Mechanism of cytotoxicity of 5-fluorouracil: Distinction between the irreversible cytotoxic effect of 5-fluorouridine and the reversible cytotoxic effect of 5-fluoro-2?-deoxyuridine on murine lymphoma L5178Y cells in culture

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Abstract
To determine the relative importance of the DNA and RNA effects in the cytotoxicity of 5-fluorouracil, we determined the effects of brief exposure to 5-fluorouridine and 5-fluoro-2′-deoxyuridine, compared with 5-fluorouracil, on the subsequent growth of murine lymphoma L5178Y cells during prolonged incubations following the removal of the drug from the culture medium. 5-Fluoro-2′-deoxyuridine markedly inhibited cell proliferation by continuous exposure. However, its inhibitory effect by exposure even at 1,000 μM for 1 h easily disappeared within 1 week after removal of the drug from the culture medium. This result indicates that the cytotoxic effect of 5-fluoro-2′-deoxyuridine is reversible on cell proliferation. On the other hand, the exposure to 5-fluorouridine, event at the low concentration of 1.5 μM for 1 h, caused a substantial and irreversible inhibition on cell proliferation. The cytotoxic effect of 5-fluorouracil was also an irreversible action similar to that of 5-fluorouridine.