Acivicin

Acivicin is an analog of glutamine. It is an inhibitor of gamma-glutamyl transferase.

Acivicin
Names
IUPAC name
(2S)-Amino[(5S)-3-chloro-4,5-dihydro-1,2-oxazol-5-yl]ethanoic acid
Other names
Antibiotic AT 125
Identifiers
CAS Number
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
PubChem CID
UNII
Properties
Chemical formula
 C5H7ClN2O3
Molar mass 178.574
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

It is a fermentation product of Streptomyces sviceus.[1] It interferes with glutamate metabolism and inhibits glutamate dependent synthesis of enzymes, and is thereby potentially helpful in treatment of solid tumors.[2]

After its discovery in 1972, acivicin was studied as an anti-cancer agent, but trials were unsuccessful due to toxicity.[3]

Research

An in vitro study showed that Acivicin at a concentration of 5 μM Acivicin inhibited by 78% the growth of human pancreatic carcinoma cells (MIA PaCa-2) after 72 hours in continuous culture. It was also found that acivicin at a concentration of 450 μM irreversibly inactivated MIA PaCa-2 γ-glutamyl transpeptidase (10 nmol/min/106 cells) with an inactivation half-life of 80 minutes.[1]

Phase I studies

Phase I dose escalating studies conducted in 23 cancer patients administered acivicin with a concomitant 96-h i.v. infusion of a mixture of 16 amino acids showed reversible, dose-limiting CNS toxicity, characterized by lethargy, confusion and decreased mental status.

References
  1. Allen, L.; Meck, R.; Yunis, A. (1980). "The Inhibition of γ-Glutamyl Transpeptidase from Human Pancreatic Carcinoma Cells by (αS,5S)-α-Amino-3-chloro-4,5-dihydro-5-isoxazoleacetic Acid (AT-125; NSC-163501)". Research Communications in Chemical Pathology and Pharmacology. 27 (1): 175–182. PMID 6102405.
  2. Hidalgo, M.; Rodriguez, G.; Kuhn, J. G.; Brown, T.; Weiss, G.; MacGovren, J. P.; von Hoff, D. D.; Rowinsky, E. K. (1998). "A Phase I and Pharmacological Study of the Glutamine Antagonist Acivicin with the Amino Acid Solution Aminosyn in Patients with Advanced Solid Malignancies". Clinical Cancer Research. 4 (11): 2763–2770. PMID 9829740.
  3. http://pubs.rsc.org/en/content/articlehtml/2015/sc/c4sc02339k
  • Obrador, E.; Carretero, J.; Ortega, A.; Medina, I.; Rodilla, V.; Pellicer, J. A.; Estrela, J. M. (2002). "γ-Glutamyl Transpeptidase Overexpression Increases Metastatic Growth of B16 Melanoma Cells in the Mouse Liver". Hepatology. 35 (1): 74–81. doi:10.1053/jhep.2002.30277. PMID 11786961.
  • Schmees, C.; Prinz, C.; Treptau, T.; Rad, R.; Hengst, L.; Voland, P.; Bauer, S.; Brenner, L.; Schmid, R. M.; Gerhard, M. (2007). "Inhibition of T-Cell Proliferation by Helicobacter pylori γ-Glutamyl Transpeptidase". Gastroenterology. 132 (5): 1820–1833. doi:10.1053/j.gastro.2007.02.031. PMID 17484877.


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