A novel angiogenesis inhibitor suppresses rat adjuvant arthritis

Peacock, Derek J.; Banquerigo, Mona Lisa; Brahn, Ernest

doi:10.1016/0008-8749(95)80025-e

Cited by 67 publications

(48 citation statements)

References 14 publications

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“…PPI-2458 markedly attenuated paw swelling in a dose-dependent manner with maximal protection at an orally administered dose of 50 mg͞kg at day 31. TNP-470 has previously been reported to protect syngeneic female Louvain and female Lewis rats from collagenand adjuvant-induced arthritis, respectively, at a s.c. daily dose of 27 mg͞kg (39)(40)(41). A combination therapy of TNP-470 with taxol, a nonspecific antiproliferative agent that blocks cell cycle progression in G 2 , significantly reduced clinical symptoms of arthritis (40).…”

Section: Discussionmentioning

confidence: 99%

A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis

Bernier

Lazarus

Clark

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

102

118

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The hallmark of rheumatoid arthritis (RA) is the progressive destruction of articular joints, characterized by invasive synovial hyperplasia and pathological neovascularization. Here we report that PPI-2458, a member of the fumagillin class of irreversible methionine aminopeptidase-2 (MetAP-2) inhibitors, potently inhibits the proliferation of human fibroblast-like synoviocytes (HFLS-RA), derived from RA patients, with a growth inhibitory concentration 50 (GI 50) of 0.04 nM and a maximum inhibition of >95% at 1 nM. Human umbilical vein endothelial cells (HUVEC) are similarly inhibited in proliferation by PPI-2458 (GI 50, 0.2 nM). We developed a method to measure the level of MetAP-2 enzyme inhibition after exposure to PPI-2458 and demonstrate that growth inhibition of PPI-2458-sensitive HFLS-RA and HUVEC is linked to MetAP-2 enzyme inhibition, in a dose-dependent fashion. The secretion of several inflammatory mediators such as IL-6 and vascular endothelial growth factor from activated HFLS-RA was not inhibited by PPI-2458. The CNS toxicity profile of PPI-2458, determined by the incidence of seizures, is significantly improved over that of the parental compound TNP-470. In the rat model of peptidoglycan-polysaccharide-induced arthritis, PPI-2458 significantly attenuated paw swelling when therapeutically administered after the onset of chronic disease. We suggest that the mechanism of PPI-2458 action, highly selective and potent antiproliferative activity on HFLS-RA and HUVEC in vitro, a significantly improved CNS toxicity profile, and marked attenuation of chronic disease in the rat peptidoglycan-polysaccharide arthritis model in vivo, positions this compound as a drug for the treatment of RA.

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Section: Discussionmentioning

confidence: 99%

A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis

Bernier

Lazarus

Clark

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

102

118

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“…Our results thus suggest that HO-1 is involved in the angiogenic process in this experimental model. Since the full expression of experimental arthritis depends on the generation of new blood vessels, 55 the inhibition of angiogenesis may play a role in the therapeutic effects of SnPP in adjuvant arthritis.…”

Section: Discussionmentioning

confidence: 99%

Potential role of heme oxygenase-1 in the progression of rat adjuvant arthritis

Devesa

Ferrándiz

Guillén

et al. 2005

Laboratory Investigation

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Rat adjuvant arthritis is an experimental model widely used to evaluate etiopathogenetic mechanisms in chronic inflammation. We have examined the participation of heme oxygenase-1 (HO-1) in this experimental arthritis. In this study, an increased nitric oxide (NO) production in the paw preceded the upregulation of HO-1, whereas selective inhibition of inducible NO synthase (iNOS) after the onset of arthritis decreased HO-1 expression, suggesting that the induction of this enzyme may depend on NO produced by iNOS. Therapeutic administration of the HO-1 inhibitor tin protoporphyrin IX was able to control the symptoms of arthritis. This agent significantly decreased leukocyte infiltration, hyperplastic synovitis, erosion of articular cartilage and osteolysis, as well as the production of inflammatory mediators. In this experimental model, HO-1 can be involved in vascular endothelial growth factor production and angiogenesis. These results support a role for HO-1 in mediating the progression of the disease in this model of chronic arthritis.

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“…VEGF is involved in RA (57) and in collagen-induced arthritis (58). In addition, neovascularization, to which TNF-␣, MMP-2, MMP-9, and VEGF are important contributors, plays an important role in RA (58), AA (59), and DTH (60).…”

Section: Discussionmentioning

confidence: 99%

Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response

Marikovsky

Ziv

Nevo³

et al. 2003

The Journal of Immunology

186

112

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Activation of macrophages leads to the secretion of cytokines and enzymes that shape the inflammatory response and increase metabolic processes. This, in turn, results in increased production of reactive oxygen species. The role of Cu/Zn superoxide dismutase (SOD-1), an important enzyme in cellular oxygen metabolism, was examined in activated peritoneal elicited macrophages (PEM) and in several inflammatory processes in vivo. LPS and TNF-α induced SOD-1 in PEM. SOD-1 induction by LPS was mainly via extracellular signal-regulated kinase-1 activation. Transgenic mice overexpressing SOD-1 demonstrated a significant increase in the release of TNF-α and of the metalloproteinases MMP-2 and MMP-9 from PEM. Disulfiram (DSF), an inhibitor of SOD-1, strongly inhibited the release of TNF-α, vascular endothelial growth factor, and MMP-2 and MMP-9 from cultured activated PEM. These effects were prevented by addition of antioxidants, further indicating involvement of reactive oxygen species. In vivo, transgenic mice overexpressing SOD-1 demonstrated a 4-fold increase in serum TNF-α levels and 2-fold stronger delayed-type hypersensitivity reaction as compared with control nontransgenic mice. Conversely, oral administration of DSF lowered TNF-α serum level by 4-fold, lowered the delayed-type hypersensitivity response in a dose-dependent manner, and significantly inhibited adjuvant arthritis in Lewis rats. The data suggest an important role for SOD-1 in inflammation, establish DSF as a potential inhibitor of inflammation, and raise the possibility that regulation of SOD-1 activity may be important in the treatment of immune-dependent pathologies.

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A novel angiogenesis inhibitor suppresses rat adjuvant arthritis

Cited by 67 publications

References 14 publications

A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis

A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis

Potential role of heme oxygenase-1 in the progression of rat adjuvant arthritis

Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response

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