© 2004 by Oxford University Press
© 2004 Oxford University Press
ARTICLE |
Effect of Deoxyribozymes Targeting c-Jun on Solid Tumor Growth and Angiogenesis in Rodents
Affiliations of authors: Centre for Vascular Research, The University of New South Wales and Department of Haematology, The Prince of Wales Hospital, Sydney, Australia (GZ, LMK); Johnson & Johnson Research, Sydney (CRD, LQS); Gribbles Pathology, Melbourne, Australia (ES); Inflammation Research Unit, University of New South Wales (NDG).
Correspondence to: Levon M. Khachigian, PhD, Centre for Vascular Research, The University of New South Wales, Sydney NSW 2052, Australia (e-mail: l.khachigian{at}unsw.edu.au)
Background: The basic region-leucine zipper protein c-Jun has been linked to cell proliferation, transformation, and apoptosis. However, a direct role for c-Jun in angiogenesis has not been shown. Methods: We used human microvascular endothelial cells (HMEC-1) transfected with a DNAzyme targeting the c-Jun mRNA (Dz13), related oligonucleotides, or vehicle in in vitro models of microvascular endothelial cell proliferation, migration, chemoinvasion, and tubule formation, a rat model of corneal neovascularization, and a mouse model of solid tumor growth and vascular endothelial growth factor (VEGF)–induced angiogenesis. All statistical tests were two-sided. Results: Compared with mock-transfected cells, HMEC-1 cells transfected with Dz13 expressed less c-Jun protein and possessed lower DNA-binding activity. Dz13 blocked endothelial cell proliferation, migration, chemoinvasion, and tubule formation. Dz13 inhibited the endothelial cell expression and proteolytic activity of MMP-2, a c-Jun–dependent gene. Dz13 inhibited VEGF-induced neovascularization in the rat cornea compared with vehicle control (Dz13 versus vehicle: 4.0 neovessels versus 30.7 neovessels, difference = 26.7 neovessels; P = .004; area occupied by new blood vessels for Dz13 versus vehicle: 0.35 mm2 versus 1.52 mm2, difference = 1.17 mm2; P = .005) as well as solid melanoma growth in mice (Dz13 versus vehicle at 14 days: 108 mm3 versus 283 mm3, difference = 175 mm3; P = .006) with greatly reduced vascular density (Dz13 versus vehicle: 30% versus 100%, difference = 70%; P<.001). Conclusion: DNAzymes targeting c-Jun may have therapeutic potential as inhibitors of tumor angiogenesis and growth.
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- Angiogenesis and c-Jun
- Judah Folkman
J Natl Cancer Inst 2004 96: 644.[Extract] [Full Text] [PDF]
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