3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography.
3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) has been proposed as a new marker for imaging tumor proliferation by positron emission tomography (PET). The uptake of [(18)F]FLT is regulated by cytosolic S-phase-specific thymidine kinase 1 (TK1). In this article, we have investigated the use of [(18)F]FLT to monitor the response of tumors to antiproliferative treatment in vivo. C3H/Hej mice bearing the radiation-induced fibrosarcoma 1 tumor were treated with 5-fluorouracil (5-FU; 165 mg/kg i.p.). Changes in tumor volume and biodistribution of [(18)F]FLT and 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) were measured in three groups of mice (n = 8-12/group): (a) untreated controls; (b) 24 h after 5-FU; and (c) 48 h after 5-FU. In addition, dynamic [(18)F]FLT-PET imaging was performed on a small animal scanner for 60 min. The metabolism of [(18)F]FLT in tumor, plasma, liver, and urine was determined chromatographically. Proliferation was determined by staining histological sections for proliferating cell nuclear antigen (PCNA). Tumor levels of TK1 protein and cofactor (ATP) were determined by Western blotting and bioluminescence, respectively. Tumor [(18)F]FLT uptake decreased after 5-FU treatment (47.8 +/- 7.0 and 27.1 +/- 3.7% for groups b and c, respectively, compared with group a; P < 0.001). The drug-induced reduction in tumor [(18)F]FLT uptake was significantly more pronounced than that of [(18)F]FDG. The PET image data confirmed lower tumor [(18)F]FLT retention in group c compared with group a, despite a trend toward higher radiotracer delivery for group c. Other than phosphorylation in tumors, [(18)F]FLT was found to be metabolically stable in vivo. The decrease in tumor [(18)F]FLT uptake correlated with the PCNA-labeling index (r = 0.71, P = 0.031) and tumor volume changes after 5-FU treatment (r = 0.58, P = 0.001). In this model system, the decrease in [(18)F]FLT uptake could be explained by changes in catalytic activity but not translation of TK1 protein. Compared with group a, TK1 levels were lower in group b (78.2 +/- 5.2%) but higher in group c (141.3 +/- 9.1%, P < 0.001). In contrast, a stepwise decrease in ATP levels was observed from group a to b to c (P < 0.001). In conclusion, we have demonstrated the ability to measure tumor response to antiproliferative treatment with [(18)F]FLT and PET. In our model system, the radiotracer uptake was correlated with PCNA-labeling index. The decrease in [(18)F]FLT uptake after 5-FU was more pronounced than that of [(18)F]FDG. [(18)F]FLT is, therefore, a promising marker for monitoring antiproliferative drug activity in oncology that warrants additional testing.
Barthel
Henryk
H
Cancer Research United Kingdom PET Oncology Group, Department of Cancer Medicine, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital Campus, London W12 0NN, United Kingdom.
Cleij
Marcel C
MC
Collingridge
David R
DR
Hutchinson
O Clyde
OC
Osman
Safiye
S
He
Qimin
Q
Luthra
Sajinder K
SK
Brady
Frank
F
Price
Pat M
PM
Aboagye
Eric O
EO
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D016903:Drug Monitoring / Q000379:methods; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014183:Transplantation, Heterologous
D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D000255:Adenosine Triphosphate; C002854:alovudine; D005472:Fluorouracil