Eicar (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide). A novel potent inhibitor of inosinate dehydrogenase activity and guanylate biosynthesis.
EICAR (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide) is a cytostatic agent that inhibits murine leukemia L1210 and human lymphocyte CEM cells at a 50% inhibitory concentration of 0.80-1.4 microM, respectively. EICAR causes a rapid and marked inhibition of inosinate (IMP) dehydrogenase (EC 1.1.1.205) activity in intact L1210 and CEM cells reflected by a concentration-dependent accumulation of IMP and depletion of GTP and dGTP levels. EICAR 5'-monophosphate is a potent inhibitor of purified L1210 cell IMP dehydrogenase (Ki/Km 0.06). Inhibition of IMP dehydrogenase by EICAR 5'-monophosphate is competitive with respect to IMP. L1210 cells that were selected for resistance to the cytostatic action of EICAR proved to be adenosine kinase-deficient. Also, studies with other mutant L1210 and CEM cell lines revealed that adenosine kinase, as well as an alternative pathway, may be responsible for the conversion of EICAR to its 5'-monophosphate. Purified 2'-deoxycytidine kinase, 2'-deoxyguanosine kinase, cytosolic 5'-nucleotidase, and nicotinamide dinucleotide (NAD) pyrophosphorylase do not seem to be markedly involved in the metabolism of EICAR.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Lewen, Belgium.
Karlsson
A
A
Wang
L
L
Bohman
C
C
Horská
K
K
Votruba
I
I
Fridland
A
A
Van Aerschot
A
A
Herdewijn
P
P
De Clercq
E
E
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003848:Deoxyguanine Nucleotides / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006147:Guanine / Q000494:pharmacology; D006151:Guanosine / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007939:Leukemia L1210 / Q000201:enzymology / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D009173:Mycophenolic Acid / Q000494:pharmacology; D011685:Purine Nucleotides / Q000378:metabolism; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology; D012263:Ribonucleosides / Q000494:pharmacology*; D012265:Ribonucleotides / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003848:Deoxyguanine Nucleotides; D011685:Purine Nucleotides; D012263:Ribonucleosides; D012265:Ribonucleotides; C059077:5-ethynyl-1-ribofuranosylimidazole-4-carboxamide; D006151:Guanosine; D012254:Ribavirin; D006147:Guanine; D006160:Guanosine Triphosphate; C029603:deoxyguanosine triphosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D000241:Adenosine; C033706:tiazofurin