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Early Detection of Tumor Response to Chemotherapy by 3'-Deoxy-3'-[¹⁸F]Fluorothymidine Positron Emission Tomography: The Effect of Cisplatin on a Fibrosarcoma Tumor Model In vivo

¹ Molecular Therapy Group, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom and ² Department of Oncology, Clinical Research Laboratory, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden

Requests for reprints: Julius Leyton, Molecular Therapy and PET Oncology Group, Imperial College London, Hammersmith Hospital, Room 240, MRC Cyclotron Building, Du Cane Road, London W12 ONN, United Kingdom. Phone: 0208-383-3798; E-mail: j.leyton{at}ic.ac.uk.

We have assessed the potential of [¹⁸F]fluorothymidine positron emission tomography ([¹⁸F]FLT-PET) to measure early cytostasis and cytotoxicity induced by cisplatin treatment of radiation-induced fibrosarcoma 1 (RIF-1) tumor–bearing mice. Cisplatin-mediated arrest of tumor cell growth and induction of tumor shrinkage at 24 and 48 hours, respectively, were detectable by [¹⁸F]FLT-PET. At 24 and 48 hours, the normalized uptake at 60 minutes (tumor/liver radioactivity ratio at 60 minutes after radiotracer injection; NUV₆₀) for [¹⁸F]FLT was 0.76 ± 0.08 (P = 0.03) and 0.51 ± 0.08 (P = 0.03), respectively, compared with controls (1.02 ± 0.12). The decrease in [¹⁸F]FLT uptake at 24 hours was associated with a decrease in cell proliferation assessed immunohistochemically (a decrease in proliferating cell nuclear antigen labeling index, LI_PCNA, from 14.0 ± 2.0% to 6.2 ± 1.0%; P = 0.001), despite the lack of a change in tumor size. There were G₁-S and G₂-M phase arrests after cisplatin treatment, as determined by cell cycle analysis. For the quantitative measurement of tumor cell proliferation, [¹⁸F]FLT-PET was found to be superior to [¹⁸F]fluorodeoxglucose-PET (NUV₆₀ versus LI_PCNA: r = 0.89, P = 0.001 and r = 0.55, P = 0.06, respectively). At the biochemical level, we found that the changes in [¹⁸F]FLT and [¹⁸F]fluorodeoxglucose uptake were due to changes in levels of thymidine kinase 1 protein, hexokinase, and ATP. This work supports the further development of [¹⁸F]FLT-PET as a generic pharmacodynamic readout for early quantitative imaging of drug-induced changes in cell proliferation in vivo.

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