(18)F-FDG and (18)F-FLT uptake early after cyclophosphamide and mTOR inhibition in an experimental lymphoma model.
To be a reliable predictor of response, tracer uptake should reflect changes in the amount of active tumor cells. However, uptake of (18)F-FDG, the most commonly used PET tracer, is disturbed by the inflammatory cells that appear early after cytotoxic therapy. The first aim of this study was to investigate whether 3'-(18)F-fluoro-3'-deoxy-l-thymidine ((18)F-FLT), a marker of cellular proliferation, is a better tracer for response assessment early after cytotoxic therapy. A second objective of this study was to investigate whether (18)F-FDG and (18)F-FLT responses were comparable early after mammalian target of rapamycin (mTOR) inhibition, as an example of proliferation-targeting therapies.


METHODS
Severe combined immunodeficient mice were subcutaneously inoculated with Granta-519 cells, a human cell line derived from a leukemic mantle cell lymphoma. Half the mice were treated with cyclophosphamide and the other half with mTOR inhibition. (18)F-FDG and (18)F-FLT uptake was evaluated by small-animal PET on day 0 (D0; before treatment), D+1, D+2, D+4, D+7, D+9, D+11, and D+14. At each time point, 2 mice of each treatment condition were sacrificed, and tumors were excised for histopathology.


RESULTS
After cyclophosphamide, (18)F-FDG and (18)F-FLT uptake decreased, with a maximum reduction of -29% for (18)F-FDG and -25% for (18)F-FLT uptake at D+2, compared with baseline. Although (18)F-FDG uptake increased from D+4 on, with a maximum on D+7, (18)F-FLT uptake remained virtually stable. Histology showed an increase in apoptotic or necrotic tumor fraction, followed by an influx of inflammatory cells. In mTOR-inhibited mice, (18)F-FDG uptake dropped until D+2 after therapy (-43%) but increased at D+4 (-27%) to form a plateau on D+7 and D+9 (-14% and -16%, respectively). Concurrently, (18)F-FLT uptake decreased to -31% on D+2, followed by an increase with a peak value of +12% on D+7, after which (18)F-FLT uptake decreased again. Cyclin D1 expression dropped from D+1 until D+4 and returned to baseline at D+7.


CONCLUSIONS
Because (18)F-FLT uptake is not significantly influenced by the temporary rise in inflammatory cells early after cyclophosphamide, it more accurately reflects tumor response. However, a formerly unknown temporary rise in (18)F-FLT uptake a few days after the administration of mTOR inhibition was defined, which makes it clear that drug-specific responses have to be considered when using PET for early treatment monitoring.
Brepoels
Lieselot
L
Department of Nuclear Medicine, University Hospital Gasthuisberg Leuven, Leuven, Belgium. lieselot.brepoels@uz.kuleuven.be
Stroobants
Sigrid
S
Verhoef
Gregor
G
De Groot
Tjibbe
T
Mortelmans
Luc
L
De Wolf-Peeters
Christiane
C
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage*; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006801:Humans; D008223:Lymphoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011494:Protein Kinases / Q000187:drug effects; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases; D014018:Tissue Distribution; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D015224:Dideoxynucleosides; D047428:Protein Kinase Inhibitors; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C401859:temsirolimus; D003520:Cyclophosphamide; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C002854:alovudine; D020123:Sirolimus