UNLABELLED: 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.
UNLABELLED: 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 immunodeficientmice 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.
Authors: Jennifer G Whisenant; Todd E Peterson; Jacob U Fluckiger; Mohammed Noor Tantawy; Gregory D Ayers; Thomas E Yankeelov Journal: Mol Imaging Biol Date: 2013-02 Impact factor: 3.488
Authors: Aung Naing; Razelle Kurzrock; Angelika Burger; Sachin Gupta; Xiudong Lei; Naifa Busaidy; David Hong; Helen X Chen; Lawrence A Doyle; Lance K Heilbrun; Eric Rohren; Chaan Ng; Chandtip Chandhasin; Patricia LoRusso Journal: Clin Cancer Res Date: 2011-07-12 Impact factor: 12.531
Authors: Nicolas Graf; Ken Herrmann; Barbara Numberger; Daniela Zwisler; Michaela Aichler; Annette Feuchtinger; Tibor Schuster; Hans-Jürgen Wester; Reingard Senekowitsch-Schmidtke; Christian Peschel; Markus Schwaiger; Ulrich Keller; Tobias Dechow; Andreas K Buck Journal: Eur J Nucl Med Mol Imaging Date: 2012-10-05 Impact factor: 9.236
Authors: Marijke De Saint-Hubert; Lieselot Brepoels; Ellen Devos; Peter Vermaelen; Tjibe De Groot; Thomas Tousseyn; Luc Mortelmans; Felix M Mottaghy Journal: Am J Nucl Med Mol Imaging Date: 2011-12-15
Authors: Vijaya L Damaraju; Maral Aminpour; Michelle Kuzma; Philip Winter; Jordane Preto; Jack Tuszynski; Alexander B J McEwan; Michael B Sawyer Journal: Clin Transl Sci Date: 2021-05-03 Impact factor: 4.689