Improved pharmacodynamic (PD) assessment of low dose PARP inhibitor PD activity for radiotherapy and chemotherapy combination trials

Autor: de Haan, Rosemarie, Pluim, Dick, van Triest, Baukelien, van den Heuvel, Michel, Peulen, Heike, van Berlo, Damien, George, Jay, Verheij, Marcel, Schellens, Jan H M, Vens, Conchita, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology
Přispěvatelé: Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Radiation Oncology, CCA - Cancer biology and immunology
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Oncology
medicine.medical_specialty
Poly Adenosine Diphosphate Ribose
Lung Neoplasms
Pharmacodynamic assay
medicine.medical_treatment
Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9]
Poly(ADP-ribose) Polymerase Inhibitors
Peripheral blood mononuclear cell
Olaparib (Lynparza tm)
Piperazines
Olaparib
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Internal medicine
Medicine
Humans
Radiology
Nuclear Medicine and imaging
Lung cancer
Chemotherapy
business.industry
RT combination trials
Hematology
Chemoradiotherapy
medicine.disease
Radiation therapy
030104 developmental biology
PARP inhibitor
chemistry
Chemoradiation
030220 oncology & carcinogenesis
Pharmacodynamics
Immunology
Phthalazines
business
Ex vivo
Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Zdroj: Radiotherapy and Oncology, 126(3), 443-449. Elsevier Ireland Ltd
Radiotherapy and Oncology, 126, 443-449
de Haan, R, Pluim, D, van Triest, B, van den Heuvel, M, Peulen, H, van Berlo, D, George, J, Verheij, M, Schellens, J H M & Vens, C 2018, ' Improved pharmacodynamic (PD) assessment of low dose PARP inhibitor PD activity for radiotherapy and chemotherapy combination trials ', Radiotherapy and Oncology, vol. 126, no. 3, pp. 443-449 . https://doi.org/10.1016/j.radonc.2017.10.017
Radiotherapy and Oncology, 126, 3, pp. 443-449
Radiotherapy and Oncology, 126(3), 443. Elsevier Ireland Ltd.
ISSN: 0167-8140
DOI: 10.1016/j.radonc.2017.10.017
Popis: Item does not contain fulltext BACKGROUND: PARP inhibitors are currently evaluated in combination with radiotherapy and/or chemotherapy. As sensitizers, PARP inhibitors are active at very low concentrations therefore requiring highly sensitive pharmacodynamic (PD) assays. Current clinical PD-assays partly fail to provide such sensitivities. The aim of our study was to enable sensitive PD evaluation of PARP inhibitors for clinical sensitizer development. MATERIAL AND METHODS: PBMCs of healthy individuals and of olaparib and radiotherapy treated lung cancer patients were collected for ELISA-based PD-assays. RESULTS: PAR-signal amplification by ex vivo irradiation enabled an extended quantification range for PARP inhibitory activities after ex vivo treatment with inhibitors. This "radiation-enhanced-PAR" (REP) assay provided accurate IC50 values thereby also revealing differences among healthy individuals. Implemented in clinical radiotherapy combination Phase I trials, the REP-assay showed sensitive detection of PARP inhibition in patients treated with olaparib and establishes strong PARP inhibitory activities at low daily doses. CONCLUSIONS: Combination trials of radiotherapy and novel targeted agent(s) often require different and more sensitive PD assessments than in the monotherapy setting. This study shows the benefit and relevance of sensitive and adapted PD-assays for such combination purposes and provides proof of clinically relevant cellular PARP inhibitory activities at low daily olaparib doses.
Databáze: OpenAIRE
Externí odkaz: