CELL-CYCLE RELATED UPTAKE, RETENTION AND TOXICITY OF IDARUBICIN, DAUNORUBICIN AND DOXORUBICIN

Exponentially growing Molt-4 cells were separated by means of counterf low centrifugation into fractions enriched for cells in early G1, late G1, S, or G2+M phase of the cell cycle. Subsequently, cells were expo sed for 2 h to Idarubicin (Ida, 0.02 - 0.15 mug/ml), Daunorubicin (Dnr , 0.1 - 0.75 mug/ml) or Doxorubicin (Dox, 0.1 - 0.75 mug/ml). Drug upt ake, measured by flow cytometry, increased progressively with cell cyc le traverse from early G1-to M-phase. The relative fraction of drug lo st following an extensive wash procedure was 72% in case of Ida and 23 % for Dnr and Dox and was independent of the cell cycle phase. Inhibit ion of DNA synthesis was determined by qualitative flow cytometric ana lysis of 5-iodo-2'-deoxyuridine (IdUrd) incorporation into DNA. The th ree drugs showed a similar gradual increase of inhibition of DNA synth esis from G1 to G2+M phase, demonstrating that cell cycle phase depend ency of drug toxicity applies to all three anthracyclines studied.