Cytostatic inhibition of endothelial cell growth by the angiogenesis inhibitor TNP-470 (AGM-1470)

Kusaka, Masami; Sudo, Katsuichi; Matsutani, Etsuya; Kozai, Yoshio; Marui, Shogo; Fujita, Toshio; Ingber, Donald E.; Folkman, Judah

doi:10.1038/bjc.1994.41

Cited by 223 publications

(125 citation statements)

References 11 publications

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“…Fumagillin class compounds, such as TNP-470, have previously been shown to have potent antiproliferative activity on endothelial cells in vitro (15,20,23,24). Our data are in full agreement with these reports, in that PPI-2458 potently inhibited HUVEC proliferation with a GI 50 of 0.2 nM and a maximum inhibition of Ͼ95% at 1 nM (Fig.…”

Section: Ppi-2458 Is a Potent Inhibitor Of Hfls-ra Proliferationsupporting

confidence: 82%

“…The fungal metabolite fumagillin and several structural analogs such as TNP-470 (AGM-1470) selectively and irreversibly inhibit MetAP-2, via covalent modification of His-231 in the catalytic site of the enzyme (15,(17)(18)(19). This inhibition of the MetAP-2 enzyme activity provides the molecular link that triggers the in vitro growth arrest of human umbilical vein endothelial cells (HUVEC) in the late G 1 phase of the cell cycle (20,21). Fumagillin class compounds have also been proven to be potent angiogenesis inhibitors in vivo, and TNP-470 has advanced into human clinical trials for several oncology indications (22).…”

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confidence: 99%

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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: Ppi-2458 Is a Potent Inhibitor Of Hfls-ra Proliferationsupporting

confidence: 82%

mentioning

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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“…(Yamaoka et al, 1993a,b;Teicher et al, 1994; Time after treatment (days) Kamei et al, 1993;Toi et al, 1993). In this study, the or hyperthermia alone (Figures 2 and 3 o-AC.~., , , (Kusaka et al, 1994).…”

Section: Tg Time Assaymentioning

confidence: 81%

“…TNP-470, a synthetic analogue of fumagillin first isolated from Aspergillus fumigatus, is known to be a potent anti-angiogenic compound (Ingber et al, 1990;Kusaka et al, 1991). It has been found to suppress not only endothelial cell growth in vitro, but also tumour growth in vivo (Brem and Folkman, 1993;Ingber et al, 1990;Kusaka et al, 1991Kusaka et al, , 1994Toi et al, 1994;Yanase et al, 1993;Yamaoka et al, 1993a,b). The antitumour effect in vivo was thought to be due to inhibition of angiogenesis.…”

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confidence: 99%

Combined effects of an angiogenesis inhibitor (TNP-470) and hyperthermia

Nishimura

Murata²,

Hiraoka³

1996

Br J Cancer

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Summary TNP-470, a synthetic analogue of fumagillin first isolated from Aspergillus fumigatus, is known to be a potent anti-angiogenic compound. The combined effects on tumour growth and tumour angiogenesis of TNP-470 and hyperthermia were investigated. The tumour used was SCCVII carcinoma of the C3H/He mouse. The tumour response was evaluated by the tumour growth (TG) time assay. The TG time is the time required for one-half of the treated tumours to reach three times the initial tumour volume. Significant delay of tumour growth was observed by TNP-470 alone (100 mg kg-1 x 2 or x 4), indicating that TNP-470 alone has antitumour effect in vivo. When TNP-470 (100 mg kg-1 x 2 or x 4) was administered after hyperthermia at 44°C, the TG times of the combined treatment were significantly longer than those of heat alone (44°C) or TNP-470 (100 mg kg-I x 2 or x 4) alone. However, the TG time of combined treatment with TNP-470 and hyperthermia at 42°C was quite similar to that of TNP-470 alone. This conflicting result on the combined effect of TNP-470 and hyperthermia may be related to the temperature-dependent vascular damage by hyperthermia. Dose-dependent inhibition of angiogenesis by TNP-470 was demonstrated in microangiograms obtained 4 days and 7 days after hyperthermia (44°C for 30 min). It is, thus, suggested that the combined effect of TNP-470 and hyperthermia is attributable to the inhibition of angiogenesis by TNP-470 following heat-induced vascular damage.

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“…Those studies and studies of other antiangiogenic strategies (20,(26)(27)(28)(29) indicate that angiogenesis inhibition may have therapeutic potential in RA in humans. However, treatment of chronic inflammatory diseases with sustained inhibition of angiogenesis may lead to adverse events due to the blockade of physiologic blood vessel growth.…”

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confidence: 99%

Angiogenesis and the persistence of inflammation in a rat model of proliferative synovitis

Ashraf

Mapp

Walsh

2010

Arthritis & Rheumatism

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Objective. To determine whether blood vessel growth at the onset of resolving synovitis leads to its subsequent persistence and whether inhibiting this angiogenesis at the onset of persistent inflammation leads to its subsequent resolution.Methods. Inflammation and angiogenesis were induced by injection of 0.03% carrageenan and/or 6 pmoles of fibroblast growth factor 2 (FGF-2) into rat knees. A brief treatment with the angiogenesis inhibitor PPI-2458 (5 mg/kg orally on alternate days) was administered 1 day before and up to 3 days after synovitis induction. Controls comprised naive and vehicle-treated rats. Synovial angiogenesis was measured using the endothelial cell proliferation index, and inflammation was determined by measuring joint swelling and macrophage percentage area. Data are presented as the geometric mean (95% confidence interval).Results. Intraarticular injection of 0.03% carrageenan into rat knees produced acute synovitis, which was not associated with synovial angiogenesis and which resolved within 29 days. Injection of FGF-2 (6 pmoles) induced synovial angiogenesis without significant synovitis. Stimulation of angiogenesis with FGF-2 at the time of carrageenan injection was followed by synovitis that persisted for 29 days. Persistence of carrageenan/FGF-2-induced synovitis was prevented by systemic administration of 3 doses of the angiogenesis inhibitor PPI-2458 during the acute phase.Conclusion. Our findings indicate that conversion of acute inflammation to chronic inflammation may be due to the stimulation of angiogenesis, and brief antiangiogenic treatment during the acute phase of synovitis may prevent its subsequent progression. Clinical studies will be needed to determine whether brief antiangiogenic treatment may reduce the burden of inflammatory joint diseases such as rheumatoid arthritis by facilitating the resolution of early synovitis.

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Cytostatic inhibition of endothelial cell growth by the angiogenesis inhibitor TNP-470 (AGM-1470)

Cited by 223 publications

References 11 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

Combined effects of an angiogenesis inhibitor (TNP-470) and hyperthermia

Angiogenesis and the persistence of inflammation in a rat model of proliferative synovitis

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