CREATINE AND PHOSPHOCREATINE ANALOGS - ANTICANCER ACTIVITY AND ENZYMATIC ANALYSIS

The brain isoform of creatine kinase has been implicated in cellular t ransformation processes. Cyclocreatine, a creatine kinase substrate an alog, was previously shown to be cytotoxic to a broad spectrum of soli d tumors. We have synthesized, enzymatically characterized, and evalua ted the antitumor activity of a series of substrate analogs of creatin e 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 th e growth of a subcutaneously implanted rat 13762 mammary adenocarcinom a. Tumor growth delays of 6-8 days were achieved, which is comparable to effects seen with standard regimens of currently used anticancer dr ugs. These studies further establish the creatine kinase system as a p romising and novel target for anticancer chemotherapy drug design.