Tumour cell retention of rucaparib, sustained PARP inhibition and efficacy of weekly as well as daily schedules

Br J Cancer. 2014 Apr 15;110(8):1977-84. doi: 10.1038/bjc.2014.91. Epub 2014 Feb 20.


Background: Poly(ADP-ribose) polymerase-1 (PARP) inhibitors (PARPi) exploit tumour-specific defects in homologous recombination DNA repair and continuous dosing is most efficacious. Early clinical trial data with rucaparib suggested that it caused sustained PARP inhibition. Here we investigate the mechanism of this durable inhibition and potential exploitation.

Methods: Uptake and retention of rucaparib and persistence of PARP inhibition were determined by radiochemical and immunological assays in human cancer cell lines. The pharmacokinetics and pharmacodynamics of rucaparib were determined in tumour-bearing mice and the efficacy of different schedules of rucaparib was determined in mice bearing homologous recombination DNA repair-defective tumours.

Results: Rucaparib accumulation is carrier mediated (Km=8.4±1.2 μM, Vmax=469±22 pmol per 10(6) cells per 10 min), reaching steady-state levels >10 times higher than the extracellular concentration within 30 min. Rucaparib is retained in cells and inhibits PARP ≥50% for ≥72 h days after a 30-min pulse of 400 nM. In Capan-1 tumour-bearing mice rucaparib accumulated and was retained in the tumours, and PARP was inhibited for 7 days following a single dose of 10 mg kg(-1) i.p or 150 mg kg(-1) p.o. by 70% and 90%, respectively. Weekly dosing of 150 mg kg(-1) p.o once a week was as effective as 10 mg kg(-1) i.p daily for five days every week for 6 weeks in delaying Capan-1 tumour growth.

Conclusions: Rucaparib accumulates and is retained in tumour cells and inhibits PARP for long periods such that weekly schedules have equivalent anticancer activity to daily dosing in a pre-clinical model, suggesting that clinical evaluation of alternative schedules of rucaparib should be considered.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • DNA Repair / drug effects
  • Drug Administration Schedule
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacokinetics
  • Homologous Recombination / drug effects
  • Humans
  • Indoles / administration & dosage*
  • Indoles / blood
  • Indoles / pharmacokinetics
  • Mice
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / genetics*
  • Xenograft Model Antitumor Assays


  • Enzyme Inhibitors
  • Indoles
  • Poly(ADP-ribose) Polymerase Inhibitors
  • rucaparib
  • Poly(ADP-ribose) Polymerases