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Chemical Compound Review

AG-K-67612     2-amino-2-(3-chloro-4,5- dihydro-1,2-oxazol...

Synonyms: SureCN1873697, AC1L1CPX, LS-86502, CTK4J6129, AR-1H7012, ...
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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


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 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


  1. Objective antitumor activity of acivicin in patients with recurrent CNS malignancies: a Southwest Oncology Group trial. Taylor, S.A., Crowley, J., Pollock, T.W., Eyre, H.J., Jaeckle, C., Hynes, H.E., Stephens, R.L. J. Clin. Oncol. (1991) [Pubmed]
  2. Mechanism of inactivation of glutamine amidotransferases by the antitumor drug L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125). Tso, J.Y., Bower, S.G., Zalkin, H. J. Biol. Chem. (1980) [Pubmed]
  3. Nephrotoxicity of S-(2-chloroethyl)glutathione in the Fischer rat: evidence for gamma-glutamyltranspeptidase-independent uptake by the kidney. Kramer, R.A., Foureman, G., Greene, K.E., Reed, D.J. J. Pharmacol. Exp. Ther. (1987) [Pubmed]
  4. The effect of modulation of gamma-glutamyl transpeptidase and nitric oxide synthase activity on GSH homeostasis in HepG2 cells. Kwiecień, I., Rokita, H., Lorenc-Koci, E., Sokolowska, M., Włodek, L. Fundamental & clinical pharmacology (2007) [Pubmed]
  5. Therapy for mouse tumors and human tumor xenografts with the antitumor antibiotic AT-125. Houchens, D.P., Ovejera, A.A., Sheridan, M.A., Johnson, R.K., Bogden, A.E., Neil, G.L. Cancer treatment reports. (1979) [Pubmed]
  6. Stimulation of human endothelial cell prostacyclin synthesis by select leukotrienes. Pologe, L.G., Cramer, E.B., Pawlowski, N.A., Abraham, E., Cohn, Z.A., Scott, W.A. J. Exp. Med. (1984) [Pubmed]
  7. gamma-Glutamyl transpeptidase mediation of tumor glutathione utilization in vivo. Hochwald, S.N., Harrison, L.E., Rose, D.M., Anderson, M., Burt, M.E. J. Natl. Cancer Inst. (1996) [Pubmed]
  8. 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). Meck, R.A., Clubb, K.J., Allen, L.M., Yunis, A.A. Cancer Res. (1981) [Pubmed]
  9. The role of glutathione conjugate metabolism and cysteine conjugate beta-lyase in the mechanism of S-cysteine conjugate toxicity in LLC-PK1 cells. Stevens, J., Hayden, P., Taylor, G. J. Biol. Chem. (1986) [Pubmed]
  10. Direct evidence for the role of the membrane potential in glutathione transport by renal brush-border membranes. Inoue, M., Morino, Y. J. Biol. Chem. (1985) [Pubmed]
  11. Role of extracellular glutathione and gamma-glutamyltranspeptidase in the disposition and kidney toxicity of inorganic mercury in rats. de Ceaurriz, J., Payan, J.P., Morel, G., Brondeau, M.T. Journal of applied toxicology : JAT. (1994) [Pubmed]
  12. Effects of bile acids and their glycine conjugates on gamma-glutamyl transpeptidase. Gardell, S.J., Tate, S.S. J. Biol. Chem. (1983) [Pubmed]
  13. Effect of L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid on urinary excretion of methylmercury in the mouse. Mulder, K.M., Kostyniak, P.J. J. Pharmacol. Exp. Ther. (1985) [Pubmed]
  14. Metabolism as a determinant of species susceptibility to 2,3,5-(triglutathion-S-yl)hydroquinone-mediated nephrotoxicity. The role of N-acetylation and N-deacetylation. Lau, S.S., Kleiner, H.E., Monks, T.J. Drug Metab. Dispos. (1995) [Pubmed]
  15. Embryotoxicity elicited by inhibition of gamma-glutamyltransferase by Acivicin and transferase antibodies in cultured rat embryos. Stark, K.L., Harris, C., Juchau, M.R. Toxicol. Appl. Pharmacol. (1987) [Pubmed]
  16. Enhanced effect of an L-glutamine antagonist, L-(alphaS,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, by Acinetobacter L-glutaminase-L-asparaginase. Holcenberg, J.S. Cancer treatment reports. (1979) [Pubmed]
  17. Biochemical mechanisms for the scheduled synergism of (alpha S, 5S)-2 amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid and 5-fluorouracil in P388 leukemia. Ardalan, B., Chandrasekaran, B., Hrishikeshavan, H.J. Cancer Chemother. Pharmacol. (1985) [Pubmed]
  18. Biliary glutathione secretion in male single comb white leghorn chickens after inhibition of gamma-glutamyl transpeptidase. Song, Z., Bottje, W.G., Cawthon, D., Beers, K. Poult. Sci. (2000) [Pubmed]
  19. Competition of leukotrienes and ICI-198,615 for [3H]LTD4 binding sites in guinea pig lung membranes suggests the involvement of two LTD4 receptor subtypes. Shirley, J.T., Cheng, J.B. J. Pharmacol. Exp. Ther. (1991) [Pubmed]
  20. Effect of L-glutamine antagonists on 5-phosphoribosyl 1-pyrophosphate levels in P388 leukemia and in murine colon adenocarcinomas in vivo. Ardalan, B., Arakawa, M., Villacorte, D., Jayaram, H., Cooney, D.A. Biochem. Pharmacol. (1982) [Pubmed]
  21. Genes regulating glutathione concentrations in X-ray-transformed rat embryo fibroblasts: changes in gamma-glutamylcysteine synthetase and gamma-glutamyltranspeptidase expression. Sierra-Rivera, E., Meredith, M.J., Summar, M.L., Smith, M.D., Voorhees, G.J., Stoffel, C.M., Freeman, M.L. Carcinogenesis (1994) [Pubmed]
  22. Differential effect of AT-125 on rat renal glutaminase activities. Shapiro, R.A., Curthoys, N.P. FEBS Lett. (1981) [Pubmed]
  23. Studies on the effects of L(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) on 4-aminophenol-induced nephrotoxicity in the Fischer 344 rat. Anthony, M.L., Beddell, C.R., Lindon, J.C., Nicholson, J.K. Arch. Toxicol. (1993) [Pubmed]
  24. The inhibition of gamma-glutamyl transpeptidase from human pancreatic carcinoma cells by (alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125; NSC-163501). Allen, L., Meck, R., Yunis, A. Res. Commun. Chem. Pathol. Pharmacol. (1980) [Pubmed]
  25. 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. Thornthwaite, J.T., Allen, L.M. Res. Commun. Chem. Pathol. Pharmacol. (1980) [Pubmed]
  26. Acivicin. An antitumor antibiotic. Poster, D.S., Bruno, S., Penta, J., Neil, G.L., McGovren, J.P. Cancer clinical trials. (1981) [Pubmed]
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