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.