In vivo study of acute hematotoxicity of three nitrosoureas, chlorozotocin (chloro-2-ethyl)-ribofuranosyl-3-nitrosourea, and (chloro-2-ethyl)-1-ribopyranosyl-3-nitrosourea.

The hematological effects of three sugar derivatives of nitrosoureas, Chlorozotocin (2-[(chloro-2-ethyl)-3-nitrosoureido]-Dglucopyranose), (chloro-2-ethyl)-1-(ribopyranosyl triacetate2',3',4')-3-nitrosourea, and (chloro-2-ethyl)-1-ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-nitrosourea, were studied in the bone marrow, spleen, and peripheral blood of mice. The three compounds were injected ¡.p.,dissolved in sterile olive oil. A single dose, corresponding to the minimal dose showing the maximum therapeutic activity, was adminis tered at Day 0; and erythrocytes, white blood cells, platelets, and hematocrit were counted at Days 1,2,3, 4, and 7. Spleen weight, bone marrow cellularity, and the hematopoietic precur sors, peripheral hematopoietic stem cells (CFU-s) and splenic colony-forming unit committed to granulocyte-macrophage dif ferentiation (CFU-c), were also measured in both organs. (Chloro-2-ethyl)-1 -(ribopyranosyl triacetate-2',3',4-')-3-nitrosourea showed the maximum hematotoxicity and provoked a significant decrease of white blood cells in the peripheral blood; the spleen weight was reduced at Day 4, and the number of hematopoietic stem cells (CFU-s) in the spleen was decreased by 2 logs with a complete recovery within 2 days, whereas the effect was significantly less on splenic granulocytic precursors (CFU-c). In the bone marrow, (chloro-2-ethyl)-1-(ribopyranosyl triacetate-2',3',4')-3-nitrosourea also decreased the cellularity and the number of CFU-s but did not decrease the number of CFU-c. Chlorozotocin and (chloro-2-ethyl)-1-ribofuranosylisopropylidine-2',3'-p-nitro-benzoate-5'-3-nitrosourea had no effect on peripheral blood, decreased the number of CFU-s and CFUc in the spleen to 10% in controls, and reduced bone marrow cellularity and the number of CFU-s to 60% of controls. Chlo rozotocin affected mostly bone marrow CFU-c (25% of controls at Day 1) with a progressive return to normal level at Day 4. RFCNU has no toxicity on the bone marrow granulocyte pre cursors. None of the three compounds produced thrombocytopenia, and all hematological effects were usually rapidly reversible.