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

Manish Patel, Katherine Ardalan, Ian Hochman, Er Ming Tian, Bach Ardalan

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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 μM/24 hour administration of 5-FU (simulating continuous exposure) and a 100 μM/1 hour schedule (simulating bolus administration). After 6 days from the initial exposure, the 10 μM/24 hour schedule (schedule A) inhibited more cell growth than the 100 μM/1 hour regimen (schedule B) by more than 38% and 17% in the two cell lines. After the 6-day observation, schedule A inhibited Avice as much T.S. activity as schedule B. Incorporation of [14C]-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 T.K activity patterns were variable over time. Thus, the exposure of 10 μM/24 hour 5-FU results in superior cytotoxicity when compared to a 100 μM/1 hour regimen and its effectiveness may be explained mechanistically by T.S. activity and DNA and RNA incorporation.

Original languageEnglish (US)
Pages (from-to)447-452
Number of pages6
JournalAnticancer research
Volume23
Issue number1 A
StatePublished - Jan 1 2003

Keywords

  • Bolus
  • DNA
  • Fluorouracil
  • Infusion
  • RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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