The effect of-beta-D-arabinofuranosylcytosine on growth, viability, and DNA synthesis of mouse L-cells.

Abstract

Summary An examination of the effects of 1-β-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 × 10 -7 m ara-C inhibited cell division for at least 24 hr, except for the single division of cells initially in G 2 . 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 × 10 -6 m or greater) ara-C rapidly killed S phase cells but temporarily blocked the progression of cells from G 1 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.