INHIBITION OF DOXORUBICIN-INDUCED CELL-DEATH IN-VITRO AND IN-VIVO BY CYCLOHEXIMIDE

We studied the effects of the protein synthesis inhibitor, cycloheximi de (CH), on cell killing by doxorubicin (DOX) in vitro and ill vivo. A t the concentration of CH used (1 mu g/ml) the cytotoxicity of DOX was reduced in cultured P388 leukemia cells. An analysis of the DNA histo gram obtained by flow cytometry showed that DOX exerts its growth-inhi bitory effect by blocking the cell cycle at the G(2)/M phase in P388 c ells. Treatment with CH diminished this blocking effect. When CH was a dded to the growth medium before DOX exposure, no change in intracellu lar DOX accumulation was observed. Treatment with CH (15 mg/kg) signif icantly diminished the lethality of DOX (20mg/kg) in mice and it also reduced the antitumor activity of mice with P388 leukemia. Thus, CH in hibited cell death induced by DOX in vitro and in vivo. These results suggest that CH has an antagonistic effect on the pharmacological acti ons of DOX in cells and mice. The cytoprotective effect of CH may be d ue to protein synthesis inhibition.