PARP-1, PARP-2, and the cellular response to low doses of ionizing radiation.
OBJECTIVE
Poly(ADP-ribose) polymerase-1 (PARP-1) is rapidly and directly activated by single-strand breaks and is required for efficient base excision repair. These properties indicate that inhibition of PARP-1 might enhance the cellular response to low doses of radiation. We tested the effect of chemical inhibition of PARP-1 on low-dose clonogenic survival in a number of cell lines and the low-dose radiation response of a PARP-1 knockout murine cell line.


METHODS
Clonogenic cell survival of V79-379A and CHO-K1 hamster fibroblasts, T98G and U373-MG human glioma cells, and 3T3 mouse embryo fibroblast PARP-1 knockout cells was measured using a precise flow cytometry-based plating assay. Chemical inhibitors of PARP enzymes were tested for their effect on clonogenic survival after a range of ionizing radiation doses.


RESULTS
Chemical inhibition of PARP activity induced marked radiosensitization of V79, CHO, and exponentially growing T98G cells in the 0.05-0.3-Gy range. This effect was not seen in U373 cells or in confluent T98G populations. Low-dose radiosensitization was not apparent in PARP-1 knockout cells.


CONCLUSIONS
Low-dose radiosensitization of actively dividing tumor cells by PARP-1 inhibitors suggests that they may have a role in enhancing the efficacy of ultrafractionated or low-dose-rate radiotherapy regimens. We hypothesize that PARP-2 compensates for the absence of PARP-1 in the knockout cell line.
Chalmers
Anthony
A
Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, United Kingdom. chalmers@gci.ac.uk
Johnston
Peter
P
Woodcock
Mick
M
Joiner
Michael
M
Marples
Brian
B
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line / Q000528:radiation effects; D045744:Cell Line, Tumor / Q000528:radiation effects; D002470:Cell Survival; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D010616:Phenanthrenes / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines / Q000494:pharmacology; D011829:Radiation Dosage; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
D001549:Benzamides; D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; C115774:NU 1025; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; C025160:3-aminobenzamide