pH regulating therapy for hepatocellular carcinoma

pH调节治疗肝细胞癌

• 批准号: 10671199
• 负责人: SADANAGA Noriaki
• 金额: $ 2.05万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671199/
• 关键词: hepatocellular carcinoma; intracellular pH (pHi); tumor specific therapy; anti-tumor therapy; arterioembolization; 腫瘍細胞内PH; 腫瘍内pH; イオンポンプ; 低酸素

Measurements of intracellular pH (pHi) have shown no significant difference in mean pHi (almost 7.2) between solid tumors and normal tissues. Two membranous ion pumps (N+/H+ antiport and Na+- dependentHCO3-/Cl- exchanger) contribute to the regulation of pHi. This study was planned to clarify the anti-tumor effect of inhibiting agents against the two ion exchangers. Human hepatocellular carcinoma (HCC) was selected as a target tumor since the extracellular pH (pHe) of the tumor has potential to be more acidic by transcatheter arterioembolization (TAE) that is one of the most effective therapy for HCC. Under in-vitro assay using human HCC cell lines, Exposure to EIPA : 5-(N-ethyl-N-isopropyl) amiloride (an inhibitor of N+/H+ antiport) and DIDS : 4,4-diisothiocyanstibene 2,2- disulfonic acid (an inhibitor of Na+-dependentHCO3-/Cl- exchanger) at pHe 6.6 caused 100-fold cell killing compared with pHe 7.2. The cytotoxicity was enhanced about 10-fold under the hypoxic condition. In vivo assay using nude mice bearing human HCC tumors at the left hind leg, the administration of these inhibiting agents at the maximal dose that no animal death occurred led to significant reduction of the tumor size with massive necrotic area. Cells from non-necrotic tissues of the tumor treated with the inhibiting agents were cultured in vitro and showed the tolerance to the pH regulating therapy compared with their wild type cells. The establishment of the HCC models on the liver of small animals was not achieved because of the technical problem, therefore the combination effects of those pH regulating therapy and TAE have not been estimated.

细胞内pH(Phi)的测量显示实体瘤和正常组织的平均phi无显著差异(几乎为7.2)。两个膜离子泵(N+/H+反向转运和Na+依赖的HCO3-/Cl-交换)参与调节pH i。本研究旨在阐明抑制这两种离子交换剂的抗肿瘤作用。经导管动脉栓塞术(TAE)是治疗肝细胞癌最有效的方法之一，由于肝细胞癌的细胞外pH(Phe)具有更强的酸性，因此被选为靶肿瘤。在人肝癌细胞株的体外实验中，与Phe 7.2相比，在Phe 6.6时，EIPA：5-(N-乙基-N-异丙基)阿米洛利(N+/H+反向转运蛋白的抑制剂)和DIDS：4，4-二异硫代半胱氨酸2，2-二磺酸(Na+依赖的HCO3-/Cl-交换的抑制剂)对细胞的杀伤作用是Phe 7.2的100倍。在低氧条件下，细胞毒作用增强约10倍。在裸鼠左后腿移植人肝癌的体内实验中，在无动物死亡的最大剂量下给予这些抑制剂，可显著缩小肿瘤的大小，并有大量的坏死区。用抑制剂处理的肿瘤非坏死区组织的细胞在体外培养，与野生型细胞相比，显示出对pH调节治疗的耐受性。由于技术上的问题，小动物肝细胞癌模型的建立尚未实现，因此这些pH调节疗法和TAE的联合作用还没有被估计。

项目成果

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Sadanaga N., et al: "The heterogeneous expression of MAGE-3 protein ; difference between primary lesions and metastatic lymph nodes in gastric carcinoma."Oncol Rep. 6. 975-977 (1999)

Sadanaga N. 等人：“MAGE-3 蛋白的异质表达；胃癌原发灶和转移淋巴结之间的差异。”Oncol Rep. 6. 975-977 (1999)