Disease relevance of Arasentan

• Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial [1].
• These findings demonstrate that the small molecule ABT-627 is a candidate for clinical testing as an antitumor agent in ovarian cancer patients, especially in combination with taxane therapy [2].
• To test the hypothesis that the endothelin axis is important in lung metastasis, lung metastatic bladder carcinoma cells were injected in mice treated with the endothelin receptor-specific antagonist, atrasentan, thereby blocking engagement of the up-regulated ET-1 ligand with its cognate receptor [3].
• Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics [4].
• Restoration of the microcirculation by treatment with Atrasentan and l-arginine minimized hypoxia and HIF-1alpha stabilization and reduced the accelerated outgrowth of micrometastases by 50% [5].
• We conclude that the MTD of daily oral atrasentan in patients with recurrent malignant glioma is 70 mg/day [6].

High impact information on Arasentan

• The effects of the ET(A)-selective endothelin receptor antagonist A-127722 were evaluated [7].
• The blood pressure of L-NAME hypertensive rats treated with the ETA-selective endothelin receptor antagonist A-127722 for 3 weeks at a low dose (10 mg.kg-1.d-1) and a high dose (30 mg.kg-1.d-1) was not different from that of rats receiving L-NAME but not the endothelin antagonist [8].
• In ovarian carcinoma xenografts, ABT-627, a specific ET(A)R antagonist, suppresses EMT determinants and tumor growth [9].
• ABT-627 effectively inhibits cell proliferation, vascular endothelial growth factor (VEGF) secretion of ovarian carcinoma cell lines, and primary cultures [2].
• The therapeutic efficacy of ABT-627 was associated with a significant reduction in microvessel density, expression of VEGF, and matrix metalloproteinase-2, and increased the percentage of apoptotic tumor cells [2].

Chemical compound and disease context of Arasentan

• Although vasoconstriction disappeared entirely, arrhythmias were only partly suppressed by ET(A) antagonists (BQ-123, 2 micromol/liter; A-127722, 20 micromol/liter) [10].
• Daily administration of ABT-627 for 2 weeks almost abolished any further increases in blood pressure, whereas A-192621 did not affect the development of DOCA-salt-induced hypertension [11].
• 5. Atrasentan reduced diabetic urine flow, proteinuria and plasma creatinine levels, but creatinine clearance was not significantly altered [12].
• Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer [13].
• Treatment with ABT-627 significantly suppressed the norepinephrine overflow induced by the ischemia/reperfusion whereas A-192621 further enhanced it, which was completely abolished by the concomitant treatment with ABT-627 [14].

Biological context of Arasentan

• Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed [4].
• This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients [4].
• In vivo, the inhibition of human ovarian tumor growth in nude mice induced by the potent ETAR antagonist, ABT-627, was associated with a reduction of Cx43 phosphorylation [15].
• Although ABT-627 did not alleviate oxidative stress in HG rats, inflammation and production of inflammatory mediators were reduced in association with prevention of microalbuminuria [16].
• Analysis of covariance including genotype, study, age, weight, sex, and ethnicity was used to identify factors influencing atrasentan single-dose (n = 44) and steady-state (n = 38) pharmacokinetic parameters [17].

Anatomical context of Arasentan

• METHODS: Twenty male Sprague-Dawley rats received either 5 mg/kg of A-127722 or vehicle (n=10 per group) intravenously 30 minutes and subcutaneously 4 hours after middle cerebral artery occlusion (MCAO) [18].
• METHODS: Atrasentan uptake was measured in HeLa cells transfected to express major alleles of organic anion transporting polypeptide 1B1 (OATP1B1) [17].
• Local pretreatment with BQ-123 or A-127722 (150 pmol), two selective and chemically unrelated endothelin ET(A) receptor antagonists, inhibits neutrophil and eosinophil accumulation in LPS-induced pleurisy at 24 h but not neutrophil migration at 4 h [19].
• 6. The data are consistent with choroidal arteriolar smooth muscle cells having two types of Et(A) receptor, one where BQ123 is an antagonist and ABT-627 an agonist, where ligands dissociate freely and this receptor is coupled to inhibition of L-type Ca(2+) channels [20].
• ABT-627 did reduce the accumulation of macrophages in both stains (36 to 53%) whereas it blocked by 76% the influx of eosinophils in Balb/c but not in C57Bl/6 mice [21].

Associations of Arasentan with other chemical compounds

• In the model of exogenous ET-1 infusion, ABT-627 had a tendency to prevent ET-1-induced renal changes more effectively compared with nifedipine [22].
• METHODS: Regional renal hemodynamics and function in vivo were quantified in pigs at baseline and during infusion of acetylcholine using electron beam computed tomography after a 12-week normal diet (N = 6), HC diet (N = 6), and HC diet orally supplemented (4 mg/kg/day) with the selective ET receptor-A (ET-A) blocker ABT-627 (HC+ET-A, N = 6) [23].
• Previously we have reported the discovery of ABT-627 (1, A-147627, active enantiomer of A-127722), a 2,4-diaryl substituted pyrrolidine-3-carboxylic acid based endothelin receptor-A antagonist [24].
• The Ki values for A-127722, PD-156707, FR139317, Ro-47-0203 and L-749329 for the ETA receptor were 0.07, 0.38, 0.80, 3.67 and 33.6 nM, respectively [25].
• 3. Atrasentan treatment significantly improved left ventricular systolic and diastolic function in response to exogenous norepinephrine, but there were no differences between genotypes [12].

Gene context of Arasentan

• Rats were fed a K(+)-deficient diet alone (LC) or with an ETA-selective antagonist ABT-627 (LA) or an ETB-selective antagonist A-192621 (LB) for 8 wk [26].
• Organic anion transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics [17].
• Moreover, inhibition of human ovarian tumor growth in nude mice after treatment with the potent ET(A)R-selective antagonist ABT-627 is associated with reduced COX-2 and vascular endothelial growth factor expression [27].
• BACKGROUND: Some men treated with atrasentan (ABT-627), an endothelin A (ETA) receptor inhibitor, had declines in their serum PSA levels [28].
• METHODS: Two PSA secreting prostate cancer cell lines (LAPC4 and LNCaP) were treated with atrasentan and an ETB receptor antagonist (A192621) in varying concentrations (10(-6)-10(-10) M) and PSA levels were measured in the culture media [28].

Analytical, diagnostic and therapeutic context of Arasentan

• In nude mice, the ET(A)R-selective antagonist atrasentan inhibits the growth and the neoangiogenesis of cervical carcinoma cell xenografts [29].
• In a phase I, single-center, double-blind, randomized, three-period, crossover design, the effects of orally administered ABT-627, a selective ET(A) receptor antagonist, on renal hemodynamics during ET-1 infusion were evaluated [22].
• The pressor response to intravenous injection of Big endothelin-1 (1 nmol/kg, intravenously) was inhibited by > 50% in rats given A-127722 at 10 mg/kg per d, which confirms the efficacy of A-127722 in blocking ETA-mediated responses when placed in drinking water [30].
• Atrasentan was rapidly absorbed after oral administration; mean time to maximum observed concentration ranged from 0.3 to 1.7 h [31].
• The beneficial effect of A-127722 was limited to animals in which successful reperfusion was demonstrated [18].

References