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The Effect of 1-ß-D-Arabinofuranosylcytosine on Growth, Viability, and DNA Synthesis of Mouse L-cells¹

Department of Medical Biophysics, University of Toronto, and the Ontario Cancer Institute, Toronto, Ontario, Canada

An examination of the effects of 1-ß-D-arabinosylcytosine (ara-C) on DNA synthesis of mouse L-cells has been made, and these effects have been compared with effects on viability. Measurements on the incorporation of radioactive precursors into acid-insoluble material showed that ara-C strongly inhibited DNA synthesis while having relatively little effect on RNA or protein synthesis. It was found that 3.6 x 10^-7 M ara-C inhibited cell division for at least 24 hr, except for the single division of cells initially in G₂. Over this time, however, there was no decrease in cell viability, even though DNA synthesis was reduced by more than 97% over the first 14 hr of exposure to ara-C. Results of studies on growth and cell viability suggest that at higher concentrations (7.2 x 10^-6 M or greater) ara-C rapidly killed S phase cells but temporarily blocked the progression of cells from G₁ into S, and thus partially protected against its own toxicity. The observed effects are discussed in relation to the current models for the mechanism of action of ara-C. Our observations do not appear to be consistent with a model in which ara-C acts by blocking the reduction of CDP nor with one in which ara-C acts by incorporation into DNA. Rather, our results agree with a model in which inhibition of DNA synthesis is the result of inhibition of DNA polymerase.

¹ Supported by the National Cancer Institute of Canada.

² Fellow of the National Cancer Institute of Canada. Present address: Laboratory of Physiological Chemistry, State University of Leiden, Leiden, The Netherlands.

Received 2/19/70. Accepted 7/ 2/70.

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