Increased cytotoxicity and decreased in vivo toxicity of FdUMP[10] relative to 5-FU.
Increased cytotoxicity and decreased in vivo toxicity of FdUMP[10] relative to 5-FU.
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相对于 5-FU，FdUMP[10] 的细胞毒性增加，体内毒性降低。
DOI：
10.1080/07328319908044843
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Gmeiner,WH
中科院分区：
文献类型：
--
作者：
Liu,J;Skradis,A;Kolar,C;Kolath,J;Anderson,J;Lawson,T;Talmadge,J;Gmeiner,WH
The efficacy of treatment with 5-Fluorouracil (5-FU) is limited, in part, by its inefficient conversion to 5-Fluoro-2′-deoxyuridine-5-O-monophosphate (FdUMP). We present data indicating that FdUMP[10], designed as a pro-drug for intracellular release of FdUMP, is cytotoxic as a consequence of uptake of the multimeric form. FdUMP[10] is stable in cell culture medium, with more than one-half of the material persisting as multimers of at least six nucleotides after a 48 h incubation at 37°C. FdUMP[10] is more than 400 times more cytotoxic than 5-FU towards human colorectal tumor cells (H630). FdUMP[10] also has decreased toxicityin vivo, with doses as high as 200 mg/kg/day (qdx3) administered to Balb/c mice without morbidity, compared to a maximum tolerated dose of 45 mg/kg/day for 5-FU using the same protocol. FdUMP[10] shows reduced sensitivity to OPRTase-and TK-mediated drug resistance, relative to 5-FU and FdU, respectively, and is much more cytotoxic than 5-FU towards cells that overexpress thymidylate synthase. Thus, FdUMP[10] is less susceptible to resistance mechanisms that limit the clinical utility of 5-FU. The increased cytotoxicity, decreased toxicityin vivo, and reduced sensitivity to drug resistance of FdUMP[10], relative to 5-FU, indicates multimeric FdUMP is potentially valuable as an antineoplastic agent, either as a single agent, or in combination with 5-FU.
