CYCLOCREATINE TRANSPORT AND CYTOTOXICITY IN RAT GLIOMA AND HUMAN OVARIAN-CARCINOMA CELLS - P-31-NMR SPECTROSCOPY

Cyclocreatine (CY), an analogue of creatine, inhibits tumor growth in vivo and proliferation of tumor cells in vitro. The goal of this study was to probe the mechanism of CY transport and cytotoxicity in C6 rat glioma cells and OC238 human ovarian carcinoma cells (creatine kinase activities of 0.16 and 0.016 units/mg protein, respectively). In both cell lines, CY significantly inhibited cell growth with no effect on membrane integrity and on the content of nucleoside triphosphates. An intrinsic P-31-nuclear magnetic resonance (P-31-NMR) signal ofphosphoc reatine, as well as accumulation of phosphocyclocreatine (PCY) after a ddition of CY, was observed for C6 glioma but not for the OC238 cells. Transport of CY in C6 glioma showed Michaelis-Menten kinetics for an active sodium-dependent component. Transport was reduced more than fiv efold in low-glucose medium. The toxicity of CY to C6 glioma cells may be due to PCY accumulation and cellular swelling. Another mechanism m ust be invoked to explain CY effects on the human ovarian cancer cells in which no PCY accumulation could be detected and no cellular swelli ng was observed.