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Pharm Res. 2017 Jun;34(6):1224-1232. doi: 10.1007/s11095-017-2139-x. Epub 2017 Mar 28.

Preclinical Evaluation of the Short-Term Toxicity of 4-(N)-Docosahexaenoyl 2´, 2´- Difluorodeoxycytidine (DHA-dFdC).

Author information

1
Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78712, USA.
2
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.
3
Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, Texas, 78712, USA.
4
Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78712, USA. Zhengrong.cui@austin.utexas.edu.

Abstract

PURPOSE:

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).

METHOD:

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.

RESULTS:

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.

CONCLUSION:

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.

KEYWORDS:

DHA; efficacy; gemcitabine; lethal-repeated dose; leukemia; repeat dose-maximum tolerated dose

PMID:
28352993
PMCID:
PMC5488709
DOI:
10.1007/s11095-017-2139-x
[Indexed for MEDLINE]
Free PMC Article

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