Combining standard drugs with low doses of histone deacetylase inhibitors (HDACIs) is a promising strategy to increase the efficacy of chemotherapy. The ability of well-tolerated doses of HDACIs that act as chemosensitizers for platinum-based chemotherapeutics has recently been proven in many types and stages of cancer in vitro and in vivo. Detection of changes in HDAC activity/expression may provide important prognostic and predictive information and influence treatment decision-making. Use of [18F] FAHA, a HDAC IIa-specific radionuclide, for molecular imaging may enable longitudinal, noninvasive assessment of HDAC activity/expression in metastatic cancer. We evaluated the synergistic anticancer effects of cisplatin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in xenograft models of nonsmall cell lung cancer (NSCLC) using [18F] FAHA and [18F] FDG PET/CT imaging. Cisplatin alone significantly increased [18F] FAHA accumulation and reduced [18F] FDG accumulation in H441 and PC14 xenografts; coadministration of cisplatin and SAHA resulted in the opposite effects. Immunochemical staining for acetyl-histone H3 confirmed the PET/CT imaging findings. Moreover, SAHA had a more significant effect on the acetylome in PC14 (EGFR exon 19 deletion mutation) xenografts than H441 (wild-type EGFR and KRAS codon 12 mutant) xenografts. In conclusion, [18F] FAHA enables quantitative visualization of HDAC activity/expression in vivo, thus, may represent a clinically useful, noninvasive tool for the management of patients who may benefit from synergistic anticancer therapy.

中文翻译：

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使用[18F] FAHA和[18F] FDG PET / CT成像对顺铂和SAHA在非小细胞肺癌中联合抗癌作用的体内评估。

将标准药物与低剂量的组蛋白脱乙酰基酶抑制剂（HDACIs）结合使用是提高化疗疗效的一种有前途的策略。最近已在体外和体内的许多类型和阶段的癌症中证明了耐受良好剂量的HDACI作为铂类化学疗法的化学增敏剂的能力。检测HDAC活动/表达的变化可能会提供重要的预后和预测信息，并影响治疗决策。使用[18F] FAHA（一种HDAC IIa特异性放射性核素）进行分子成像，可以对转移性癌症中的HDAC活性/表达进行纵向无创评估。我们使用[18F] FAHA和[18F] FDG PET / CT成像评估了顺铂和组蛋白脱乙酰基酶抑制剂亚磺酰苯胺异羟肟酸（SAHA）在非小细胞肺癌（NSCLC）异种移植模型中的协同抗癌作用。在H441和PC14异种移植物中，单独使用顺铂可显着增加[18F] FAHA的积累，并减少[18F] FDG的积累；顺铂和SAHA的共同给药产生相反的作用。乙酰组蛋白H3的免疫化学染色证实了PET / CT成像结果。此外，SAHA对PC14（EGFR外显子19缺失突变）异种移植物中的乙酰基的作用比H441（野生型EGFR和KRAS密码子12突变体）异种移植物更显着。总之，[18F] FAHA可实现体内HDAC活性/表达的定量可视化，因此可能代表临床有用，