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Regulation of the Cytidine Phospholipid Pathways in Human Cancer Cells and Effects of 1-ß-D-Arabinofuranosylcytosine: A Noninvasive ³¹P Nuclear Magnetic Resonance Study

Pediatric Oncology Branch [P. F. D., M. C.] and Medicine Branch [G. Z., D. S., C. E. M., J. S. C.], National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Using ³¹P nuclear magnetic resonance spectroscopy we have noninvasively observed metabolic control through the cytidine pathways of phosphatidylcholine and phosphatidylethanolamine synthesis in intact actively metabolizing MDA-MB-231 human breast cancer cells. Perfusion with the phospholipid precursors ethanolamine or choline (2 mM) indicates that the cytidylyltransferase enzymes are rate limiting for both pathways. Complete inhibition of choline kinase with ethanolamine allowed the observation of the utilization of phosphocholine by the rate-limiting enzyme choline-phosphate cytidylyltransferase. The rate was dependent on the phosphocholine concentration. Inhibition of glycerophosphorylcholine phosphodiesterase with accumulation of substrate was also observed and allows an estimate of the flux through the degradative pathways.

The human lymphoma cell line MOLT-4 was also found to contain high levels of phosphocholine and phosphoethanolamine. The levels of these precursors in the MOLT-4 line are lowered by 40% after 6 h when perfused with high dose 1-ß-D-arabinofuranosylcytosine (Ara-C) (400 µm) but are unaffected by 2 µm Ara-C or dideoxycytidine. High dose Ara-C also resulted in lysis in 8–10 h. However, the MDA-MB-231 cell line which is not sensitive to Ara-C showed no change in its spectrum when perfused with Ara-C. A potential mechanism based on classic phospholipid metabolism for the lytic effect of high dose Ara-C is discussed.

¹ Present address: Pittsburgh NMR Institute, 3260 Fifth Avenue, Pittsburgh, PA 15213.

² To whom requests for reprints should be addressed, at Clinical Pharmacology Branch, National Cancer Institute, Building 10, Room 6N119, Bethesda, MD 20892.

Received 12/15/88. Revised 5/22/89. Accepted 10/25/89.

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