title: PARP-1, PARP-2, and the cellular response to low doses of ionizing radiation.
abstract: 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.
authors.affiliation: Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, United Kingdom. chalmers@gci.ac.uk
authors.forename: Anthony
authors.initials: A
authors.lastname: Chalmers
authors.forename: Peter
authors.initials: P
authors.lastname: Johnston
authors.forename: Mick
authors.initials: M
authors.lastname: Woodcock
authors.forename: Michael
authors.initials: M
authors.lastname: Joiner
authors.forename: Brian
authors.initials: B
authors.lastname: Marples
mesh_terms: 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
chemical_list: 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