Back to Search
Start Over
A novel antisense inhibitor of MMP-9 attenuates angiogenesis, human prostate cancer cell invasion and tumorigenicity.
- Source :
-
Cancer Gene Therapy . Nov2003, Vol. 10 Issue 11, p823. 10p. - Publication Year :
- 2003
-
Abstract
- Androgen deprivation therapy causes a paradoxical elevation of matrix metalloproteinases (MMPs) including MMP-9 resulting in aggressive tumor phenotype in many patients with prostate cancer. In this study, we have evaluated a novel antisense phosphorodiamidate Morpholino oligomer (PMO) targeted against MMP-9 in models of angiogenesis and in human prostate xenograft in athymic mice. The treatment of androgen-independent DU145 human prostate cells with a 21-mer MMP-9 antisense PMO caused a dose-dependent inhibition of cell proliferation compared to scrambled or MMP-2 antisense PMO at similar concentrations. This was associated with decreases in MMP-9 expression, gelatinolytic activity and increased stability of the insulin-like growth factor-binding protein (IGFBP-3), a proapoptotic factor and MMP-9 substrate. In vitro invasion assays revealed a 40-60% inhibition of DU145 cell invasion in the presence of 25?µM MMP-9 antisense PMO. A significant decrease in endothelial cell migration and vascularization was observed in the Matrigel plug assay in mice when treated intraperitoneally with 300?µg/day MMP-9 antisense for 21 days. In the highly vascular DU145 tumor xenografts, MMP-9 inhibition caused decreased tumor growth with regression in 50% of the animals. Histological analysis revealed increased apoptosis and fibrous tissue deposits in the MMP-9 antisense-treated tumors compared to the scrambled and saline controls. No apparent toxicity or mortality was associated with the MMP-9 PMO treatment. In summary, the MMP-9 antisense PMO inhibited in vitro prostate cancer cell proliferation, invasion and in vivo angiogenesis. These data establish the feasibility of developing a site-directed, nontoxic antisense therapeutic agent for inhibiting local invasion and metastasis.Cancer Gene Therapy (2003) 10, 823-832. doi:10.1038/sj.cgt.7700642 [ABSTRACT FROM AUTHOR]
- Subjects :
- *ANTISENSE peptides
*OLIGOMERS
*NEOVASCULARIZATION
*XENOGRAFTS
*PROSTATE
Subjects
Details
- Language :
- English
- ISSN :
- 09291903
- Volume :
- 10
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- Cancer Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 11309218
- Full Text :
- https://doi.org/10.1038/sj.cgt.7700642