Olaparib, Monotherapy or with Ionizing Radiation, Exacerbates DNA Damage in Normal Tissues: Insights from a New p21 Reporter Mouse.
Many drugs targeting the DNA damage response are being developed as anticancer therapies, either as single agents or in combination with ionizing radiation (IR) or other cytotoxic agents. Numerous clinical trials in this area are either in progress or planned. However, concerns remain about the potential of such treatments to increase toxicity to normal tissues. In order to address this issue, a novel reporter mouse line was created through the simultaneous incorporation of multiple reporters, β-galactosidase, and firefly luciferase, into the DNA damage-inducible p21 (CDKN1A) locus. The data demonstrate that in situ β-galactosidase staining facilitates high fidelity mapping of p21 expression across multiple organs and tissues at single-cell resolution, whereas the luciferase reporter permits noninvasive bioluminescent imaging of p21 expression. This model was used to determine the capacity of a number of DNA-damaging agents, including IR, cisplatin, and etoposide to induce p21 expression in normal tissues. In addition, the PARP inhibitor olaparib was examined alone or in combination with IR as well as cisplatin. A single exposure to olaparib alone caused DNA damage to cells in the mucosal layer lining mouse large intestine. It also exacerbated DNA damage induced in this organ and the kidney by coadministered IR. These studies suggest that olaparib has carcinogenic potential and illustrate the power of this new model to evaluate the safety of new therapeutic regimens involving combination therapies.



Olaparib causes DNA damage to normal tissues and might be a carcinogen. Mol Cancer Res; 14(12); 1195-203. ©2016 AACR.
University of Dundee, School of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom.
Michael
M
McMahon
University of Dundee, School of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom.
Tania G
TG
Frangova
University of Dundee, School of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom.
Colin J
CJ
Henderson
University of Dundee, School of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom. c.r.wolf@dundee.ac.uk.
C Roland
CR
Wolf
D000818:Animals; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D049409:Luciferases, Firefly / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010793:Phthalazines / Q000633:toxicity*; D010879:Piperazines / Q000633:toxicity*; D011839:Radiation, Ionizing; D059010:Single-Cell Analysis; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010793:Phthalazines; D010879:Piperazines; D049409:Luciferases, Firefly; D001616:beta-Galactosidase; D002945:Cisplatin; C531550:olaparib