Differential effects of cytotoxic agents on hematopoietic progenitors

Abstract

In order to predict the effect of chemotherapeutic agents on the hematopoietic progenitor compartment, it is necessary to have a hypothesis concerning the dynamics of the cells within the compartment. By viewing this compartment as a continuum of cells with varying self-renewal capacity, one can assess the significance of the stem cell damage incurred following a single drug dose. Vinblastine, 5-fluorouracil, cyclophosphamide, busulfan, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were investigated. The acute toxicity of the drug-exposed marrow was studied by the colony-forming units-spleen (CFU-S) and agar diffusion chamber assay. Busulfan and BCNU were found to kill CFU-S preferentially. By following CFU-S recovery for 14 days post drug, different recovery patterns are noted. Busulfan and BCNU produce prolonged depression in CFU-S, whereas cyclophosphamide and 5-fluorouracil show relatively rapid recovery. If one determines the Rs (a measure of proliferative capacity) after drug, busulfan and, to a lesser extent, BCNU produce a prolonged depression without return to normal even 650 days post drug. No such depression is noted with the other drugs. The data from the recovery curves and Rs support the notion of stem cells being heterogeneous with regard to self-renewal capacity. The agar diffusion chamber and CFU-S acute survival curves would not have predicted which drugs cause significant proliferative damage. Only with the use of CFU-S recovery and ratio of CFU-S can prolonged marrow damage be ascertained.