¹Division of Cancer Biology, Department of Biomedical and Therapeutic Sciences, University of Illinois, Peoria, Illinois, USA

²Department of Neurosurgery, University of Illinois, Peoria, Illinois, USA

³Department of Neuro-pathology, University of Illinois, Peoria, Illinois, USA

⁴Department of Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA

⁵Department of Neuro-Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA

⁶Department of Neurological Surgery, Okayama University Medical School, Okayama, Japan

⁷Department of Propedeutic Surgery, Athens University School of Medicine, Athens, Greece

⁸Department of Neurology, University of Ioannina School of Medicine, Ioannina, Greece

Correspondence to: J S Rao, Division of Cancer Biology, Department of Biomedical and Therapeutic Sciences and Department of Neurosurgery, Box 1649, University of Illinois College of Medicine at Peoria, Peoria, Illinois, IL 61656, USA, E-mail: jsrao@uic.edu

Matrix metalloproteinase 9 (MMP-9) is known to play a major role in cell migration and invasion in both physiological and pathological processes. Our previous work has shown that increased MMP-9 levels are associated with human glioma tumor progression. In this study, we evaluated the ability of an adenovirus containing a 528 bp cDNA sequence in antisense orientation to the 5' end of the human MMP-9 gene (Ad-MMP-9AS) to inhibit the invasiveness and migratory capacity of the human glioblastoma cell line SBN19 in in vitro and in vivo models. Infection of glioma cells with Ad-MMP-9AS reduced MMP-9 enzyme activity by approximately 90% compared with mock- or Ad-CMV-infected cells. Migration and invasion of glioblastoma cells infected with Ad-MMP-9AS were significantly inhibited relative to Ad-CMV-infected controls in spheroid and Matrigel assays. Intracranial injections of SNB19 cells infected with Ad-MMP-9AS did not produce tumors in nude mice. However, injecting the Ad-MMP-9AS construct into subcutaneous U87MG tumors in nude mice caused regression of tumor growth. These results support the theory that adenoviral-mediated delivery of the MMP-9 gene in the antisense orientation has therapeutic potential for treating gliomas.

Oncogene (2002) 21, 8011-8019. doi:10.1038/sj.onc.1205894

ECM; MMP-9; MT-MMP; adenovirus; antisense; glioma

ECM, extracellular matrix; MMP, matrix metalloproteinase; MT-MMP, membrane-type MMP; Ad, adenovirus; CMV, cytomegalovirus; MOI, multiplicities of infection; PFU, plaque-forming units; PMA, phorbol myristate acetate