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 成像在体内评价顺铂和 SAHA 在非小细胞肺癌中的联合抗癌作用

将标准药物与低剂量组蛋白去乙酰化酶抑制剂 (HDACIs) 相结合是提高化疗疗效的一种有前途的策略。耐受性良好的 HDACI 剂量作为铂类化疗药物的化学增敏剂的能力最近已在体外和体内多种类型和阶段的癌症中得到证实。检测 HDAC 活性/表达的变化可以提供重要的预后和预测信息并影响治疗决策。[ ^18的使用F] FAHA，一种 HDAC IIa 特异性放射性核素，用于分子成像，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 [ 18} F] FAHA 和 [ ¹⁸ F] FDG PET/CT 成像评估了顺铂和组蛋白去乙酰化酶抑制剂辛二酰苯胺异羟肟酸 (SAHA) 在非小细胞肺癌 (NSCLC) 异种移植模型中的协同抗癌作用。单独顺铂显着增加 [ ¹⁸ F] FAHA 积累并减少 [ ¹⁸F] H441 和 PC14 异种移植物中的 FDG 积累；顺铂和SAHA的共同给药导致相反的效果。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）异种移植物中乙酰组的影响比 H441（野生型EGFR和KRAS密码子 12 突变）异种移植物更显着。总之，[ ¹⁸ F] FAHA 能够对体内HDAC 活性/表达进行定量可视化，因此，它可能代表一种临床上有用的非侵入性工具，用于管理可能受益于协同抗癌治疗的患者。