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.
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]fluorodeoxyglucose-PET (NUV60 versus LIPCNA: 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]fluorodeoxyglucose 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.
Leyton
Julius
J
Molecular Therapy Group, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom. j.leyton@ic.ac.uk
Latigo
John R
JR
Perumal
Meg
M
Dhaliwal
Harmandeep
H
He
Qimin
Q
Aboagye
Eric O
EO
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D015224:Dideoxynucleosides / Q000493:pharmacokinetics; D005354:Fibrosarcoma / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D005462:Fluorine Radioisotopes; D006593:Hexokinase / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009381:Neoplasms, Radiation-Induced / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000201:enzymology; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013937:Thymidine Kinase / Q000378:metabolism
D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D000255:Adenosine Triphosphate; D006593:Hexokinase; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C002854:alovudine; D002945:Cisplatin