title: Establishing a model for assessing DNA damage in murine brain cells as a molecular marker of chemotherapy-associated cognitive impairment.
abstract: OBJECTIVE
  Chemotherapy-associated cognitive impairment often follows cancer chemotherapy. We explored chemotherapy-induced DNA damage in the brain cells of mice treated with 5-fluorouracil (5FU), an antineoplastic agent, to correlate the extent of DNA damage to behavioral functioning in an autoshaping-operant mouse model of chemotherapy-induced learning and memory deficits (Foley et al., 2008).
  
  
  METHODS
  Male, Swiss-Webster mice were injected once with saline or 75 mg/kg 5FU at 0, 12, and 24h and weighed every 24h. Twenty-four h after the last injection, the mice were tested in a two-day acquisition and the retention of a novel response task for food reinforcement. Murine brain cells were analyzed for the presence of single- and double-strand DNA breaks by the single cell gel electrophoresis assay (the Comet assay).
  
  
  RESULTS
  We detected significant differences (p<0.0001) for all DNA damage characteristics (DNA "comet" tail shape, migration pattern, tail moment and olive moments) between control mice cohort and 5FU-treated mice cohort: tail length - 119 vs. 153; tail moment - 101 vs. 136; olive moment - 60 vs. 82, correspondingly. We found a positive correlation between increased response rates (r=0.52, p<0.05) and increased rate of errors (r=0.51, p<0.05), and DNA damage on day 1. For all 15 mice (saline-treated and 5FU-treated mice), we found negative correlations between DNA damage and weight (r=-0.75, p<0.02).
  
  
  CONCLUSIONS
  Our results indicate that chemotherapy-induced DNA damage changes the physiological status of the brain cells and may provide insights to the mechanisms for cognitive impairment after cancer chemotherapy.
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, United States.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Krynetskiy
authors.forename: Natalia
authors.initials: N
authors.lastname: Krynetskaia
authors.forename: Diana
authors.initials: D
authors.lastname: Rihawi
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Wieczerzak
authors.forename: Victoria
authors.initials: V
authors.lastname: Ciummo
authors.forename: Ellen
authors.initials: E
authors.lastname: Walker
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D054316:Biomarkers, Pharmacological; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D003216:Conditioning, Operant / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D005472:Fluorouracil / Q000009:adverse effects*; D008297:Male; D051379:Mice; D023421:Models, Animal; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D012055:Reinforcement Schedule
chemical_list: D000964:Antimetabolites, Antineoplastic; D054316:Biomarkers, Pharmacological; D005472:Fluorouracil
keywords: 5-Fluorouracil; Acquisition; Autoshaping; Chemotherapy; Cognition; DNA damage