Dose and interval relationship for the interaction of WR-2721 and nitrogen mustard with normal and malignant cells.

The protective effect of WR-2721 on nitrogen mustard (HN2) cytotoxicity against hematopoietic stem cells as well as the potentiation effect previously noted against leukemia cells was further examined for dose and interval dependency for these opposite effects. For AKR leukemia cells, a dose dependent potentiation of HN2 cytotoxicity was noted with WR-2721. The magnitude of the potentiation was about 10-fold with 5 mg/mouse WR-2721 and nearly 100-fold at 10 mg/mouse. Interval studies showed maximum potentiation occurred when WR-2721 was given close in time to HN2 and decreased in magnitude as the interval between the agents increased. However, a pronounced potentiation of cytotoxicity was also found when HN2 followed WR-2721 by 4 to 12 hr. For hematopoietic stem cells, a protective effect of WR-2721 on HN2 cytotoxicity was observed. This effect decreased rapidly with interval between the agents with no protection noted for an interval of 6 hr. These results indicate that agents like WR-2721 may have an important therapeutic role in chemotherapy.