Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) inhibits growth of a broad spectrum of cancer cells derived from solid tumors.
In an effort to investigate the role of creatine kinase and its substrates in malignancy we have tested the effect of cyclocreatine [1-carboxymethyl-2-iminoimidazolidine (CCr)] on the growth of tumor cells in vitro and in vivo. CCr is phosphorylated by creatine kinase to yield a synthetic phosphagen [(N-phosphorylcyclocreatine (CCr approximately P)] with thermodynamic and kinetic properties distinct from those of creatine phosphate. We show that CCr accumulates as CCr approximately P in tumor cells expressing a high level of creatine kinase, and that the accumulation of this phosphagen is detrimental to tumor cell growth. Tumor cell lines expressing a low level of creatine kinase accumulate much less CCr approximately P, and consequently are growth inhibited only at higher concentrations of CCr. When these resistant cells are transfected with a creatine kinase B expression vector, they express creatine kinase, accumulate CCr approximately P, and are growth inhibited. In vivo, in nude mouse xenografts, the rate of growth of a high creatine kinase expressing tumor cell line is inhibited in animals fed 1% CCr. Our results indicate that CCr inhibits the growth of tumor cells in vitro and in vivo.
Lillie
J W
JW
AMIRA, Inc., Cambridge, Massachusetts 02142.
O'Keefe
M
M
Valinski
H
H
Hamlin
H A
HA
Varban
M L
ML
Kaddurah-Daouk
R
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D003402:Creatine Kinase / Q000378:metabolism / Q000502:physiology; D003404:Creatinine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D048289:Imidazolidines; D007527:Isoenzymes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D010725:Phosphocreatine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000502:physiology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology
D000970:Antineoplastic Agents; D048289:Imidazolidines; D007527:Isoenzymes; D010725:Phosphocreatine; C012487:phosphocyclocreatine; C012260:cyclocreatine; D003404:Creatinine; D003402:Creatine Kinase