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A previous study using a single injection of (chloro-2-ethyl)ribofuranosyl-3-nitrosourea has indicated the low acute hematotoxicity of this nitrosourea. However, because the hematotoxicity of nitrosourea is usually cumulative, we have studied the effect of injecting (chloro-2-ethyl)ribofuranosyl-3-nitrosourea (15 mg/kg) dissolved in 0.2 ml sterile oil C57BL X i.p. into DBA/2F1 mice for 5 consecutive weeks. The dose per injection represents the minimal dose necessary to show the maximal therapeutic efficacy on L1210 leukemia. Bone marrow cellularity and histology, spleen weight, bone marrow and splenic pluripotent stem cells, and colony-forming units committed to granulocyte-macrophage differentiation were measured 1, 2, 4, 7, and 14 days after the last injection in treated and control mice receiving oil only. No morphological or histological changes were found in the spleen and bone marrow of treated mice. In both organs, the number of splenic pluripotent hematopoietic stem cells decreased by about 1 log 1 day after the last injection but rapidly returned to normal values on Days 4 to 14. Granulocyte-macrophage-committed precursors were affected in both organs, at 20% of control values for bone marrow and 5% of control values for spleen on Day 1, with a transient and partial recovery on Day 4 followed by a second drop to 20 and 25% on Day 14. This effect on granulocyte-macrophage precursors contrasts with the absence of significant effect when the same treatment is used on peripheral white blood cell counts. Our results demonstrate that (chloro-2-ethyl)ribofuranosyl-3-nitrosourea belongs to the class of new nitrosoureas with low cumulative hematotoxicity.