ArticleBritish journal of cancer2014
Tumour cell retention of rucaparib, sustained PARP inhibition and efficacy of weekly as well as daily schedules.
Article in British journal of cancer, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 46 citations in OpenAlex.
- Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer.British journal of cancer · 2016Trial
- Dual FAK and EPHA2 targeting by brigatinib tackles PARP inhibitor adaptive survival response in high-grade serous ovarian cancer.Science translational medicine · 2026Article
- Challenges and opportunities to address the emerging burden of targeted therapies in ovarian cancer.Gynecologic oncology reports · 2025Review
- Article
- Imaging PARP with [European journal of nuclear medicine and molecular imaging · 2022Article
- KP372-1-Induced AKT Hyperactivation Blocks DNA Repair to Synergize With PARP Inhibitor RucaparibFrontiers in oncology · 2022Article
- The Development of Rucaparib/Rubraca®: A Story of the Synergy Between Science and Serendipity.Cancers · 2020Review
- Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy.The Journal of clinical investigation · 2020Article
- Brain metastasis in epithelial ovarian cancer by BRCA1/2 mutation status.Gynecologic oncology · 2019Article
- Rucaparib: A Review in Ovarian Cancer.Targeted oncology · 2019Review
- PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers.Journal of clinical medicine · 2019Review
- Exploring the Frequency of Homologous Recombination DNA Repair Dysfunction in Multiple Cancer Types.Cancers · 2019Article
- PARP inhibition prevents escape from a telomere-driven crisis and inhibits cell immortalisation.Oncotarget · 2018Article
- Article
- Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors.Breast cancer research : BCR · 2017Article
- Rucaparib: First Global Approval.Drugs · 2017Review
- Proteome-wide Profiling of Clinical PARP Inhibitors Reveals Compound-Specific Secondary Targets.Cell chemical biology · 2016Article
- Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors.Cancer cell · 2016Article
- Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System.Molecular cancer therapeutics · 2015Article
- Proteome-wide analysis of mutant p53 targets in breast cancer identifies new levels of gain-of-function that influence PARP, PCNA, and MCM4.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundPoly(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.
methodsUptake 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.
resultsRucaparib 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.
conclusionsRucaparib 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.
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