In vivo biological activity of the histone deacetylase inhibitor LA0824 is detectable with 3′-deoxy-3′-[18F]fluorothymidine positron emission tomography
In vivo biological activity of the histone deacetylase inhibitor LA0824 is detectable with 3′-deoxy-3′-[18F]fluorothymidine positron emission tomography
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DOI：
10.1158/0008-5472.can-05-3962
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发表时间：
2006-08-01
期刊：
影响因子：
11.2
通讯作者：
Aboagye, Eric O.
中科院分区：
文献类型：
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作者：
Leyton, Julius;Alao, John P.;Aboagye, Eric O.
组蛋白去乙酰化酶抑制剂（HDACI）作为调节基因表达和抑制肿瘤细胞增殖的生长抑制化合物而出现。我们评估了3 '-脱氧-3'-[F-18]氟胸苷-正电子发射断层扫描（[F-18]FLT-PET）是否可以用于在体内非侵入性地测量新型HDACI LAQ 824的生物活性。我们最初发现，胸苷激酶1（TK 1; EC2.7.1.21），负责[F-18]FLT在细胞中的保留的酶，在体外以药物浓度依赖性方式受到LAQ 824的调节。在携带HCT 116结肠癌异种移植物的小鼠中，LAQ 824以剂量依赖性方式显著降低肿瘤[F-18]FLT摄取。在治疗的第4天，在媒介物以及5和25 mg/kg LAQ 824治疗组中，60分钟时的[F-18]FLT肿瘤与心脏比率（NUV 60）分别为2.16 +/-0.15，1.86 +/-0.13和1.45 +/-0.20（P 25 mg/kg LAQ 824，为在这种情况下使用[F-18]FLT-PET提供了依据。我们还观察到Rb低磷酸化和p21水平的增加，这些因素可能导致体内TK 1转录的改变。总之，我们已经证明了[F-18]FLT-PET用于监测HDACI LAQ 824的生物活性的实用性。药物诱导的肿瘤[F-18]FLT吸收变化至少部分归因于TK 1转录和翻译的减少。
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'-[F-18]fluorothymidine-positron emission tomography ([F-18]FLT-PET) could he 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 [F-18]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 [F-18]FLT uptake in a dose-dependent manner. At day 4 of treatment, [F-18]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 25 mg/kg LAQ824, providing a rationale for the use of [F-18]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 [F-18]FLT-PET for monitoring the biological activity of the HDACI, LAQ824. Drug-induced changes in tumor [F-18]FLT uptake were due, at least in part, to reductions in TK1 transcription and translation.