组蛋白去乙酰化酶抑制剂处理后，[¹²³I]间碘苄胍、[¹⁸F]氟多巴和[³H]去甲肾上腺素在小鼠嗜铬细胞瘤细胞和肿瘤中的摄取增加。
Increased uptake of [¹²³I]meta-iodobenzylguanidine, [¹⁸F]fluorodopamine, and [³H]norepinephrine in mouse pheochromocytoma cells and tumors after treatment with the histone deacetylase inhibitors.
机构信息
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 1E-3140, 10 Center Drive MSC-1109, Bethesda, Maryland 20892-1109, USA.
出版信息
Endocr Relat Cancer. 2011 Jan 13;18(1):143-57. doi: 10.1677/ERC-10-0090. Print 2011 Feb.
[¹³¹I]meta-iodobenzylguanidine ([¹³¹I]MIBG) is the most commonly used treatment for metastatic pheochromocytoma and paraganglioma. It enters the chromaffin cells via the membrane norepinephrine transporter; however, its success has been modest. We studied the ability of histone deacetylase (HDAC) inhibitors to enhance [¹²³I]MIBG uptake by tumors in a mouse metastatic pheochromocytoma model. HDAC inhibitors are known to arrest growth, induce differentiation and apoptosis in various cancer cells, and further inhibit tumor growth. We report the in vitro and in vivo effects of two HDAC inhibitors, romidepsin and trichostatin A, on the uptake of [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in mouse pheochromocytoma (MPC) cells by using the transporter-blocking agent desipramine and the vesicular-blocking agent reserpine. HDAC inhibitors increased [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in significantly increased uptake of [(18)F]fluorodopamine positron emission tomography (PET) in pheochromocytoma liver metastases (19.1 ± 3.2% injected dose per gram of tumor (%ID/g) compared to liver metastases in pretreatment scans 5.9 ± 0.6%; P<0.001). Biodistribution analysis after inhibitors treatment confirmed the PET results. The uptake of [(123)I]MIBG was significantly increased in liver metastases 9.5 ± 1.1% compared to 3.19 ± 0.4% in untreated control liver metastases (P<0.05). We found that HDAC inhibitors caused an increase in the amount of norepinephrine transporter expressed in tumors. HDAC inhibitors may enhance the therapeutic efficacy of [(131)I]MIBG treatment in patients with advanced malignant pheochromocytoma and paraganglioma.
[¹³¹I]间碘苄胍 ([¹³¹I]MIBG) 是治疗转移性嗜铬细胞瘤和副神经节瘤最常用的方法。它通过细胞膜去甲肾上腺素转运体进入嗜铬细胞；然而，其效果并不理想。我们研究了组蛋白去乙酰化酶（HDAC）抑制剂增强[¹²³I]MIBG 在小鼠转移性嗜铬细胞瘤模型中摄取肿瘤的能力。已知 HDAC 抑制剂可在各种癌细胞中阻止生长、诱导分化和凋亡，并进一步抑制肿瘤生长。我们报告了两种 HDAC 抑制剂罗米地辛和曲古抑菌素 A 对小鼠转移性嗜铬细胞瘤模型中[³H]去甲肾上腺素、[¹²³I]MIBG 和[¹⁸F]氟多巴摄取的体外和体内影响。通过使用转运体阻断剂去甲丙咪嗪和囊泡阻断剂利血平评估了两种抑制剂对小鼠嗜铬细胞瘤（MPC）细胞中去甲肾上腺素转运体活性的影响。HDAC 抑制剂增加了 MPC 细胞中的[³H]去甲肾上腺素、[¹²³I]MIBG 和[¹⁸F]氟多巴摄取。在体内，抑制剂治疗导致嗜铬细胞瘤肝转移的[¹⁸F]氟多巴正电子发射断层扫描（PET）摄取显著增加（与预处理扫描相比，每克肿瘤的注射剂量（%ID/g）为 19.1±3.2%，而肝转移为 5.9±0.6%；P<0.001）。抑制剂治疗后的生物分布分析证实了 PET 结果。与未治疗的对照组肝转移相比，肝转移中[¹²³I]MIBG 的摄取显着增加（9.5±1.1% 比 3.19±0.4%；P<0.05）。我们发现 HDAC 抑制剂导致肿瘤中去甲肾上腺素转运体表达量增加。HDAC 抑制剂可能增强晚期恶性嗜铬细胞瘤和副神经节瘤患者[¹³¹I]MIBG 治疗的疗效。
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