Disease relevance of Fumidil

• Purified fumagillin inhibited endothelial cell proliferation in vitro and tumour-induced angiogenesis in vivo; it also inhibited tumour growth in mice, but prolonged administration was limited because it caused severe weight loss [1].
• The anti-angiogenic agent fumagillin covalently modifies a conserved active-site histidine in the Escherichia coli methionine aminopeptidase [2].
• The effect of the potent angiogenesis inhibitor O-(chloroacetyl-carbamoyl)fumagillol (TNP-470), a semisynthetic analogue of fumagillin, on tumor growth and metastasis was studied using rodent tumors [3].
• Suppression of hepatoma growth and angiogenesis by a fumagillin derivative TNP470: possible involvement of nitric oxide synthase [4].
• Fumagillin analog in the treatment of Kaposi's sarcoma: a phase I AIDS Clinical Trial Group study. AIDS Clinical Trial Group No. 215 Team [5].

High impact information on Fumidil

• The molecular target of fumagillin is methionine aminopeptidase-2 (MetAP-2) [6].
• Fumagillin-based drugs inhibit MetAP-2 but not MetAP-1, and the three-dimensional structure also indicates the likely determinants of this specificity [6].
• The fungal metabolite fumagillin suppresses the formation of new blood vessels, and a fumagillin analog is currently in clinical trials as an anticancer agent [6].
• We demonstrate that fumagillin selectively inhibits the S. cerevisiae MetAP-2 protein in vivo [7].
• This fumagillin binding protein was found to be a metalloprotease, methionine aminopeptidase (MetAP-2), that is highly conserved between human and Saccharomyces cerevisiae [7].

Chemical compound and disease context of Fumidil

• A fumagillin derivative angiogenesis inhibitor, AGM-1470, inhibits activation of cyclin-dependent kinases and phosphorylation of retinoblastoma gene product but not protein tyrosyl phosphorylation or protooncogene expression in vascular endothelial cells [8].
• Current therapies for microsporidiosis include benzimidazoles, which bind tubulin-inhibiting microtubule assembly, and fumagillin and its derivatives, which bind and inhibit methionine amino peptidase type 2 (MetAP2) [9].
• PURPOSE: To present a rare case of microsporidial keratoconjunctivitis in an otherwise healthy contact lens wearer without human immunodeficiency virus infection who responded to treatment with systemic albendazole and topical fumagillin [10].
• TNP-470 (TNP), an analog of fumagillin, inhibits cell proliferation and tumorigenesis in estrogen-induced pituitary tumors in rats [11].

Biological context of Fumidil

• A 1.8 A resolution crystal structure of free and inhibited human MetAP-2 shows a covalent bond formed between a reactive epoxide of fumagillin and histidine-231 in the active site of MetAP-2 [6].
• Inhibition of hepatic stellate cell proliferation and activation by the semisynthetic analogue of fumagillin TNP-470 in rats [12].
• In this study, we investigated, by microarray analysis, the effects of two known antiangiogenic agents (endostatin and fumagillin) on the gene expression profiles of human umbilical vein endothelial cells (HUVEC) in order to elucidate pathways common to the effects of these agents [13].
• Consistently, fumagillin induced apoptosis, owing to early mitochondrial damage, in malignant, but not in normal mesothelial cells [14].
• Fumagillin, an antibiotic reported to exhibit selective activity against ras transformed cells showed very marked and selective cytostatic effects against HT1080scc2 cells with IC50 values as low as 1 x 10(-11) M [15].

Anatomical context of Fumidil

• The fumagillin analogue TNP-470 inhibits DNA synthesis of vascular smooth muscle cells stimulated by platelet-derived growth factor and insulin-like growth factor-I. Possible involvement of cyclin-dependent kinase 2 [16].
• In addition, we show that Nf1-deficient astrocytes overexpress MetAP2 in vitro and in vivo, and that treatment with the MetAP2 inhibitor fumagillin significantly reduces Nf1-/- astrocyte proliferation in vitro [17].
• To understand the importance of fumagillin binding to p67, we measured the level of p67 in mouse C2C12 myoblasts treated with fumagillin [18].
• PURPOSE: Inhibitory effects of TNP-470, a synthetic analogue of the antibiotic fumagillin secreted by Aspergillus fumigatus, were studied with respect to growth and lung metastasis of the hormone-independent rat prostatic carcinoma cell line AT6 [19].
• Fumagillin suppresses HIV-1 infection of macrophages through the inhibition of Vpr activity [20].

Associations of Fumidil with other chemical compounds

• These results, in agreement with a recent structural study, suggest that fumagillin and ovalicin inhibit MetAP2 by irreversible blockage of the active site [21].
• The antiangiogenic agent fumagillin (Fg) and its analog TNP-470 bind to intracellular metalloprotease methionine aminopeptidase-2 (MetAP-2) and inhibit endothelial cell growth in a p53-dependent manner [22].
• An analog of fumagillin, AGM-1470, is currently undergoing clinical trials for the treatment of a variety of cancers [23].
• With this in vitro method, the 50% inhibitory concentrations of fumagillin, thiabendazole, albendazole, oxibendazole, and propamidine isethionate for E. cuniculi in rabbit kidney cells were determined [24].
• Gliotoxin significantly slowed ciliary beat frequency in association with epithelial damage at concentrations above 0.2 microgram/ml; other Aspergillus toxins, i.e., fumagillin and helvolic acid, were also cilioinhibitory but at much higher concentrations [25].

Gene context of Fumidil

• In the MAP1A KO context, modulating MAP2 activity by treatment with various concentrations of the specific drug fumagillin impaired plant development, with particularly strong effects on the root system [26].
• Bone morphogenetic protein (BMP) is a potent inducer of ectopic bone formation, and TNP-470, a synthetic analog of fumagillin, is an antiangiogenic agent that strongly inhibits neovascular formation in vivo [27].
• When HUVEC and A549 cells were treated simultaneously with MetAP-2 siRNA and PPI-2458, or fumagillin, which irreversibly inhibit MetAP-2 enzyme activity, no additive effect on maximum growth inhibition was observed [28].
• We show that fumagillin increases the stability of p67 by decreasing its turnover rate [18].
• The binding is highly specific as judged by the failure of fumagillin to inhibit MetAP-1 in vivo [7].

Analytical, diagnostic and therapeutic context of Fumidil

• Site-directed mutagenesis of His-231 demonstrated its importance for the catalytic activity of MetAP2 and confirmed that the same residue is covalently modified by fumagillin [21].
• Potential efficacy of fumagillin in intestinal microsporidiosis due to Enterocytozoon bieneusi in patients with HIV infection: results of a drug screening study. The French Microsporidiosis Study Group [29].
• Samples of the spore diffusate were subject to reversed phase high performance liquid chromatography (HPLC), thin layer chromatography (TLC), high performance thin layer chromatography (HPTLC), or organic extraction followed by TLC or HPLC to identify the presence of gliotoxin, fumagillin, helvolic acid, fumigaclavine-C, and aurasperone-C [30].
• Interaction between tacrolimus and fumagillin in two kidney transplant recipients [31].
• Fischer 344 rat recipients of Lewis allografts were treated with TNP-470, a synthetic fumagillin derivative and a well-established angiogenesis inhibitor [32].

References