Creatine and phosphocreatine analogs: anticancer activity and enzymatic analysis.
The brain isoform of creatine kinase has been implicated in cellular transformation processes. Cyclocreatine, a creatine kinase substrate analog, was previously shown to be cytotoxic to a broad spectrum of solid tumors. We have synthesized, enzymatically characterized, and evaluated the antitumor activity of a series of substrate analogs of creatine kinase. Using in vitro assays, we demonstrate that several of these analogs are cytotoxic to the human ME-180 cervical carcinoma, the MCF-7 breast adenocarcinoma and the HT-29 colon adenocarcinoma cell lines at low mM concentrations. Analogs that were active in vitro delayed the growth of a subcutaneously implanted rat 13,762 mammary adenocarcinoma. Tumor growth delays of 6-8 days were achieved, which is comparable to effects seen with standard regimens of currently used anticancer drugs. These studies further establish the creatine kinase system as a promising and novel target for anticancer chemotherapy drug design.
Bergnes
G
G
Amira Inc., Cambridge, MA 02139, USA.
Yuan
W
W
Khandekar
V S
VS
O'Keefe
M M
MM
Martin
K J
KJ
Teicher
B A
BA
Kaddurah-Daouk
R
R
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002277:Carcinoma / Q000188:drug therapy; D016923:Cell Death / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D003401:Creatine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D003402:Creatine Kinase / Q000378:metabolism*; D003404:Creatinine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010725:Phosphocreatine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy
D000970:Antineoplastic Agents; D010725:Phosphocreatine; C012260:cyclocreatine; D003404:Creatinine; D003402:Creatine Kinase; D003401:Creatine