano, R. Franco, G. Hallden, and G. Portella Bevacizumab Increases Viral Distribution in Human Anaplastic Thyroid Carcinoma Xenografts and Enhances the Effects of E1A-Defective Adenovirus dl922-947 Clin. Cancer Res., October 15, 2008; 14(20): 6505 - 6514. [Abstract] [Full Text] [PDF]

				S. Ganesh, M. Gonzalez-Edick, D. Gibbons, M. Van Roey, and K. Jooss Intratumoral Coadministration of Hyaluronidase Enzyme and Oncolytic Adenoviruses Enhances Virus Potency in Metastatic Tumor Models Clin. Cancer Res., June 15, 2008; 14(12): 3933 - 3941. [Abstract] [Full Text] [PDF]

				D. Kolodkin-Gal, G. Zamir, Y. Edden, E. Pikarsky, A. Pikarsky, H. Haim, Y. S. Haviv, and A. Panet Herpes Simplex Virus Type 1 Preferentially Targets Human Colon Carcinoma: Role of Extracellular Matrix J. Virol., January 15, 2008; 82(2): 999 - 1010. [Abstract] [Full Text] [PDF]

				M. Magzoub, S. Jin, and A. S. Verkman Enhanced macromolecule diffusion deep in tumors after enzymatic digestion of extracellular matrix collagen and its associated proteoglycan decorin FASEB J, January 1, 2008; 22(1): 276 - 284. [Abstract] [Full Text] [PDF]

				T. D. McKee, P. Grandi, W. Mok, G. Alexandrakis, N. Insin, J. P. Zimmer, M. G. Bawendi, Y. Boucher, X. O. Breakefield, and R. K. Jain Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. Cancer Res., March 1, 2006; 66(5): 2509 - 2513. [Abstract] [Full Text] [PDF]

				D. M. Shayakhmetov, Z.-Y. Li, S. Ni, and A. Lieber Targeting of Adenovirus Vectors to Tumor Cells Does Not Enable Efficient Transduction of Breast Cancer Metastases Cancer Res., February 1, 2002; 62(4): 1063 - 1068. [Abstract] [Full Text] [PDF]

				E. I. Deryugina, L. Soroceanu, and A. Y. Strongin Up-Regulation of Vascular Endothelial Growth Factor by Membrane-type 1 Matrix Metalloproteinase Stimulates Human Glioma Xenograft Growth and Angiogenesis Cancer Res., January 1, 2002; 62(2): 580 - 588. [Abstract] [Full Text] [PDF]