Disease relevance of AT 125

• Thirty-two patients with recurrent or residual malignant astrocytomas were treated with AT-125 [1].
• L-(alphaS, 5S)-alpha-Amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125), an antitumor drug isolated from Streptomyces sviceus, is an active site-directed affinity analog of glutamine [2].
• Pretreatment with AT-125 ameliorated 2-bromohydroguinone-induced renal toxicity but did not protect against the CEG-induced renal lesion [3].
• In the present studies, we attempted to inhibit gammaGT activity in human hepatoblastoma (HepG2) cells to examine whether the administration of gammaGT inhibitors, acivicin (AC) and 1,2,3,4-tetrahydroisoquinoline (TIQ) influences cell proliferation and enhances cytostatic action of doxorubicin (DOX) and cisplatin (CP) on HepG2 cells [4].
• The antimetabolite antibiotic L-(alphaS,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) showed significant antitumor activity against L1210 and P388 mouse leukemias and the M5076 mouse ovarian tumor [5].

High impact information on AT 125

• High concentrations of the gamma-GTPase inhibitors, glutathione and AT-125, blocked the metabolism of LTC by endothelium [6].
• The significant reduction in tumor utilization of serum glutathione after treatment with AT-125, a GGTP inhibitor, indicates that GGTP is important in tumor glutathione metabolism [7].
• Inhibition of cell cycle progression of human pancreatic carcinoma cells in vitro by L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, Acivicin (NSC 163501) [8].
• S-(1,2-Dichlorovinyl)-L-glutathione is not toxic when the cells are pretreated with AT-125, an inhibitor of gamma-glutamyl transpeptidase [9].
• Transport of GSH was studied in isolated rat kidney cortical brush-border membrane vesicles in which gamma-glutamyltransferase had been inactivated by a specific affinity labeling reagent, L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) [10].

Chemical compound and disease context of AT 125

• The role of extracellular glutathione (GSH) and membrane-bound gamma-glutamyltranspeptidase (gamma-GT) as contributory factors in the disposition and toxicity of inorganic mercury (HgCl2, 1 mg kg-1, i.p.) was investigated in rats pretreated with acivicin (AT-125, 10 mg kg-1), a gamma-GT inhibitor [11].

Biological context of AT 125

• These compounds stimulate hydrolysis of glutamine and S-methylglutathione and the rate of the inactivation of the enzyme by the gamma-glutamyl site-directed reagent, AT-125 (L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) [12].
• The dose-dependent changes in urinary excretion elicited by AT-125 were paralleled by increased rates of decline of 203Hg body burden and decreased rates of excretion in the feces [13].
• The kinetics of the AT-125-mediated inhibition of gamma-GT differed between species, indicative of potential differences in the regulation of gamma-GT [14].
• Acivicin (also known as AT-125) and IgG isolated from goat anti-gamma-glutamyltransferase antiserum were used to inhibit the activity of gamma-glutamyltransferase (GGT, EC 2.3.2.2) in rat conceptuses cultured from Days 10 to 11 of gestation [15].
• The LD50 of six daily doses of NSC-163501 in BDF1 female mice decreased from 7.5 to 0.3 mg/kg/day by combination treatment with the enzyme [16].

Anatomical context of AT 125

• Transport of intact 2-3H-glycine-labeled GSH occurred into an osmotically active intravesicular space of AT-125-treated membranes [10].
• In the AT-125 pretreatment arm the concentration of PRPP increased 18- and 7-fold above baseline in the tumor and the small intestine, respectively [17].
• After two samples were obtained to establish baseline values, retrograde infusion of AT-125 (30 microLmol/kg BW) was given to inhibit gammaGT activity in the biliary tree [18].

Associations of AT 125 with other chemical compounds

• Incubation of lung membranes with 5 mM AT-125 for 120 min at 25 degrees C resulted in greater than 98% recovery of LTC4 [19].
• Following i.p. administration of LD10 doses of AT-125, DON and azaserine, the specific activities of PRPP anabolizing and catabolizing enzymes were determined [20].
• This indicates that when CP was used as a cytostatic, GSH level rose after treatment with its combination with both AC and aminoguanidine [4].

Gene context of AT 125

• The resynthesis of GSH during a DEM exposure was found to be dependent upon the expression of GGT, as demonstrated by inhibition with AT-125 [21].
• Differential effect of AT-125 on rat renal glutaminase activities [22].
• AT-125 pretreatment did not appear to protect against PAP-induced nephrotoxicity as assessed by renal histopathology, clinical chemistry and proton nuclear magnetic resonance (1H NMR) spectroscopy of urine [23].
• It was found that MIA PaCa-2 gamma-glutamyl transpeptidase (10 nmol/min/10(6) cells) was irreversibly inactivated by AT-125 with an inactivation half-life of 80 minutes at 450 microM [24].
• It was found by DNA flow cytometry that AT-125 preferentially inhibited the cell cycle progression in G1-phase of BT-20 more so than MCF-7 breast carcinoma cells in vitro and that cells washed free of the drug now possessed S-phase DNA content [25].

Analytical, diagnostic and therapeutic context of AT 125

• The effect of the glutamine analog, AT-125, on the cell cycle of MCF-7 and BT-20 human breast carcinoma cells using DNA flow cytometry [25].
• Acivicin [(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid; AT-125; NSC-163501] is a fermentation product of Streptomyces sviceus which is active in a variety of mouse tumor models including the L1210 and P388 leukemias, the M5076 ovarian carcinoma, and the MX-1 human breast tumor xenograft [26].

References