Poly(ADP-Ribose) polymerase inhibition synergizes with 5-fluorodeoxyuridine but not 5-fluorouracil in ovarian cancer cells

Cancer Res. 2011 Jul 15;71(14):4944-54. doi: 10.1158/0008-5472.CAN-11-0814. Epub 2011 May 25.

Abstract

5-Fluorouracil (5-FU) and 5-fluorodeoxyuridine (FdUrd, floxuridine) have activity in multiple tumors, and both agents undergo intracellular processing to active metabolites that disrupt RNA and DNA metabolism. These agents cause imbalances in deoxynucleotide triphosphate levels and the accumulation of uracil and 5-FU in the genome, events that activate the ATR- and ATM-dependent checkpoint signaling pathways and the base excision repair (BER) pathway. Here, we assessed which DNA damage response and repair processes influence 5-FU and FdUrd toxicity in ovarian cancer cells. These studies revealed that disabling the ATM, ATR, or BER pathways using small inhibitory RNAs did not affect 5-FU cytotoxicity. In stark contrast, ATR and a functional BER pathway protected FdUrd-treated cells. Consistent with a role for the BER pathway, the poly(ADP-ribose) polymerase (PARP) inhibitors ABT-888 (veliparib) and AZD2281 (olaparib) markedly synergized with FdUrd but not with 5-FU in ovarian cancer cell lines. Furthermore, ABT-888 synergized with FdUrd far more effectively than other agents commonly used to treat ovarian cancer. These findings underscore differences in the cytotoxic mechanisms of 5-FU and FdUrd and suggest that combining FdUrd and PARP inhibitors may be an innovative therapeutic strategy for ovarian tumors.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Ataxia Telangiectasia Mutated Proteins
  • Benzimidazoles / pharmacology
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • Checkpoint Kinase 2
  • DNA Repair
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / metabolism
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Female
  • Floxuridine / pharmacology*
  • Fluorouracil / pharmacology*
  • Humans
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / enzymology*
  • Ovarian Neoplasms / genetics
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Transfection
  • Tumor Suppressor Proteins / metabolism
  • X-ray Repair Cross Complementing Protein 1

Substances

  • Antimetabolites, Antineoplastic
  • Benzimidazoles
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors
  • RNA, Small Interfering
  • Tumor Suppressor Proteins
  • X-ray Repair Cross Complementing Protein 1
  • veliparib
  • Floxuridine
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Protein Kinases
  • Checkpoint Kinase 2
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human
  • Checkpoint Kinase 1
  • Protein Serine-Threonine Kinases
  • Fluorouracil