An examination of the effects of 1-/3-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 IO"7 M ara-C inhibited cell division for at least 24 hr, except for the single division

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... f 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 IO"6 M or greater) ara-C rapidly killed S phase cells but temporarily blocked the progression of cells from GÃOE 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.