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

ABSTRACT:

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 a

SUBMITTER: Murray J 

PROVIDER: S-EPMC3992512 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature