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Effects of Ethanolamine and Choline on Thiotepa Cellular Accumulation and Cytotoxicity in L1210 Cells

Division of Developmental Therapeutics, University of Maryland Cancer Center [M. J. E., S. W. S., and B. E. W.], and Division of Medical Oncology, Department of Medicine [M. J. E.], University of Maryland School of Medicine, Baltimore, Maryland 21201

The amino alcohols, ethanolamine and choline, were studied for their effects on (a) L1210 cell growth, (b) N,N',N''-triethylenethiophosphoramide (thiotepa)-induced growth inhibition of L1210 cells, and (c) ¹⁴C accumulation by L1210 cells incubated with [¹⁴C]thiotepa. Ethanolamine, at concentrations up to 300 µM, had no effect on L1210 cell growth but, at concentrations > 300 µM, produced a dose-dependent reduction in cell growth. Choline, at concentrations up to 20 mM, had no effect on L1210 cell growth. Neither ethanolamine, at 250 µM, nor choline, at 10 mM, altered the ability of thiotepa to reduce L1210 cell growth. Neither ethanolamine, at 250 µM, nor choline, at 10 mM, affected the rapid phase of ¹⁴C accumulation by L1210 cells incubated with [¹⁴C]thiotepa. The slow phase of ¹⁴C accumulation by L1210 cells incubated with 5µM [¹⁴C] thiotepa, a process which is 80–85% due to production of [¹⁴C]phosphatidylethanolamine, was not affected by 250 µM choline. In contrast, ethanolamine produced a dose-dependent reduction in this slow rate of ¹⁴C accumulation. The reduction in the slow rate of ¹⁴C accumulation produced by ethanolamine was due almost entirely to a decrease in the accumulation of nonexchangeable ¹⁴C. Kinetic analysis of the inhibition of ¹⁴C accumulation produced by 25, 100, and 250 µM ethanolamine was compatible with competitive inhibition. Thin layer chromatography of cell extracts showed that the ability of ethanolamine to reduce ¹⁴C accumulation by L1210 cells incubated with [¹⁴C]thiotepa was due solely to reduction in production of [¹⁴C]phosphatidylethanolamine. These results are all compatible with and predicted by our previously described scheme wherein thiotepa enters cells by simple diffusion and serves as a prodrug for aziridine, some of which is hydrolyzed to ethanolamine which is then incorporated into phosphatidylethanolamine via normal metabolic synthetic pathways.

¹ To whom requests for reprints should be addressed, at Division of Developmental Therapeutics, University of Maryland Cancer Center, 655 W. Baltimore St., Baltimore, MD 21201.

Received 11/17/89. Revised 3/14/90.

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