Distribution of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil in mice bearing colorectal cancer xenografts: rationale for therapeutic use and as a positron emission tomography probe for thymidylate synthase.
Distribution of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil in mice bearing colorectal cancer xenografts: rationale for therapeutic use and as a positron emission tomography probe for thymidylate synthase.
复制标题
1-(2-脱氧-2-氟-β-D-阿拉伯呋喃糖基)尿嘧啶在结直肠癌异种移植小鼠中的分布：治疗用途和作为胸苷酸合成酶的正电子发射断层扫描探针的基本原理。
作者：
J. Eiseman;C. Brown;Paul Kinahan;J. Collins;L. Anderson;E. Joseph;Deborah R. Hamburger;S. Pan;C. Mathis;M. Egorin;R. Klecker
PURPOSE
In colorectal, breast, and head and neck cancers, response to 5-fluorouracil is associated with low expression of thymidylate synthase. In contrast, tumors with high expression of thymidylate synthase may be more sensitive to prodrugs such as 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil (FAU) that are activated by thymidylate synthase. These studies were designed to evaluate FAU as a potential therapeutic and diagnostic probe.
EXPERIMENTAL DESIGN
[18F]-FAU and [3H]-FAU were synthesized with >97% radiochemical purity. [3H]-FAU or [18F]-FAU was administered intravenously to severe combined immunodeficient mice bearing either HT29 (low thymidylate synthase) or LS174T (high thymidylate synthase) human colon cancer xenografts. Four hours after [3H]-FAU dosing, tissue distribution of total radioactivity and incorporation of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) 5-methyluracil (FMAU), derived from thymidylate synthase activation of FAU, into tumor DNA was measured. Positron emission tomography (PET) images were obtained for 90 minutes after injection of [18F]-FAU. Thymidylate synthase activity was determined in vitro in tumors from untreated mice by [3H] release from [3H]dUMP. Each cell line was incubated in vitro with [3H]-FAU or [3H]-FMAU in the absence or presence of 5-fluoro-2'-deoxyuridine (FdUrd) and then was analyzed for incorporation of radiolabel into DNA.
RESULTS
Thymidylate synthase enzymatic activity in LS174T xenografts was approximately 3.5-fold higher than in HT29 xenografts, and incorporation of radioactivity derived from [3H]-FAU into LS174T DNA was approximately 2-fold higher than into HT29 DNA. At 240 minutes, radioactivity derived from [3H]-FAU was approximately 2-fold higher in tumors than in skeletal muscle. At times up to 90 minutes, PET imaging detected only small differences in uptake of [18F]-FAU between the tumor types. Fluorine-18 in skeletal muscle was higher than in tumor for the first 90 minutes and plateaued earlier, whereas [18F] in tumor continued to increase during the 90-minute imaging period. For both cell lines in vitro, FdUrd decreased the rate of incorporation of [3H]-FAU into DNA, whereas the incorporation of [3H]-FMAU was increased.
CONCLUSIONS
These results for FAU incorporation into DNA in vitro and in vivo further support clinical evaluation of FAU as a therapeutic agent in tumors with high concentrations of thymidylate synthase that are less likely to respond to 5-fluorouracil treatment. The high circulating concentrations of thymidine reported in mice may limit their utility in evaluating FAU as a PET probe.
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影响因子：
4
作者：
Caldeira L;Yun SD;da Silva N;Filss C;Scheins J;Telmann L;Herzog H;Shah J
通讯作者：
Shah J
通过改进的氚释放测定改进了胸苷酸合成酶活性的测量。
影响因子：
--
作者：
Armstrong,RD;Diasio,RB
通讯作者：
Diasio,RB
2-[11C]胸苷正电子发射断层扫描作为接受 AG337 治疗的患者胸苷酸合成酶抑制的指标。
DOI：
10.1093/jnci/95.9.675
发表时间：
2003
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Wells,Paula;Aboagye,Eric;Gunn,RogerN;Osman,Safiye;Boddy,AlanV;Taylor,GordonA;Rafi,Imran;Hughes,AndrewN;Calvert,AHilary;Price,PatM;Newell,DavidR
通讯作者：
Newell,DavidR
影响因子：
45.3
作者：
Allegra, CJ;Paik, S;Wieand, HS
通讯作者：
Wieand, HS