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We have assessed the potential of [18 F]fluorothymidine positron emission tomography ([ 18 F]FLT-PET) to measure early cytostasis and cytotoxicity induced by cisplatin treatment of radiation-induced fibrosarcoma 1 (RIF-1) tumorbearing mice. Cisplatin-mediated arrest of tumor cell growth and induction of tumor shrinkage at 24 and 48 hours, respectively, were detectable by [18 F]FLT-PET. At 24 and 48 hours, the normalized uptake at 60 minutes (tumor/liver radioactivity ratio at 60 minutes after radiotracer injection; NUV 60 ) for [18 F]FLT was 0.76 F 0.08 (P = 0.03) and 0.51 F 0.08 (P = 0.03), respectively, compared with controls (1.02 F 0.12). The decrease in [18 F]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 F 2.0% to 6.2 F 1.0%; P = 0.001), despite the lack of a change in tumor size. There were G 1 -S and G 2 -M phase arrests after cisplatin treatment, as determined by cell cycle analysis. For the quantitative measurement of tumor cell proliferation, [18 F]FLT-PET was found to be superior to [18 F]fluorodeoxglucose-PET (NUV 60 versus LI PCNA : r = 0.89, P = 0.001 and r = 0.55, P = 0.06, respectively

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This study shows that in vivo [18F]FLT kinetics depend on TK1 protein expression. ATP may be important in realising this effect. Thus, [18F]FLT-PET has the potential to yield specific information on tumour proliferation in diagnostic imaging and therapy monitoring.

Histone deacetylase inhibitors (HDACI) are emerging as growth inhibitory compounds that modulate gene expression and inhibit tumor cell proliferation. We assessed whether 3 ¶-deoxy-3 ¶-[18 F]fluorothymidine-positron emission tomography ([ 18 F]FLT-PET) could be used to noninvasively measure the biological activity of a novel HDACI LAQ824 in vivo. We initially showed that thymidine kinase 1 (TK1; EC2.7.1.21), the enzyme responsible for [18 F]FLT retention in cells, was regulated by LAQ824 in a drug concentration-dependent manner in vitro. In HCT116 colon carcinoma xenograftbearing mice, LAQ824 significantly decreased tumor [18 F]FLT uptake in a dose-dependent manner. At day 4 of treatment, [ 18 F]FLT tumor-to-heart ratios at 60 minutes (NUV60) were 2.16 F 0.15, 1.86 F 0.13, and 1.45 F 0.20 in vehicle, and 5 and 25 mg/kg LAQ824 treatment groups, respectively (P V 0.05). LAQ825 at 5 mg/kg also significantly reduced both TK1 levels and [18 F]FLT uptake at day 10 but not at day 2 (P V 0.05). [ 18 F]FLT NUV60 correlated significantly with cellular proliferation (r = 0.68; P = 0.0019) and was associated with druginduced histone H4 hyperacetylation. Of interest to [18 F]FLT-PET imaging, both TK1 mRNA copy numbers and protein levels decreased in the order vehicle >5 mg/kg LAQ824 > 25 mg/kg LAQ824, providing a rationale for the use of [ 18 F]FLT-PET in this setting. We also observed increases in Rb hypophosphorylation and p21 levels, factors that could have contributed to the alteration in TK1 transcription in vivo. In conclusion, we have shown the utility of [18 F]FLT-PET for monitoring the biological activity of the HDACI, LAQ824. Drug-induced changes in tumor [18 F]FLT uptake were due, at least in part, to reductions in TK1 transcription and translation. (Cancer Res 2006; 66(15): 7621-9)

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