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18 F-FDG and 18 F-FLT Uptake Early After Cyclophosphamide and mTOR Inhibition in an Experimental Lymphoma Model

2009; Society of Nuclear Medicine and Molecular Imaging; Volume: 50; Issue: 7 Linguagem: Inglês

10.2967/jnumed.109.062208

1535-5667

Lieselot Brepoels, Sigrid Stroobants, Gregor Verhoef, Tjibbe de Groot, Luc Mortelmans, Christiane De Wolf‐Peeters,

PI3K/AKT/mTOR signaling in cancer

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. Conclusion: 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.