Quantification of 2'-Fluoro-2'-deoxyuridine and 2'-Fluoro-2'-deoxycytidine in DNA and RNA Isolated from Rats and Woodchucks Using LC/MS/MS
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- 作者：Frank C. Richardson ; Chenghong Zhang ; S. Russ Lehrman ; Hasan Koc ; James A. Swenberg ; Katherine A. Richardson ; and Raymond A. Bendele
- 刊名：Chemical Research in Toxicology
- 出版年：2002
- 出版时间：July 2002
- 年：2002
- 卷：15
- 期：7
- 页码：922 - 926
- 全文大小：44K
- 年卷期：v.15,no.7(July 2002)
- ISSN：1520-5010
文摘
Apatmers are synthesized using 2'-fluoropyrimdines in place of normal pyrmidines to stabilizethem against enzymatic degradation, and thereby improve their therapeutic efficacy. Despitethis stabilizing effect, the apatmers can still be degraded by nucleases in the blood. Primertemplate extension studies have demonstrated that mammalian DNA polymerases canincorporate these 2'-fluoropyrimidines into growing strands of DNA. The toxicologic effects ofthese compounds have been examined in rats and woodchucks, animals known to be susceptibleto the toxic effects of other modified pyrimidines. Whether these nucleosides can be incorporatedinto DNA in vivo has not been established. These studies report the development ofmethodologies and the results of studies designed to determine if and to what extent2'-fluoropyrimidines are incorporated into tissue DNA following long-term treatment. Ratswere dosed intravenously with either 2'-fluorouridine (2'-FU) or 2'-fluorocytidine (2'-FC) atdoses of 5, 50, and 500 mg/kg/day for 90 days. Woodchucks were dosed intravenously witheither 2'-FU or 2'-FC at doses of 0.75 or 7.5 mg/kg/day for 90 days. The amounts of 2'-FU or2'-FC in DNA and RNA were quantified using newly developed LC/MS/MS methodologies.Administration of 2'-FU to rats and woodchucks resulted in incorporation of the compoundinto DNA from liver, spleen, testis, muscle, and kidney. Incorporation also occurred in RNAfrom rat liver (only tissue examined). Similarly, administration of 2'-FC to rats and woodchucksresulted in incorporation into liver DNA (only tissue examined). These data demonstrate that2'-fluoropyrimidines are incorporated into DNA and RNA of various tissues of rats andwoodchucks following long-term administration.