Effect of cycloheximide on the bone marrow toxicity of nitrogen mustard

Cycloheximide (CHM), a potent inhibitor of protein synthesis, has been reported to protect rat intestinal crypt cells from mitotic inhibition by nitrogen mustard (HN2). For investigation of the effect of CHM on the bone marrow toxicity of HN2, CHM (1.0 mg/kg) and HN2 in doses up to 2.5 mg/kg were given i.p. to rats. Twenty-eight % (13 of 46) of rats given HN2 alone died within 5 days. Only 4% (2 of 45) of rats pretreated with CHM died within 5 days after the administration of HN2. Rats pretreated with CHM had significantly less leukopenia and granulocytopenia than did rats given HN2 alone, and their bone marrow cellularity, assessed by histological sections and total femoral marrow cell counts, was greater than that of animals given HN2 alone. Bone marrow DNA synthesis, as measured by in vitro [3H]thymidine incorporation, was decreased 2 hr after HN2 injection, appeared to recover at 4 hr, but was further decreased at 24 and 48 hr. CHM given up to 20 min before HN2 reversed the effect of HN2 on DNA synthesis at 2 and 4 hr. A variable protective effect of CHM was observed at 24 and 48 hr. These studies indicate that CHM increases the survival of HN2-treated rats and partially protects rat bone marrow cells from HN2 cytotoxicity.