In vivo studies of the PARP inhibitor, AZD-2281, in combination with fractionated radiotherapy: An exploration of the therapeutic ratio.
OBJECTIVE
Pre-clinical data have shown that PARP inhibitors (PARPi) may increase the efficacy of radiotherapy in prostate cancer. However, it is uncertain as to whether PARPi lead to clonogenic kill when combined with radiotherapy (RT).


METHODS
We tested the PARP inhibitor AZD-2281 as a radiosensitizing agent under oxic and hypoxic conditions for clonogenic survival in vitro and in vivo using the human prostate cancer cell line, 22Rv1. In addition, the effects of PARPi+RT on normal tissue were investigated using a crypt clonogenic assay.


RESULTS
AZD-2281 inhibited cellular PARP activity under both oxic and hypoxic conditions. The addition of AZD-2281 radiosensitized 22Rv1 cells under oxia, acute hypoxia and chronic hypoxia in vitro. The combination of AZD-2281 with fractionated radiotherapy resulted in a significant growth delay and clonogenic kill in vivo. No increased gut toxicity was observed using this combined PARPi+radiotherapy regimen.


CONCLUSIONS
This is the first preclinical study to demonstrate direct clonogenic kill in vivo by the addition of AZD-2281 to radiotherapy. As we did not observe gut toxicity, the use of PARPi in the context of prostate cancer radiotherapy warrants further investigation in clinical trials.
Princess Margaret Cancer Centre (Radiation Medicine Program, University Health Network), Toronto, Canada; Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Canada; Department of Radiation Oncology, University Hospital of Tuebingen, Germany.
Cihan
C
Gani
Princess Margaret Cancer Centre (Radiation Medicine Program, University Health Network), Toronto, Canada; Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Canada.
Carla
C
Coackley
Princess Margaret Cancer Centre (Radiation Medicine Program, University Health Network), Toronto, Canada; Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Canada.
Ramya
R
Kumareswaran
OncoRay - National Centre for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Christina
C
Schütze
OncoRay - National Centre for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Mechthild
M
Krause
Princess Margaret Cancer Centre (Radiation Medicine Program, University Health Network), Toronto, Canada; Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Canada.
Gaetano
G
Zafarana
Princess Margaret Cancer Centre (Radiation Medicine Program, University Health Network), Toronto, Canada; Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Canada. Electronic address: rob.bristow@rmp.uhn.on.ca.
Robert G
RG
Bristow
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods*; D019583:Dose Fractionation, Radiation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D008819:Mice, Nude; D010793:Phthalazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D047368:Tumor Burden
D000970:Antineoplastic Agents; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; C531550:olaparib
AZD-2281; Clonogenic assay; EF5; Gamma H2AX; Growth delay; Gut toxicity; PARP inhibitors; Prostate cancer