title: Poly(ADP-ribose) polymerase inhibitors combined with external beam and radioimmunotherapy to treat aggressive lymphoma.
abstract: OBJECTIVE
  To assess the possible radiosensitizing capabilities of two different poly(ADP-ribose) polymerase (PARP) inhibitors in combination with external beam and I-tositumomab in a non-Hodgkin's lymphoma cell line.
  
  
  METHODS
  Epstein-Barr virus-infected human Raji lymphoma cells with lentivirally transfected green fluorescent protein and luciferase in log-phase growth were incubated with various doses of AZD-2281 and ABT-888 24 h before external beam radiation exposure. A 500 nmol/l concentration of AZD-2281 and ABT-888 was used to assess the growth curve of Raji lymphoma cells over 5 days. The number of double-stranded breaks was visually assessed using a H2AX antibody and confocal microscopy. Intracellular PARP activity was measured 2 h after incubation with AZD-2281 (500 nmol/l) and ABT-888 using a colorimetric PARP assay kit. The radiosensitizing effect of AZD-2281 (500 nmol/l) with various doses of I-tositumomab was assessed after 24 h.
  
  
  RESULTS
  A volume of 500 nmol/l of AZD-2281 and 500 nmol/l of ABT-888, in combination with 0, 4, 8, and 12 Gy external beam radiation, showed a 5.2, 7.1, 10.1, and 33.1% radiosensitization. A measure of 500 nmol/l AZD-2281 and ABT-888 significantly reduced the percentage of viable cells on days 3-5 compared with controls. The maximal relative reduction in viable cells was 78.5%, and this occurred with AZD-2281 (500 nmol/l) on day 5. AZD-2281 revealed a higher number of double-stranded breaks with confocal microscopy than did ABT-888. Two hours after incubation of Raji cells with 500 nmol/l of AZD-2281 or ABT-888, the colorimetric PARP activity assay showed a reduction of 30.36% with ABT-888 and of 47.8% with AZD-2281. Combining AZD-2281 (500 nmol/l) with 0, 5 μCi (0.185 MBq), 10 μCi (0.37 MBq) and 20 μCi (0.74 MBq) ¹³¹I-tositumomab revealed a significant reduction in cell viability after 24 h with 5 μCi (0.185 MBq) (P<0.01) and 10 μCi (0.37 MBq) (P<0.01) radiation dose.
  
  
  CONCLUSIONS
  PARP inhibitors AZD-2281 and ABT-888 are highly radiosensitizing agents when used before external beam radiation and ¹³¹I-tositumomab.
authors.affiliation: Division of Nuclear Medicine, Russell H. Morgan Department of Radiology and Radiological Sciences, Sidney Kimmell Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-0817, USA.
authors.forename: Niklaus G
authors.initials: NG
authors.lastname: Schaefer
authors.forename: Engles
authors.initials: E
authors.lastname: James
authors.forename: Richard L
authors.initials: RL
authors.lastname: Wahl
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D016499:Radioimmunotherapy
chemical_list: D000911:Antibodies, Monoclonal; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; C521013:veliparib; D011065:Poly(ADP-ribose) Polymerases; C119496:tositumomab I-131; C531550:olaparib