Potassium oxonate modulation of 5-fluorouracil-induced myelotoxicity in murine and human colony forming assays of hematopoietic precursor cells.
Potassium oxonate (Oxo) is one of three components of S-1, an anticancer drug developed to improve the selective toxicity of 5-fluorouracil (5-FU). Oxo has been shown to reduce gastrointestinal toxicity. In this study, using murine and human granulocyte/macrophage colony forming (mCFU-GM, hCFU-GM) assays, we investigated whether Oxo can reduce 5-FU-induced myelotoxicity. The respective concentrations of 5-FU for 50% reduction (IC(50)) in mCFU-GM and hCFU-GM assays were 1.1 and 0.76 microM. The concentration-response curve was substantially steeper in the mCFU-GM assay than in the hCFU-GM assay. In the mCFU-GM assay, Oxo prevented growth suppression by 1 and 2 microM 5-FU, and at greater than 1 microM, it prevented suppression by 1 microM 5-FU almost completely. In the hCFU-GM assay, in contrast, Oxo prevented 5-FU suppression only slightly, and without a dose-response relationship. The difference between the mCFU-GM and hCFU-GM results may have stemmed from the spontaneous decomposition of Oxo during the longer culture period and Oxo's toxicity for human cells. Considering the human pharmacokinetic data, we concluded that Oxo has the potential to reduce 5-FU-induced myelotoxicity in human.
Kouchi
Yasuhide
Y
Drug Safety Research Laboratory, Taiho Pharmaceutical Co. Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, 771-0194, Tokushima, Japan. y-kouchi@taiho.co.jp
Maeda
Yasuhiro
Y
Ohuchida
Akinobu
A
Nomura
Naruo
N
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000037:antagonists & inhibitors / Q000633:toxicity*; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010094:Oxonic Acid / Q000493:pharmacokinetics / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D010094:Oxonic Acid; D005472:Fluorouracil