title: Cognitive impact of cytotoxic agents in mice.
abstract: OBJECTIVE
  Adjuvant chemotherapy is associated with changes in cognition in a subgroup of cancer patients. Chemotherapy is generally given as a combination of cytotoxic agents, which makes it hard to define the agent responsible for these observed changes. Literature on animal experiments has been difficult to interpret due to variance in experimental setup.
  
  
  METHODS
  We examined the effects of cytotoxic agents administered separately on various cognitive measures in a standardized animal model. Male C57Bl/6 mice received cyclophosphamide, docetaxel, doxorubicin, 5-fluorouracil, methotrexate, or topotecan. These agents represent different compound classes based on their working mechanism and are frequently prescribed in the clinic. A control group received saline. Behavioral testing started 2 or 15 weeks after treatment and included testing general measures of behavior and cognitive task performance: spontaneous behavior in an automated home cage, open field, novel location recognition (NLR), novel object recognition (NOR), Barnes maze, contextual fear conditioning, and a simple choice reaction time task (SCRTT).
  
  
  RESULTS
  Cyclophosphamide, docetaxel, and doxorubicin administration affected spontaneous activity in the automated home cage. All cytotoxic agents affected memory (NLR and/or NOR). Spatial memory measured in the Barnes maze was affected after administration with doxorubicin, 5-fluorouracil, and topotecan. Decreased inhibition in the SCRTT was observed after treatment with cyclophosphamide, docetaxel, and topotecan.
  
  
  CONCLUSIONS
  Our data show that, in mice, a single treatment with a cytotoxic agent causes cognitive impairment. Not all cytotoxic agents affected the same cognitive domains, which might be explained by differences in working mechanisms of the various agents.
authors.affiliation: Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Seigers
authors.forename: M
authors.initials: M
authors.lastname: Loos
authors.forename: O
authors.initials: O
authors.lastname: Van Tellingen
authors.forename: W
authors.initials: W
authors.lastname: Boogerd
authors.forename: A B
authors.initials: AB
authors.lastname: Smit
authors.forename: S B
authors.initials: SB
authors.lastname: Schagen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced* / Q000523:psychology*; D003603:Cytotoxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects / Q000523:psychology; D005472:Fluorouracil / Q000633:toxicity; D008297:Male; D008568:Memory / Q000187:drug effects; D008727:Methotrexate / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D011930:Reaction Time / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D005472:Fluorouracil; D008727:Methotrexate