title: In vitro and in vivo enhancement of chemoradiation using the oral PARP inhibitor ABT-888 in colorectal cancer cells.
abstract: OBJECTIVE
  Poly(ADP-ribose) polymerase plays a critical role in the recognition and repair of DNA single-strand breaks and double-strand breaks (DSBs). ABT-888 is an orally available inhibitor of this enzyme. This study seeks to evaluate the use of ABT-888 combined with chemotherapy and radiation therapy (RT) in colorectal carcinoma models.
  
  
  METHODS
  RT clonogenic assays were performed on HCT116 and HT29 cells treated with 5-fluorouracil, irinotecan, or oxaliplatin with or without ABT. The surviving fraction at 2 Gy and dose-modifying factor at 10% survival were analyzed. Synergism was assessed by isobologram analysis for combination therapies. γH2AX and neutral comet assays were performed to assess the effect of therapy on DSB formation/repair. In vivo assessments were made by use of HCT116 cells in a xenograft mouse model. Tumor growth delay was measured at a volume of 500 mm(3).
  
  
  RESULTS
  Both lines were radiosensitized by ABT alone, and ABT further increased chemotherapy dose-modifying factors to the 1.6 to 1.8 range. All combinations were synergistic (combination indices <0.9). ABT treatment significantly increased DSB after RT (γH2AX, 69% vs 43%; P=.017) and delayed repair. We found tumor growth delays of 7.22 days for RT; 11.90 days for RT and ABT; 13.5 days for oxaliplatin, RT, and ABT; 14.17 days for 5-fluorouracil, RT, and ABT; and 23.81 days for irinotecan, RT, and ABT.
  
  
  CONCLUSIONS
  ABT-888 radiosensitizes at similar or higher levels compared with classic chemotherapies and acts synergistically with these chemotherapies to enhance RT effects. In vivo confirmation of these results indicates a potential role for combining its use with existing chemoradiation regimens.
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. jwshelt@emory.edu
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Shelton
authors.forename: Timothy V
authors.initials: TV
authors.lastname: Waxweiler
authors.forename: Jerome
authors.initials: J
authors.lastname: Landry
authors.forename: Huiying
authors.initials: H
authors.lastname: Gao
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Xu
authors.forename: Lanfang
authors.initials: L
authors.lastname: Wang
authors.forename: Bassel
authors.initials: B
authors.lastname: El-Rayes
authors.forename: Hui-Kuo G
authors.initials: HK
authors.lastname: Shu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D059248:Chemoradiotherapy / Q000379:methods*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D020552:Comet Assay / Q000379:methods; D004249:DNA Damage; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D045325:HCT116 Cells; D019073:HT29 Cells; D006657:Histones / Q000032:analysis; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; C468783:H2AX protein, human; D006657:Histones; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D000077150:Oxaliplatin; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin