3'-[18F]fluoro-3'-deoxythymidine ([18F]-FLT) as positron emission tomography tracer for imaging proliferation in a murine B-Cell lymphoma model and in the human disease.
Here we describe the evaluation of 3'-[(18)F]fluoro-3'-deoxythymidine [[(18)F]-FLT] as a tracer for positron emission tomography (PET) in a murine model of B-cell lymphoma and in human malignant lymphoma. The human B-cell line DoHH2 expressed high levels of active thymidine kinase 1 (TK-1) as the key enzyme of [(18)F]-FLT metabolism. Immunostaining confirmed high levels of TK-1 in DoHH2 derived xenograft tumors in SCID/SCID mice. In vitro studies demonstrated a time-dependent uptake of [(18)F]-FLT, an efficient phosphorylation to the respective monophosphate and the incorporation of [(18)F]-FLT into the perchloric acid insoluble fraction in DoHH2 cells, indicating the incorporation of this tracer into the DNA. After incubation with [(18)F]FLT for 240 min, 12.5% +/- 1.0% of radioactivity applied to the medium was intracellularly trapped in DoHH2 cells. Specific accumulation of [(18)F]-FLT in the malignant cell clone was confirmed in biodistribution studies in SCID/SCID mice bearing DoHH2-derived tumors. The percentage of injected dose of [(18)F]-FLT per gram of tumor tissue correlated with the tumor-proliferation index as evaluated in BrdUrd-labeling experiments. In a pilot study of 11 patients with both indolent and aggressive lymphoma, [(18)F]-FLT was suitable and comparable to [(18)F]-FDG in the ability to detect malignant lesions by PET scan. Furthermore, we found a close correlation (r = 0.95, P < 0.005) of the [(18)F]-FLT standardized uptake values with the Ki67-labeling index of tissue biopsies (n = 10) in these patients. These results suggest that [(18)F]-FLT represents a novel tracer for PET that enables imaging of proliferation in human lymphoma in vivo.
Department of Nuclear Medicine, University of Ulm, 89081 Ulm, Germany.
Martin
M
Wagner
Ulrike
U
Seitz
Andreas
A
Buck
Bernd
B
Neumaier
Stefan
S
Schultheiss
Markus
M
Bangerter
Martin
M
Bommer
Frank
F
Leithäuser
Edgar
E
Wawra
Gerd
G
Munzert
Sven N
SN
Reske
D000818:Animals; D002455:Cell Division / Q000502:physiology; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005462:Fluorine Radioisotopes; D006801:Humans; D016393:Lymphoma, B-Cell / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010865:Pilot Projects; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013937:Thymidine Kinase / Q000378:metabolism; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C002854:alovudine