Human semicarbazide-sensitive amine oxidase (SSAO) or vascular adhesion protein-1 (VAP-1) is a copper-containing amine oxidase (AOC3, EC 1.4.3.6) that has both enzymatic and adhesive function. SSAO catalyzes the oxidative deamination of primary amines, resulting in the formation of the corresponding aldehyde and release of hydrogen peroxide and ammonia. Membrane-bound SSAO is an inflammation-inducible endothelial cell adhesion molecule that mediates the interaction between leukocytes and activated endothelial cells in inflamed vessels. Both the direct adhesive and enzymatic functions seem to be involved in the adhesion cascade. LJP 1207 [NЈ-(2-phenyl-allyl)-hydrazine hydrochloride] is a potent (human SSAO IC 50 ϭ 17 nM), selective, and orally available SSAO inhibitor that blocks both the enzymatic and adhesion functions of SSAO/VAP-1. In a mouse model of ulcerative colitis, LJP 1207 significantly reduces mortality, loss of body weight, and colonic cytokine levels. Quantitative histopathological assessment of colitis activity in this model showed a highly significant suppression of inflammation, injury, and ulceration scores in the animals treated with the SSAO/VAP-1 inhibitor. LJP 1207 also reduced serum levels of tumor necrosis factor-␣ and interleukin 6 in lipopolysaccharide (LPS)-challenged mice and prolonged survival post-LPS-induced endotoxemia. Therapeutic and prophylactic administration of LJP 1207 in the rat carrageenan footpad model also markedly inhibited swelling and inflammation. Overall, the data suggest that small molecule SSAO/VAP-1 inhibitors may provide clinical benefit in the treatment of acute and chronic inflammatory diseases.SSAO is a copper-containing amine oxidase that converts primary amines into the corresponding aldehydes while releasing ammonia and hydrogen peroxide (Buffoni and Ignesti, 2000): RCH 2 NH 2 ϩ H 2 O ϩ O 2 3 RCHO ϩ NH 3 ϩ H 2 O 2 . The products of this reaction are notable for their pharmacologic activity. For example, formaldehyde and oxygen free radicals are produced when SSAO processes the physiological substrate methylamine.In mammals, two forms of SSAO have been identified: a tissue-bound form and a soluble plasma form (Lyles, 1996). Several lines of evidence suggest that soluble SSAO originates from the tissue-bound form through proteolytic cleavage (Stolen et al., 2004a). Membrane-bound SSAO is located in the plasma membrane and possesses a single transmembrane portion, a short intracytoplasmic tail, and a large extracellular domain that contains the active center (Li et al., 1998). It is a highly glycosylated dimer with a molecular mass of 180 kDa and contains two subunits and two cupric ions per mole. The active site, containing one Cu 2ϩ and one carbonyl cofactor identified as TPQ connected by a water molecule, is located inside each subunit and communicates with the solvent through a hydrophobic channel (Holt et al., 1998). The TPQ oxygen atoms are hydrogen-bonded to water molecules and/or to the side chain of a conserved amino acid.In contrast to the be...
The accumulation of the glycosaminoglycan hyaluronan (HA) in the extracellular matrix (ECM) of solid tumors contributes to increased tumor interstitial fluid pressure IFP), localized edema and reduced intratumoral blood flow. We recently reported that sustained enzymatic depletion of tumor HA with a pegylated recombinant human hyaluronidase PH20 (PEGPH20) decreases tumor IFP and water content, while significantly increasing vascular perfusion within HA-rich prostate PC3 tumors (Thompson et al, 2010). As localized tissue hypoxia reduces the effectiveness of radiation therapy (Baumgartner et al, 1998), we hypothesized that PEGPH20 treatment would reduce tumor hypoxia, thereby radio-sensitizing tumor cells. To evaluate whether PEGPH20 sensitizes HA-rich tumors, radiotherapy resistant human prostate PC3 cells (2×106) were inoculated into the right tibia periosteum of nude mice (NCR nu/nu) and tumor growth monitored with a high resolution 3D ultrasound. When the tumors reached ∼800 mm3 (n ≥ 8/group), mice were staged into 4 treatment groups: (1) vehicle control; (2) mono-radiotherapy at 2.5 Gy, q3d; (3) PEGPH20 monotherapy, 4.5 mg/kg, i.v. q3d; or (4) PEGPH20 plus radiotherapy. To increase intra-tumoral blood flow, PEGPH20 was administrated 3 hours prior to radiation therapy. Histological evaluation of a subset of mice confirmed that HA was completely degraded 3 hours post- PEGPH20 treatment. At study Day 15, tumor growth inhibition (TGI) with radiation alone or PEGPH20 alone was 99.2% (p=0.009) and 71.4% (p=0.08), respectively, relative to vehicle treated animals. PEGPH20 plus radiotherapy inhibited tumor growth by 140.6% (p=0.0002), relative to vehicle treated animals. The mean tumor size of the PEGPH20 plus radiotherapy group was reduced to ∼550 mm3, with 3-out-of-8 partial regressors (i.e. tumor size decrease to 50% or less of tumor staging size). These findings suggest that PEGPH20-mediated HA removal, and subsequent increase in tumoral blood flow, may increase the efficacy of radiation therapy in hyaluronan-rich tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2501. doi:10.1158/1538-7445.AM2011-2501
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.