Increase of [(18)F]FLT tumor uptake in vivo mediated by FdUrd: toward improving cell proliferation positron emission tomography.
OBJECTIVE
3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT), a cell proliferation positron emission tomography (PET) tracer, has been shown in numerous tumors to be more specific than 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) but less sensitive. We studied the capacity of a nontoxic concentration of 5-fluoro-2'-deoxyuridine (FdUrd), a thymidine synthesis inhibitor, to increase uptake of [(18)F]FLT in tumor xenografts.


METHODS
The duration of the FdUrd effect in vivo on tumor cell cycling and thymidine analogue uptake was studied by varying FdUrd pretreatment timing and holding constant the timing of subsequent flow cytometry and 5-[(125)I]iodo-2'-deoxyuridine biodistribution measurements. In [(18)F]FLT studies, FdUrd pretreatment was generally performed 1 h before radiotracer injection. [(18)F]FLT biodistributions were measured 1 to 3 h after radiotracer injection of mice grafted with five different human tumors and pretreated or not with FdUrd and compared with [(18)F]FDG tumor uptake. Using microPET, the dynamic distribution of [(18)F]FLT was followed for 1.5 h in FdUrd pretreated mice. High-field T2-weighted magnetic resonance imaging (MRI) and histology were used comparatively in assessing tumor viability and proliferation.


RESULTS
FdUrd induced an immediate increase in tumor uptake of 5-[(125)I]iodo-2'-deoxyuridine, that vanished after 6 h, as also confirmed by flow cytometry. Biodistribution measurements showed that FdUrd pretreatment increased [(18)F]FLT uptake in all tumors by factors of 3.2 to 7.8 compared with controls, while [(18)F]FDG tumor uptake was about fourfold and sixfold lower in breast cancers and lymphoma. Dynamic PET in FdUrd pretreated mice showed that [(18)F]FLT uptake in all tumors increased steadily up to 1.5 h. MRI showed a well-vascularized homogenous lymphoma with high [(18)F]FLT uptake, while in breast cancer, a central necrosis shown by MRI was inactive in PET, consistent with the histomorphological analysis.


CONCLUSIONS
We showed a reliable and significant uptake increase of [(18)F]FLT in different tumor xenografts after low-dose FdUrd pretreatment. These results show promise for a clinical application of FdUrd aimed at increasing the sensitivity of [(18)F]FLT PET.
Viertl
David
D
Service of Nuclear Medicine, University Hospital of Lausanne, CH-1011 Lausanne, Switzerland. David.Viertl@chuv.ch
Bischof Delaloye
Angelika
A
Lanz
Bernard
B
Poitry-Yamate
Carole
C
Gruetter
Rolf
R
Mlynarik
Vladimir
V
Ametamey
Simon M
SM
Ross
Tobias L
TL
Lehr
Hans-Anton
HA
André
Pierre-Alain
PA
Perillo-Adamer
Florence
F
Kosinski
Marek
M
Dupertuis
Yves M
YM
Buchegger
Franz
F
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015224:Dideoxynucleosides / Q000493:pharmacokinetics* / Q000494:pharmacology; D005434:Flow Cytometry; D005467:Floxuridine / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D049268:Positron-Emission Tomography / Q000379:methods*; D013997:Time Factors; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D015224:Dideoxynucleosides; D005467:Floxuridine; C002854:alovudine