Publications [#99276] of Gayathri R Devi

Papers Published

1. CA London, HS Sekhon, V Arora, DA Stein, PL Iversen, GR Devi, A novel antisense inhibitor of MMP-9 attenuates angiogenesis, human prostate cancer cell invasion and tumorigenicity., Cancer gene therapy, vol. 10 no. 11 (November, 2003), pp. 823-32, ISSN 0929-1903 [doi]
   (last updated on 2013/05/16)

   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 microM 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 microg/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.

   Keywords:
   Angiogenesis Inhibitors • Animals • Carcinogenicity Tests • Cell Survival • Enzyme Inhibitors • Humans • Insulin-Like Growth Factor Binding Protein 3 • Male • Matrix Metalloproteinase 9 • Matrix Metalloproteinase Inhibitors* • Mice • Mice, Nude • Neoplasm Invasiveness • Neovascularization, Pathologic • Oligonucleotides, Antisense • Prostate • Prostatic Neoplasms • Tumor Cells, Cultured • blood supply • chemistry • drug effects • drug therapy • drug therapy* • genetics • metabolism • pathology* • pharmacology*