Cytokinetic differences in the action of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide as compared with that of amsacrine and doxorubicin

Abstract

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (DACA) is a topoisomerase II-directed DNA intercalator with high experimental solid-tumour activity. The effect of DACA on the cytokinetics of cultured Lewis lung adenocarcinoma cells was compared with those of two clinical drugs of this class, doxorubicin and amsacrine. Cells were exposed to drugs for a 1-h period at concentrations that reduced viability by approximately 99% as measured by clonogenic assays. Subsequent progress through the cell cycle was monitored by propidium staining of fixed cells and flow cytometry. DACA, amsacrine and doxorubicin did not inhibit the G1- to S-phase transition but did delay progression through the S-phase. The effect was maximal in the late S-phase and, because of the differential rates of progress of cells in various cycle positions, led to the development of a synchronous S-phase peak. This peak moved to the G2/M-phase position at 11 h after the removal of DACA or at 14 h after the removal of amsacrine or doxorubicin. The effects of the drugs on cells initially in the G2-phase was measured by scoring mitotic cells in the presence and absence of colchicine. DACA had an immediate inhibitory effect on the progression of cells from the G2-phase to mitosis. This effect was much greater for DACA than for the other two drugs, consistent with the greater effect of DACA on the G2/M-phase to G1-phase transition. The results suggest that DACA causes cell-cycle changes expected for a DNA-damaging drug but differs from doxorubicin and amsacrine mainly by its effect on the transition of G2-phase cells to mitosis and the G1-phase.