title: Preclinical Evaluation of the Short-Term Toxicity of 4-(N)-Docosahexaenoyl 2´, 2´- Difluorodeoxycytidine (DHA-dFdC).
abstract: This study was designed to test the short-term toxicity of DHA-dFdC in a mouse model and its efficacy in a mouse model of leukemia at or below its repeat-dose maximum tolerated dose (RD-MTD).
  
  
  
  A repeat-dose dose-ranging toxicity study was designed to determine the tolerability of DHA-dFdC when administered to DBA/2 mice by intravenous (i.v.) injection on a repeat-dose schedule (i.e. injections on days 0, 3, 7, 10, and 13). In order to determine the effect of a lethal dose of DHA-dFdC, mice were injected i.v. with three doses of DHA-dFdC at 100 mg/kg on days 0, 3, and 5 (i.e. a lethal-RD). The body weight of mice was recorded two or three times a week. At the end of the study, major organs (i.e. heart, liver, spleen, kidneys, lung, and pancreas) of mice that received the lethal-RD or RD-MTD were weighed, and blood samples were collected for analyses. Finally, DHA-dFdC was i.v. injected into DBA/2 mice with syngeneic L1210 mouse leukemia cells to evaluate its efficacy at or below RD-MTD.
  
  
  
  The RD-MTD of DHA-dFdC is 50 mg/kg. At 100 mg/kg, a lethal-RD, DHA-dFdC decreases the weights of mouse spleen and liver and significantly affected certain blood parameters (i.e. white blood cells, lymphocytes, eosinophils, and neutrophil segmented). At or below its RD-MTD, DHA-dFdC significantly prolonged the survival of L1210 leukemia-bearing mice.
  
  
  
  DHA-dFdC has dose-dependent toxicity, affecting mainly spleen at a lethal-RD. At or below its RD-MTD, DHA-dFdC is effective against leukemia in a mouse model.
authors.affiliation: Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78712, USA.
authors.forename: Solange
authors.initials: S
authors.lastname: Valdes
authors.affiliation: Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78712, USA.
authors.forename: Youssef W
authors.initials: YW
authors.lastname: Naguib
authors.affiliation: Department of Veterinary Sciences, Michale E. Keeling Center for Comparative Medicine and Research, University of Texas M.D. Anderson Cancer Center, Bastrop, Texas, 78602, USA.
authors.forename: Rick A
authors.initials: RA
authors.lastname: Finch
authors.affiliation: Department of Veterinary Sciences, Michale E. Keeling Center for Comparative Medicine and Research, University of Texas M.D. Anderson Cancer Center, Bastrop, Texas, 78602, USA.
authors.forename: Wallace B
authors.initials: WB
authors.lastname: Baze
authors.affiliation: Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, Texas, 78712, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Jolly
authors.affiliation: Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78712, USA. Zhengrong.cui@austin.utexas.edu.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Cui
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity*; D004339:Drug Compounding; D005260:Female; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy*; D020714:Maximum Tolerated Dose; D008811:Mice, Inbred DBA; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: DHA; efficacy; gemcitabine; lethal-repeated dose; leukemia; repeat dose-maximum tolerated dose