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Formation of 1-ß-D-Arabinofuranosylcytosine Diphosphate Choline in Cultured Human Leukemic RPMI 6410 Cells¹

Cancer Research Unit (McEachern Laboratory) [G. J. L., J. H. P., A. R. P. P.] and Department of Pharmacology [G. J. L., A. R. P. P.], University of Alberta, Edmonton, Alberta, Canada T6G 2H7

When incubated with 1-ß-D-arabinofuranosylcytosine (ara-C), RPMI 6410 cells formed a hitherto unrecognized ara-C metabolite, 1-ß-D-arabinofuranosylcytosine diphosphate choline. This compound was characterized by (a) chromatographic behavior, (b) chemical and enzymatic hydrolysis, (c) phosphorus content, and (d) incorporation of [5-³H]ara-C and [methyl-¹⁴C]choline.

Formation of 1-ß-D-arabinofuranosylcytosine diphosphate choline by RPMI 6410 cells was enhanced in the presence of 3-deazauridine (DU) and was preceded by that of 1-ß-D-arabinofuranosylcytosine triphosphate. The antiproliferative effects of ara-C and DU toward RPMI 6410 cells were potentiated when the agents were present together. The anabolism of ara-C during a 24-hr interval of culture was markedly enhanced by the presence of DU; cellular concentrations of 1-ß-D-arabinofuranosylcytosine triphosphate and 1-ß-D-arabinofuranosylcytosine diphosphate choline were 5- and 15-fold higher than those in the absence of DU. This enhancement appears to be the basis of the potentiation of cytotoxicity resulting from combination of the agents.

Pretreatment of RPMI 6410 cells with DU resulted in enhanced rates of cellular uptake of ara-C. ara-C uptake under these circumstances was blocked by the inhibitor of nucleoside transport, nitrobenzylthioinosine.

¹ Supported by the National Cancer Institute of Canada. A portion of this work was described in a preliminary communication (18).

² Research Student of the National Cancer Institute of Canada.

³ To whom requests for reprints should be addressed.

Received 10/10/77. Accepted 3/14/78.