5-Fluorouracil, 1,3-bis(2-chloroethyl)-1-nitrosourea, and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea: effect on the human granulopoietic system.

The reaction pattern of the normal (nonleukemic) human granulopoietic system to single-agent treatment with 5-fluorouracil (FUra) and to a combination of FUra with two nitrosoureas, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU), was studied serially by morphologic and in vitro culture methods. The granulopoietic toxicity of FUra was acute and rapidly (by day 21) reversible. In contrast, the toxicity of the combination regimens was long lasting. Evidence exists that an early toxicity (that of FUra) and a delayed toxicity (that of the nitrosourea) were overlapping. Toxicity of BCNU and MeCCNU was most pronounced at the level of in vitro colony-forming units of the granulopoietic system (G-CFUc). G-CFUc compartments of bone marrow and peripheral blood continued to be reduced in size at the time of recovery of the peripheral blood granulocyte count from nitrosourea-induced toxicity. This finding may be responsible for the cumulative toxicity to the human hematopoietic system that frequently has been observed after repeated administration of nitrosourea compounds.