In vitro and in vivo myelotoxicity of CAI to human and murine hematopoietic progenitor cells.
Carboxyamido-triazole (CAI), an agent that targets calcium-sensitive signal transduction pathways, has both antiproliferative and antimetastatic properties. The objective of this study was to evaluate the myelotoxicity of CAI to normal human and murine hematopoietic cells. In vitro toxicity of CAI was determined by inhibition of myeloid [colony-forming unit-granulocyte/macrophage (CFU-gm)] and erythroid [burst-forming unit-erythroid (BFU-e)] colony formation in clonal assays. The effects of oral CAI on CD2F1 mouse marrow and splenic cellularity, marrow progenitor content, and peripheral blood cell counts were assessed in relation to plasma CAI levels. In vitro, CAI caused a concentration-dependent inhibition of CFU-gm and BFU-e colonies following continuous drug exposure. Murine CFU-gm and BFU-e were inhibited > 90% by 10 and 15 micrograms/mL CAI, respectively. However, suppression of human CFU-gm and BFU-e did not exceed 65% at the same concentrations. In vivo, CAI reduced the number of CFU-gm and BFU-e per femur after the initial dose and through day 4. Variations in colony inhibition paralleled changes in CAI plasma concentrations. While colony inhibition increased in vitro with escalating drug concentrations, this was not observed in vivo with additional CAI doses. The low toxicity of CAI in vivo combined with the significant difference between toxicity for human and mouse progenitors in vitro suggests a relatively low adverse potential to the bone marrow for this new signal transduction inhibitory agent.
D000818:Animals; D001854:Bone Marrow Cells; D002455:Cell Division / Q000187:drug effects; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D007700:Kinetics; D007958:Leukocyte Count; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D010976:Platelet Count; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D014230:Triazoles / Q000633:toxicity*
D007377:Interleukin-3; D011994:Recombinant Proteins; D014230:Triazoles; D004921:Erythropoietin; C062058:carboxyamido-triazole; D016178:Granulocyte-Macrophage Colony-Stimulating Factor