In vivoBiological 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 ([ 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)

Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity

“…Based on these findings, we examined the effect of CCT129202 on the pathway downstream of p21, in particular the Rb/E2F pathway, to identify potential end points. (31). Taken together, these observations support the in vivo use of [ 18 F]FLT imaging for detecting the biological effects of CCT129202.…”

“…PET Imaging [ 18 F]FLT was synthesized and characterized as previously reported (31). Before imaging studies, size-matched tumor-bearing mice were randomized into four cohorts (day 2 vehicle and CCT129202-treated groups, and day 7 vehicle and CCT129202-treated groups) and given daily doses of CCT129202 at 100 mg/kg body weight or vehicle i.p.…”

“…The last drug dose was injected 2 h before imaging. The scanning procedure and the image analysis have been described previously (31). Tumor radioactivity uptake normalized that of heart at 60 min post-injection (NUV 60 ) was used for comparison.…”

“…It is, therefore, desirable to develop and validate noninvasive imaging methods that measure the biochemical effect of Aurora kinase inhibition. Imaging biomarker assays such as [ (31).…”

Targeting Somatostatin Receptors: Preclinical Evaluation of Novel 18F-Fluoroethyltriazole-Tyr3-Octreotate Analogs for PET

“…Dynamic PET scans were performed on a dedicated smallanimal PET scanner (Inveon PET module; Siemens Molecular Imaging Inc.) as reported previously (29,30). Briefly, tail veins were cannulated under general anesthesia (isoflurane).…”