Differential toxicity of anticancer drugs on late (GM-CFC) and early (LTC-IC) hemopoietic progenitors in vitro

The clinical hematological toxicity of cytotoxic drugs can be acute, with a nadir of neutrophil count after 2 weeks and recovery the following week, o r subacute, with a nadir of neutrophil count after 3 weeks and recovery in the following 2-3 weeks. The explanation usually given for this difference is that drugs in the first group are more toxic to mature hemopoietic precu rsors, while drugs of the second type are more toxic to undifferentiated ce lls. In an attempt to verify this hypothesis, we compared in vitro the effe ct of toxic doses of etoposide and tallimustine as representatives of drugs with acute toxicity, and of BCNU, melphalan, and carzelesin as representat ives of drugs with subacute toxicity. Their effects were studied separately on more differentiated and earlier progenitors represented by granulocyte- macrophage colony-forming cells (GM-CFC) and long-term culture-initiating c ells (LTC-IC), respectively. Etoposide, melphalan, BCNU, and carzelesin sho wed higher toxicity in differentiated than in early precursors: the concent ration of drug inhibiting 70% (ID70) of GM-CFC inhibited only by 10-40% the growth of LTC-IC. Tallimustine, in contrast, inhibited both GM-CFC and LTC -IC at comparable levels. These results do not correspond to the clinical p attern of myelotoxicity observed for those drugs. We conclude that the diff erential effects of antitumor drugs on later (GM-CFC) or earlier (LTC-IC) h emopoietic precursors may not represent a valid model for the pattern of my elotoxicity observed in humans.