Toxicity of coumarin (1,2-benzopyrone) on human peripheral blood mononuclear cells and human and murine bone marrow progenitor stem cells.
Coumarin (1,2-benzopyrone), in combination with cimetidine, has been subjected to separate clinical trials for the treatment of advanced renal cell carcinoma, malignant melanoma, and non-small cell lung cancer. While objective tumor regressions were observed only in renal carcinoma, no symptomatic or organ dysfunction toxicity was observed in any of the trials. The purpose of the present in vitro study was to determine the concentrations of coumarin and 7-hydroxycoumarin (7-HC) that would be toxic to human peripheral blood mononuclear cells (PB-MNC) and human and murine bone marrow (GM) progenitor stem cells. Coumarin was nontoxic for PB-MNC in concentrations up to 100 micrograms/ml. Concentrations of coumarin or 7-HC greater than or equal to 200 micrograms/ml produced significant suppression of human marrow GM stem cell activity. Coumarin greater than or equal to 25 micrograms/ml produced suppression of murine marrow GM stem cell activity. Differences in human and murine marrow sensitivity probably reflect interspecies differences in metabolism of coumarin. Correlations between toxic concentrations in vitro and maximally achievable serum concentration in vivo in humans await the results of further clinical trials.
Gallicchio
V S
VS
Division of Hematology/Oncology, University of Kentucky Medical Center, Lexington 40536-0084.
Hulette
B C
BC
Harmon
C
C
Marshall
M E
ME
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003374:Coumarins / Q000633:toxicity*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008297:Male; D051379:Mice; D013234:Stem Cells / Q000187:drug effects*; D014468:Umbelliferones / Q000633:toxicity*
D003374:Coumarins; D014468:Umbelliferones; C031477:7-hydroxycoumarin; C030123:coumarin