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Cyclocreatine Accumulation Leads to Cellular Swelling in C6 Glioma Multicellular Spheroids: Diffusion and One-Dimensional Chemical Shift Nuclear Magnetic Resonance Microscopy¹

Department of Hormone Research, Weizmann Institute of Science, Rehovot 76100, Israel

Cyclocreatine, an analogue of creatine, inhibits tumor cell proliferation in vitro and in vivo. The effects of cyclocreatine in large C6 glioma multicellular spheroids were mapped here by magnetic resonance microscopy. Diffusion-weighted images of C6 glioma spheroids resolved the bright viable rim and the dark necrotic center. Sequential sets of diffusion images, following cyclocreatine administration, showed increasing selfdiffusion coefficients of the intracellular water in the viable rim (0.49 x 10^-5 cm²/s for untreated spheroids, 0.62 x 10^-5 cm²/s after 48 h perfusion with 20 mM cyclocreatine). This fact correlated with cellular swelling apparent in histological sections. The radial distribution of cyclocreatine and soluble lipids across perfused C6 spheroids was measured by one-dimensional chemical shift imaging. Cyclocreatine accumulation was prominent throughout the viable cell layer, with no cyclocreatine accumulation in the necrotic center. In both cyclocreatine-treated and control spheroids the lipid signal was highest in the necrotic center and lower in the inner viable cell layer.

¹ This work was supported by a research grant from The Frenkel Foundation and equipment was funded by The Wolfson Foundation and The Israel Academy of Sciences. M. N. is an incumbent of the Helena Rubinstein Career Development Chair in Cancer Research.

² To whom requests for reprints should be addressed, at Department of Hormone Research, Weizmann Institute of Science, Rehovot 76100, Israel.

Received 6/13/94. Accepted 10/31/94.

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