Enhanced cell killing through the use of cell kinetics-directed treatment schedules for two-drug combinations in vitro.

Kinetics-directed drug treatment schedules were tested in Chinese hamster ovary cells. Ten hr after treatment with 1,2:5,6-dianhydrogalactitol (DAG) (at a dose lethal to less than 5% of the cells), a 150% enrichment of cells into the S phase of the cell cycle was observed. This blockade in S phase was reversible and was followed at 18 hr after an exposure to DAG by a 200% increase in the fraction of cells in the G2-M phases of the cell cycle. Bleomycin, known to be most effective against G2 + M cells, had the greatest effect on cell killing when administered at that time. Rapid analysis by flow microfluorometry techniques was used to determine the DAG-induced kinetics changes, thus allowing treatment with the second drugs at the most opportune time. The DAG-induced kinetics changes were also demonstrated in a line of human adenocarcinoma of the stomach in vitro and in Ehrlich ascites tumor cells in vivo. In all cases, the enrichment of cells into S phase was reversible at the doses used and was followed by a reversible blockade in G2-M.