title: Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) inhibits growth of a broad spectrum of cancer cells derived from solid tumors.
abstract: 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.
authors.affiliation: AMIRA, Inc., Cambridge, Massachusetts 02142.
authors.forename: J W
authors.initials: JW
authors.lastname: Lillie
authors.forename: M
authors.initials: M
authors.lastname: O'Keefe
authors.forename: H
authors.initials: H
authors.lastname: Valinski
authors.forename: H A
authors.initials: HA
authors.lastname: Hamlin
authors.forename: M L
authors.initials: ML
authors.lastname: Varban
authors.forename: R
authors.initials: R
authors.lastname: Kaddurah-Daouk
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D048289:Imidazolidines; D007527:Isoenzymes; D010725:Phosphocreatine; C012487:phosphocyclocreatine; C012260:cyclocreatine; D003404:Creatinine; D003402:Creatine Kinase