1. ¹Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York, USA
2. ²Department of Medicine, New York University School of Medicine, New York, New York, USA
3. ³Department of Veterans Affairs, Manhattan Campus of New Harbor Health Care System, New York, New York, USA
4. ⁴Department of Otolaryngology—Head and Neck Surgery, New York University School of Medicine, New York, New York, USA
5. ⁵Department of Pathology, New York University School of Medicine, New York, New York, USA
6. ⁶Cancer Institute, New York University School of Medicine, New York, New York, USA

Correspondence: John G. Hay, New York University School of Medicine, Room NBV 7N24, 550 First Avenue, New York, New York 10016, USA. E-mail: john.hay@med.nyu.edu

^†Deceased.

Received 21 February 2006; Accepted 15 June 2007; Published online 24 July 2007.

Abstract

The success of replicating adenoviruses for cancer therapy is limited by inefficient virus delivery and poor distribution within the tumor mass. Stromal matrix within the tumor may hinder the free cell-to-cell spread of the virus. In this study, in vitro cell culture experiments showed that collagen I blocked the passage of an adenoviral vector through a membrane. On the basis of reports of the effective collagen I–degrading activity of matrix metalloproteinase-8 (MMP-8), we constructed an adenovirus to express the MMP-8 transgene (AdMMP8). A549 cells infected in vitro with AdMMP8 did not show altered growth but were able to modify a fibrillar collagen substrate to allow viral diffusion. Further, AdMMP8 did not affect replication of the wild-type virus (Adwt300). Established human A549 lung cancer and BxPC-3 pancreatic cancer xenograft tumors that were injected with Adwt300 together with the non-replicating AdMMP8 virus showed significantly reduced growth compared with control tumors. Histochemical analysis showed reduced amounts of collagen within necrotic areas of MMP-8-injected tumors compared with controls. These results demonstrate that intra-tumoral expression of MMP-8 is a possible strategy for improving viral spread and improving the oncolytic activity of replicating adenovirus.