Effects of ACNU, a water-soluble nitrosourea derivative, on survival and cell kinetics of cultured HeLa S3 cells.

Effects of a water-soluble nitrosourea, 1(4-aminomethylpyrimidine-5yl)methyl-3-(2-chloroethyl)-3-nit rosourea hydrochloride (ACNU) was investigated on cultured HeLa S3 cells with regard to their lethality and cell progression through the cell cycle. The survival curve of exponentially growing cells exposed to increasing concentrations of the drug for 1 hr was characterized by a threshold type of response (Do = 7.0 micrograms/ml X 1 hr, Dq 3.5 micrograms/ml X 1 hr). Throughout the cell cycle, ACNU exerted its main killing effect on cells in the G1 and G2 + M phases, whereas cells in S were resistant to the drug. The change in their age-response was due to the Do value of the dose-survival curve rather than the Dq. Effects of cell progression were also examined at a low concentration of ACNU (5.0 micrograms/ml), which allowed 80% of treated cells to survive. Delayed transit was observed in the S phase, and more markedly in the G2 + M phase. The magnitude of these perturbations depended on the position of the cell cycle at which the drug was administered. Cells treated in the G1 and early S phases showed a much longer duration of S and G2 + M phases than cells treated in mid-S phase. Cells treated in the late S and G2 phases could normally pass through mitosis, but were subsequently blocked in the G2 phase following a prolonged S phase in the next cell cycle. These studies revealed that there seems to be some positive relationship of the effect of ACNU on cell progression and cell killing throughout the cell cycle.