Radiolabeled 2'-fluorodeoxyuracil-beta-D-arabinofuranoside (FAU) and 2'-fluoro-5-methyldeoxyuracil-beta -D-arabinofuranoside (FMAU) as tumor-imaging agents in mice.
OBJECTIVE
The purpose of the present study was to evaluate, in conjunction with the National Cancer Institute, the feasibility of using two thymidine analogs, 2'-fluorodeoxyuracil-beta-D-arabinofuranoside (FAU, NSC-678515) and 2'-fluoro-5-methyldeoxyuracil-beta-D-arabinofuranoside (FMAU, NSC-678516), as 18-fluorine-labeled positron emission tomography (PET) imaging agents.


METHODS
The in vivo distribution and DNA incorporation of [2-(14)C]FAU, [2-(14)C]FMAU, and [2-(14)C]thymidine (as a control) were studied in SCID mice bearing human xenografts of T-cell leukemia CCRF-CEM. Levels of drug-associated radioactivity in blood, tumor and normal tissues including liver, kidneys, heart, lungs, spleen, brain, and skeletal muscle were determined.


RESULTS
At 1 h after dosing, radioactivity from all three compounds was distributed in a generally nonspecific manner, except that spleen and tumor tissue had relatively high concentrations of radioactivity from [(14)C]thymidine. At 4 h after dosing, the concentrations of radioactivity from [(14)C]thymidine and [(14)C]FMAU were relatively high in spleen and tumor tissue, and that from [(14)C]FAU was highest in tumor tissue. The tumor/skeletal muscle concentration ratios were 2.25+/-0.69 and 3.07+/-0.42 for [(14)C]FAU and [(14)C]FMAU, respectively. At 24 h after dosing, only spleen and tumor tissues contained appreciable amounts of radioactivity from either compound. In tumor tissue, the levels of radioactivity from [(14)C]FMAU were two- to threefold greater than those from [(14)C]thymidine or [(14)C]FAU. Examination of purified genomic DNA from tumor, liver, kidneys, brain, and skeletal muscle showed that, at 24 h after dosing, only DNA from tumor tissue contained appreciable concentrations of radioactivity. Radioactivity from [(14)C]FMAU in tumor DNA was 45% greater than that from [(14)C]thymidine and about threefold greater than that from [(14)C]FAU.


CONCLUSIONS
The extent of accumulation of [(14)C]FMAU in tumor tissue and incorporation into tumor DNA indicate that [(18)F]FMAU could be useful as a functional PET tumor-imaging agent.
Wang
Hui
H
Department of Pharmacology and Toxicology, University of Alabama, Birmingham, AL 35294, USA.
Oliver
Patsy
P
Nan
Li
L
Wang
Shuyi
S
Wang
Zhi
Z
Rhie
Julie K
JK
Zhang
Ruiwen
R
Hill
Donald L
DL
D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004273:DNA, Neoplasm / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000000981:diagnostic imaging*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013154:Spleen / Q000000981:diagnostic imaging; D013936:Thymidine / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014183:Transplantation, Heterologous
C457880:2'-fluorodeoxyuracil-arabinofuranoside; D004273:DNA, Neoplasm; D019275:Radiopharmaceuticals; D001086:Arabinofuranosyluracil; C034935:clevudine; D013936:Thymidine