title: In vivo biological activity of the histone deacetylase inhibitor LAQ824 is detectable with 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography.
abstract: 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 ([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 < or = 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 < or = 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.
authors.affiliation: Molecular Therapy and Cancer Cell Biology, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: Julius
authors.initials: J
authors.lastname: Leyton
authors.forename: John P
authors.initials: JP
authors.lastname: Alao
authors.forename: Marco
authors.initials: M
authors.lastname: Da Costa
authors.forename: Alexandra V
authors.initials: AV
authors.lastname: Stavropoulou
authors.forename: John R
authors.initials: JR
authors.lastname: Latigo
authors.forename: Meg
authors.initials: M
authors.lastname: Perumal
authors.forename: Radhakrishna
authors.initials: R
authors.lastname: Pillai
authors.forename: Qimin
authors.initials: Q
authors.lastname: He
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: David M
authors.initials: DM
authors.lastname: Vigushin
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D015224:Dideoxynucleosides / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D049268:Positron-Emission Tomography; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011897:Random Allocation; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D015224:Dideoxynucleosides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C477361:LAQ824; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C002854:alovudine