Cytotoxic effects and mechanisms of an alteration in the dose and duration of 5-fluorouracil

5-Fluorouracil (5-FU) is the most routinely administered drug in the treatment of colon cancer. The main mechanism of the drug is not completely understood and its method of administration has been strongly disputed. A 24-hour infusion of 5-FU has clinically yielded better response rates and lower toxicities in comparison to bolus administration, but an exploration into possible mechanisms needs to be performed. Experiments were conducted with two 5-FU resistant cell lines where cytotoxicity, thymidylate synthase (T S.) activity, thymidine kinase (T.K.) activity, DNA and RNA incorporation, and T.S. expression were contrasted between a 10 muM/24 hour administration of 5-FU (simulating continuous exposure) and a 100 muM/1 hour schedule (simulating bolus administration). After 6 days from the initial exposure, the 10 muM/24 hour schedule (schedule A) inhibited more cell growth than the 100,muM/1 hour regimen (schedule B) by more than 38% and 17% in the two cell lines. After the 6-day observation, schedule A inhibited twice as much T.S. activity as schedule B. Incorporation of [C-14]-5-FU into DNA and total RNA was higher in cells exposed to schedule A in comparison to schedule B over the 6 days. T.S. expression and TK activity patterns were variable over time. Thus, the exposure of 10 muM/24 hour 5-FU results in superior cytotoxicity when compared to a 100 muM/1 hour regimen and its effectiveness may be explained mechanistically by TS. activity and DNA and RNA incorporation.