CYTOKINETIC DIFFERENCES IN THE ACTION OF N-[2-(DIMETHYLAMINO)ETHYL]ACRIDINE-4-CARBOXAMIDE AS COMPARED WITH THAT OF AMSACRINE AND DOXORUBICIN

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (DACA ) is a topoisomerase II-directed DNA intercalator with high experiment al solid-tumour activity. The effect of DACA on the cytokinetics of cu ltured Lewis lung adenocarcinoma cells was compared with those of two clinical drugs of this class, doxorubicin and amsacrine. Cells were ex posed to drugs for a 1-h period at concentrations that reduced viabili ty by approximately 99% as measured by clonogenic assays. Subsequent p rogress through the cell cycle was monitored by propidium staining of fixed cells and flow cytometry. DACA, amsacrine and doxorubicin did no t inhibit the G1- to S-phase transition but did delay progression thro ugh the S-phase. The effect was maximal in the late S-phase and, becau se of the differential rates of progress of cells in various cycle pos itions, led to the development of a synchronous S-phase peak. This pea k moved to the G2/M-phase position at 11 h after the removal of DACA o r at 14 h after the removal of amsacrine or doxorubicin. The effects o f 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-ph ase to mitosis. This effect was much greater for DACA than for the oth er two drugs, consistent with the greater effect of DACA on the G2/M-p hase to G1-phase transition. The results suggest that DACA causes cell -cycle changes expected for a DNA-damaging drug but differs from doxor ubicin and amsacrine mainly by its effect on the transition of G2-phas e cells to mitosis and the G1-phase.