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, or 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 precursors, while drugs of the second type are more toxic to undifferentiated cells. In an attempt to verify this hypothesis, we compared in vitro the effect of toxic doses of etoposide and tallimustine as representatives of drugs with acute toxicity, and of BCNU, melphalan, and carzelesin as representatives 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 cells (LTC-IC), respectively. Etoposide, melphalan, BCNU, and carzelesin showed higher toxicity in differentiated than in early precursors: the concentration 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 pattern of myelotoxicity observed for those drugs. We conclude that the differential effects of antitumor drugs on later (GM-CFC) or earlier (LTC-IC) hemopoietic precursors may not represent a valid model for the pattern of myelotoxicity observed in humans.
Ghielmini
M
M
Division of Oncology, Ospedale S. Giovanni, Bellinzona, Switzerland.
Bosshard
G
G
Pampallona
S
S
Genini
D
D
Bernier
J
J
Sessa
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D066298:In Vitro Techniques; D051379:Mice; D017154:Stromal Cells / Q000187:drug effects
D000970:Antineoplastic Agents