Dihydrofluorouracil (FUH 2), 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 μM, of either FUra, FUH 2, or α-fluoro-β-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 (LD 50) = 18 μM] than to FUH 2 [LD 50 = 50 μM], with no sensitivity to α-fluoro-β-alanine even at 250 μM. Bone marrow cells had a toxicity profile similar to that of FUra (LD 50 = 10 μM) but were relatively insensitive to FUH 2 (LD 50 > 250 μM), with no sensitivity to α-fluoro-β-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 FUH 2. These cells were less sensitive to both FUra (LD 50 ~ 80 μM) and FUH 2 (LD 50 ~ 350 μM). Initial studies on the mechanism of toxicity of FUH 2 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 FUH 2 (a quantitatively important catabolite of FUra) is cytotoxic, and it suggests that FUH 2 may contribute to the toxicity of FUra in vivo, possibly by being anabolized to FUra.
|Original language||English (US)|
|Number of pages||4|
|State||Published - 1985|
ASJC Scopus subject areas
- Cancer Research