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An Evaluation of the Toxicities of 2' -Fluorouridine and 2'-Fluorocytidine-HCI in F344 Rats and Woodchucks (Marmota monax)
Frank C. Richardson
NeXstar Pharmaceuticals, Inc., Boulder, Colorado 80301
Bud C. Tennant
Marmotech, Inc., Ithaca, New York 14850
Denny J. Meyer
NeXstar Pharmaceuticals, Inc., Boulder, Colorado 80301
Katherine A. Richardson
Molecular Biology Experimental Design, Louisville, Colorado 80027
Peter C. Mann
Experimental Pathology Laboratories, Research Triangle Park, North Carolina 27709
Gregory R. Mcginty
NeXstar Pharmaceuticals, Inc., Boulder, Colorado 80301
Julie L. Wolf
NeXstar Pharmaceuticals, Inc., Boulder, Colorado 80301
Philip M. Zack
NeXstar Pharmaceuticals, Inc., Boulder, Colorado 80301
Raymond A. Bendele
NeXstar Pharmaceuticals, Inc., Boulder, Colorado 80301
The toxicities of 2'-fluorouridine (2'-FU) and 2'-fluorocytidine-HCl (2'-FC) were separately evaluated in 2 species, male Fischer 344 (F334) rats and woodchucks. Particular attention was focused on the ability of these nucleosides to induce toxicities similar to those induced by the antiviral drug fialuridine (FIAU). 2'-FU or 2'-FC was administered to F344 male rats by intravenous injection at doses of 5, 50, and 500 mg/kg/day for 90 consecutive days and to male and female woodchucks at doses of 0.75 and 7.5 mg/kg/ day for 90 consecutive days. Clinical chemistry, hematology, and urinalysis (woodchuck only) profiles were assessed during and at the termination of the study. At necropsy, organs were weighed and tissues collected for routine histologic analysis. Cytochrome c oxidase activity, citrate synthase activity, and mitochondrial DNA content were measured, and micronucleus formation in the bone marrow (rats only) was evaluated. No adverse clinical effects were observed in either species. Rats treated with high doses of either 2'-FU or 2'-FC had body weights that were 90% of those of controls. 2'-FU and 2'-FC both induced a moderate decrease in the median lymphocyte count, and 2'-FC and 2'-FU induced a mild increase in mean corpuscular hemoglobin and mean corpuscular volume. Both compounds caused slight to moderate, reversible, histologic changes in the spleen and thymus. In the woodchuck, 2'-FC caused a slight increase in mean absolute lymphocytes, and 2'-FC and 2'-FU slightly increased hepatic periportal vacuolation and/ or mononuclear cell infiltration. In summary, neither compound showed evidence of the toxicity induced by fialuridine in either species. Although compound effects were observed, none of these effects were considered to be adverse, and the no-observed adverse effect level was determined to be 500 mg/kg/day for both compounds in the male F344 rat and 7.5 mg/kg/day in the woodchuck.
Key Words: Nucleoside analogs • aptamer • mtDNA • cytochrome c oxidase • intravenous
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Toxicologic Pathology, Vol. 27, No. 6,
607-617 (1999)
DOI: 10.1177/019262339902700601
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