Protection of mouse bone marrow by WR-2721 after fractionated irradiation

The ability of WR-2721 to protect mouse bone marrow after single or fractionated doses of radiation was assessed using both a clonogenic assay (survival of colony-forming units spleen (CFU) and a functional assay (lethality at 30 days) of stem cell survival. Cell survival curves and dose-response curves for radiation alone and drug with radiation were constructed over the dose range of .5 to 8 Gy and 1.5 to 15 Gy, respectively. The fractionated regimen consisted of four fractions ranging from 0.5 to 1.75 Gy given at 6-hr intervals for a total treatment time of 19.5 hr. WR-2721 was given 30 min before each fraction at a dose of 200 mg/kg. The protection factor was smaller after fractionated doses than after single doses for both assays, 1.3 (95% c.l., 1.0-1.6) vs. 2.3 (95% c.l., 2.0-2.6) for CFU survival and 1.34 vs. 1.8 for lethality at 30 days. No drug cytotoxicity could be demonstrated in the fractionated schedule. These data suggest that protection by WR-2721 is dependent on size of dose and will be less after clinically relevant, small dose fractions. However, some protection does remain even in the low dose range, where proportionally more damage is due to single-hit irreparable events.