Effect of dose fractionation of daunorubicin on survival of leukemic cells.

Mice bearing transplanted AKR leukemia received daunorubicin either as a single dose or as four equally divided doses (0.2 mg/mouse; four times) with the time interval between the divided doses varying from 12 to 36 hr; survival of leukemia colony-forming cells was then assayed. When daunorubicin was administered in any of the fractionated schedules, the dose-survival curve was exponential with a shoulder region demonstrable. As expected, there was significantly less cell killing for the fractionated schedule than for a comparable accumulated single dose; however, with administration of the fourth dose for any interval studied, the increment in cell killing was so large that it was quite similar to that resulting from a single 0.8-mg/mouse dose. We examined the time course of cell killing for the 24-hr fractionation schedule and found greater killing than expected after each subsequent dose with the most pronounced increase occurring after the fourth dose. Possible mechanisms for this effect are discussed.