WR-2721 as cytotoxic and radioprotective agent in treatment of murine lymphoma with total body irradiation.

The effectiveness of fractionated total body irradiation (TBI) in treatment of non-Hodgkin's lymphoma is limited by bone marrow toxicity. Because WR-2721 effectively protects bone marrow, we tested its potential in treatment of I-347 lymphoma in BALB/c mice, using various single and fractionated TBI regimens. In most treatment schedules, WR-2721 did not cause net lymphoma protection; in fact, it was cytotoxic. Lymphoma regrowth delay times for the 21 treatment groups were quite effectively fitted by a mathematical model with three components: 1) a dose-dependent radiation effect; 2) a small radioprotective effect by WR-2721; and 3) significant cytotoxicity of WR-2721. Bone marrow radioprotection was reduced when TBI was fractionated, but there was no evidence of WR-2721 cytotoxicity to marrow. The therapeutic gain due to WR-2721 was 2.5 for the five-fraction regimen, compared to 2.3 for a single fraction. The cumulative WR-2721 toxicity to lymphoma combined with marrow protection suggests that WR-2721 could increase the clinical therapeutic ratio of TBI, particularly fractionated TBI, in treatment of lymphoma.