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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Dihydrofluorouracil, a fluorouracil catabolite with antitumor activity in murine and human cells.

Dihydrofluorouracil (FUH2), the initial catabolite of 5-fluorouracil (FUra), was examined to determine whether this derivative had antitumor activity or host cell (bone marrow) toxicity. Studies were undertaken with Ehrlich ascites tumor and bone marrow cells isolated from CF-1 mice. Cells were exposed for 1 h either to no drug (control) or to varying concentrations, ranging from 1 to 250 microM, of either FUra, FUH2, or alpha-fluoro-beta-alanine. Cells were then cultured and colony formation was assessed after 10 to 14 days. Ehrlich ascites tumor cells were more sensitive to FUra [50% lethal dose (LD50) = 18 microM] than to FUH2 [LD50 = 50 microM], with no sensitivity to alpha-fluoro-beta-alanine even at 250 microM. Bone marrow cells had a toxicity profile similar to that of FUra (LD50 = 10 microM) but were relatively insensitive to FUH2 (LD50 greater than 250 microM), with no sensitivity to alpha-fluoro-beta-alanine. Subsequent studies examined colony formation of the human breast carcinoma cell line MCF-7 following 1 h exposure to varying concentrations of FUra and FUH2. These cells were less sensitive to both FUra (LD50 approximately 80 microM) and FUH2 (LD50 approximately 350 microM). Initial studies on the mechanism of toxicity of FUH2 demonstrated that this FUra catabolite could produce inhibition of thymidylate synthase activity in Ehrlich ascites tumor cells with a pattern similar to that resulting from exposure to FUra. This is the first study to demonstrate that FUH2 (a quantitatively important catabolite of FUra) is cytotoxic, and it suggests that FUH2 may contribute to the toxicity of FUra in vivo, possibly by being anabolized to FUra.[1]


  1. Dihydrofluorouracil, a fluorouracil catabolite with antitumor activity in murine and human cells. Diasio, R.B., Schuetz, J.D., Wallace, H.J., Sommadossi, J.P. Cancer Res. (1985) [Pubmed]
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