title: Radioprotection and cell cycle arrest of intestinal epithelial cells by darinaparsin, a tumor radiosensitizer.
abstract: OBJECTIVE
  It was recently reported that the organic arsenic compound darinaparsin (DPS) is a cytotoxin and radiosensitizer of tumor cells in vitro and in subcutaneous xenograft tumors. Surprisingly, it was also found that DPS protects normal intestinal crypt epithelial cells (CECs) from clonogenic death after ionizing radiation (IR). Here we tested the DPS radiosensitizing effect in a clinically relevant model of prostate cancer and explored the radioprotective effect and mechanism of DPS on CECs.
  
  
  METHODS
  The radiation modification effect of DPS was tested in a mouse model of orthotopic xenograft prostate cancer and of IR-induced acute gastrointestinal syndrome. The effect of DPS on CEC DNA damage and DNA damage responses was determined by immunohistochemistry.
  
  
  RESULTS
  In the mouse model of IR-induced gastrointestinal syndrome, DPS treatment before IR accelerated recovery from body weight loss and increased animal survival. DPS decreased post-IR DNA damage and cell death, suggesting that the radioprotective effect was mediated by enhanced DNA damage repair. Shortly after DPS injection, significant cell cycle arrest was observed in CECs at both G1/S and G2/M checkpoints, which was accompanied by the activation of cell cycle inhibitors p21 and growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A). Further investigation revealed that DPS activated ataxia telangiectasia mutated (ATM), an important inducer of DNA damage repair and cell cycle arrest.
  
  
  CONCLUSIONS
  DPS selectively radioprotected normal intestinal CECs and sensitized prostate cancer cells in a clinically relevant model. This effect may be, at least in part, mediated by DNA damage response activation and has the potential to significantly increase the therapeutic index of radiation therapy.
authors.affiliation: Department of Radiation Oncology, School of Medicine, Stanford University, Stanford, California.
authors.forename: Junqiang
authors.initials: J
authors.lastname: Tian
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Doi
authors.forename: Matthias
authors.initials: M
authors.lastname: Saar
authors.forename: Jennifer
authors.initials: J
authors.lastname: Santos
authors.forename: Xuejun
authors.initials: X
authors.lastname: Li
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peehl
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Knox
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D001152:Arsenicals / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004386:Duodenum / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000528:radiation effects*; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000528:radiation effects; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy; D011833:Radiation Injuries, Experimental / Q000188:drug therapy; D011836:Radiation Tolerance / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013577:Syndrome
chemical_list: D001152:Arsenicals; D011837:Radiation-Protective Agents; D011838:Radiation-Sensitizing Agents; C515055:darinaparsin; D005978:Glutathione