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In vivo Biological Activity of the Histone Deacetylase Inhibitor LAQ824 Is detectable with 3'-Deoxy-3'-[¹⁸F]Fluorothymidine Positron Emission Tomography

¹ Molecular Therapy and ² Cancer Cell Biology, Imperial College London, Faculty of Medicine, Hammersmith Hospital, London, United Kingdom; ³ Department of Oncology, Clinical Research Laboratory, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden; ⁴ Novartis Institutes for Biomedical Research, Cambridge, Massachusetts; and ⁵ Cancer Research United Kingdom Center for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, United Kingdom

Requests for reprints: Eric Aboagye, Molecular Therapy and PET Oncology Research Group, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Room 240, MRC Cyclotron Building, Du Cane Road, London W12 ONN, United Kingdom. Phone: 44-20-8383-33759; E-mail: e.aboagye{at}ic.ac.uk.

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'-[¹⁸F]fluorothymidine–positron emission tomography ([¹⁸F]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 [¹⁸F]FLT retention in cells, was regulated by LAQ824 in a drug concentration–dependent manner in vitro. In HCT116 colon carcinoma xenograft–bearing mice, LAQ824 significantly decreased tumor [¹⁸F]FLT uptake in a dose-dependent manner. At day 4 of treatment, [¹⁸F]FLT tumor-to-heart ratios at 60 minutes (NUV60) were 2.16 ± 0.15, 1.86 ± 0.13, and 1.45 ± 0.20 in vehicle, and 5 and 25 mg/kg LAQ824 treatment groups, respectively (P 0.05). LAQ825 at 5 mg/kg also significantly reduced both TK1 levels and [¹⁸F]FLT uptake at day 10 but not at day 2 (P 0.05). [¹⁸F]FLT NUV60 correlated significantly with cellular proliferation (r = 0.68; P = 0.0019) and was associated with drug-induced histone H4 hyperacetylation. Of interest to [¹⁸F]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 [¹⁸F]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 [¹⁸F]FLT-PET for monitoring the biological activity of the HDACI, LAQ824. Drug-induced changes in tumor [¹⁸F]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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