Biochemical and molecular effects of UCN-01 in combination with 5-fluorodeoxyuridine in A431 human epidermoid cancer cells

Jean L. Grem, Kathleen D. Danenberg, Vivian Kao, Peter V. Danenberg, Diana Nguyen

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Concurrent and pre-exposure of A431 human epidermoid cancer cells to UCN-01, an investigational anticancer drug, with 5-fluoro-2′-deoxyuridine (FdUrd), which targets thymidylate synthase, produced more than additive cytotoxicty, A 24-h exposure to 10 nM FdUrd led to inhibition of TS, a 2.5-fold increase in total thymidylate synthase protein content, profound dTTP depletion and a 6.3-fold increase in the ratio of dATP to dTTP, but did not cause single-strand breaks in DNA. However, FdUrd enhanced UCN-01-associated DNA strand breaks. Concurrent thymidine exposure led to repletion of dTTP pools, and cytoprotection against FdUrd alone and with UCN-01. UCN-01 arrested cells in G1, decreased the percentage of FdUrd-treated cells in S phase and reduced FdUrd-DNA incorporation, suggesting the latter was not important for cytotoxicity. Delayed induction of high molecular mass DNA fragmentation and poly(ADP-ribose) polymerase cleavage was observed with the combination of UCN-01 and FdUrd. These findings suggest that while FdUrd-mediated deoxynucleotide imbalance alone was insufficient to induce apoptosis in this p53-mutant cell line, it magnified UCN-01's effects, most likely by interfering with DNA repair. The clinical evaluation of UCN-01 combined with 5-fluoropyrimidines may be of interest.

Original languageEnglish (US)
Pages (from-to)259-270
Number of pages12
JournalAnti-Cancer Drugs
Volume13
Issue number3
DOIs
StatePublished - 2002

Keywords

  • 7-Hydroxy-staurospaurine
  • DNA damage
  • Fluoropyrimidines
  • Thymidylate synthase
  • UCN-01

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

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