Effects of a new amsacrine derivative, N-5-dimethyl-9-(2-methoxy-4-methylsulfonylamino)phenylamino-4- acridinecarboxamide, on cultured mammalian cells

The effects of N-5-dimethyl-9-(2-methoxy-4-methylsulfonylamino)-phenylamino-4- acridinecarboxamide (CI-921; NSC 343499), a lipophilic and water-soluble derivative of amsacrine (NSC 249992), on cell viability, growth, clonogenicity, and progression through the cell cycle were investigated in suspension cultures of Friend erythroleukemic cells and in in suspension cultures of Friend erythroleukemic cells and in adherent cultures of Chinese hamster ovary cells. CI-921 was less toxic toward stationary than toward exponentially growing Chinese hamster ovary cells; colony formation was inhibited by 50% following a 1-h pulse of 190 versus 80 nM CI-921, respectively. Cell viability was unaffected in Friend erythroleukemic cell cultures at concentrations up to 50 nM, although growth was inhibited by 50% following 24 h of continuous exposure to 9.5 nM or a 1 h pulse of 67.5 nM CI-921. Constant exposure of Friend erythroleukemic cells to 10 nM CI-921 slowed proliferation and resulted in prolongation of cell transit through late S and G2 phases. Higher drug concentrations (50 nM) caused a complete cessation of growth marked by greatly suppressed cell transit through S phase and an irreversible block in G2 phase, about 30 min prior to division. In such cases, unbalanced growth was observed with total RNA and protein content of drug-treated cells increasing by 74 and 34%, respectively. Pulse exposure of cells to CI-921 resulted in transient accumulations of cells in S and/or G2 phase depending upon dose. The cell cycle distribution of stationary cultures treated for 1 h with drug and replated at a low cell density were identical to that of controls. Binding of the drug affected the sensitivity of DNA in situ to acid denaturing conditions which provides additional evidence that CI-921 binds to DNA by intercalation.