The synthetic phosphagen cyclocreatine phosphate inhibits the growth of a broad spectrum of solid tumors.
BACKGROUND
The brain isoform of creatine kinase (CKBB), an enzyme involved in energy metabolism, has been implicated in cellular transformation process. Cyclocreatine (CCr), a creatine kinase (CK) substrate analogue, was shown to inhibit the growth of a broad spectrum of solid tumors expressing high levels of CK. Cyclocreatine phosphate (CCrP) generated by CK, was proposed to be the active form responsible for growth inhibition.


METHODS
We synthesized CCrP and tested its cellular uptake and anti tumor activity in stem cell assays and in athymic mouse models.


RESULTS
CCrP seems to be taken up by cells and inhibits the growth of solid tumors with high levels of CK. CCr and CCrP have similar specificity and potency.


CONCLUSIONS
The observation that only high-CK cell lines were responsive to CCrP, similar to CCr, indicates that the enzyme requirement was not bypassed. We propose that CK is a target for CCrP, and is involved in mediating its antiproliferative activity.
Schimmel
L
L
Amira Inc., Cambridge, MA 02139, USA.
Khandekar
V S
VS
Martin
K J
KJ
Riera
T
T
Honan
C
C
Shaw
D G
DG
Kaddurah-Daouk
R
R
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003404:Creatinine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D048289:Imidazolidines; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010725:Phosphocreatine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D048289:Imidazolidines; D010725:Phosphocreatine; C012487:phosphocyclocreatine; C012260:cyclocreatine; D003404:Creatinine