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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.

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.
AuthorsJulius Leyton, John P Alao, Marco Da Costa, Alexandra V Stavropoulou, John R Latigo, Meg Perumal, Radhakrishna Pillai, Qimin He, Peter Atadja, Eric W-F Lam, Paul Workman, David M Vigushin, Eric O Aboagye
JournalCancer research (Cancer Res) Vol. 66 Issue 15 Pg. 7621-9 (Aug 01 2006) ISSN: 0008-5472 [Print] United States
PMID16885362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Dideoxynucleosides
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • LAQ824
  • RNA, Messenger
  • Radiopharmaceuticals
  • Thymidine Kinase
  • thymidine kinase 1
  • alovudine
Topics
  • Animals
  • Cell Cycle (drug effects)
  • Cell Growth Processes (drug effects)
  • Colonic Neoplasms (diagnostic imaging, drug therapy, enzymology, metabolism)
  • Dideoxynucleosides (pharmacokinetics)
  • Drug Interactions
  • Female
  • HCT116 Cells
  • Histone Deacetylase Inhibitors
  • Humans
  • Hydroxamic Acids (pharmacology)
  • Mice
  • Mice, Inbred BALB C
  • Positron-Emission Tomography
  • RNA, Messenger (biosynthesis, genetics)
  • Radiopharmaceuticals (pharmacokinetics)
  • Random Allocation
  • Thymidine Kinase (biosynthesis, genetics, metabolism)
  • Xenograft Model Antitumor Assays

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