Effect of chemotherapy to the liver with pretreatment of interferon for hepatocellular carcinoma to aim at the acquisition of the sensitivity for anti-cancer drugs.

干扰素预处理对肝细胞癌化疗对肝脏的影响，旨在获得抗癌药物的敏感性。

• 批准号: 13671305
• 负责人: TOMINAGA Masahiro
• 金额: $ 2.3万
• 依托单位: Kobe University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671305/
• 关键词: Hepatocellular carcinoma; Percutaneous Isolated Hepatic Perfusion; Interferon; 肝細胞癌; C型肝炎

We have detected hepatitis C virus (HCV) core protein induced the tolerance against the anti-cancer drugs. Interferon (IFN) is well known to decrease viral load of HCV. Percutaneous Isolated Hepatic Perfusion (PIHP) is a high dose chemotherapy to the liver, while reducing the systemic exposure of the cytotoxic drugs. We investigate the efficacy of the chemotherapy to the liver using PIHP with pretreatment of IFN for patients who has hepatocellular carcinoma (HCC) with HCV.(A)Basic study1)Analysis of the mechanism in the acquirement of the tolerance against anti-cancer drugs.We cultured HCV core protein expression cells and controlled cells in the medium including Actinomycin D (Act.D) or Doxorubicin (Doxo). CyclosporinA, which is a inhibitor of P-glycoprotein, suppress the survival of HCV core protein expression cells (Act.D ; 151%→10.2%, Doxo ; 86%→2.4%). P-glycoprotein is one of the mediators relating to the mechanism in the acquirement of the tolerance against anti-cancer drugs in the HCV core protein expression cells.(B)Clinical study1)Retrospecthe study : Patients treated by PIHP who had HCC with HCV were categorized into two groups according to the HCV-RNA levels. Group I ; HCV-RNA<3x10^2Kcopy/ml, GroupII ; HCV-RNA≧3x10^2Kcopy/ml. We compared the tumor effect between group I and II. Local tumor control was significantly effective in group I compared with group II. CR+PR ; 86% in group I vs 25% in group II2)Prospective study : We produced the protocol of the pretreatment of IFN-α (IFN-α 300 x 10^4 IU/day, everyday, 1week). PIHP was performed in 2 cases after pretreatment of IFN. These 2 cases has partial response after 1 month of PIHP. Based on these results, pretreatment of IFN increases the sensitivity of anti-tumor drugs in HCC patients with HCV However, pancytopenia which is a side effect of IFN is the most problem to be improved.

我们已经检测到丙型肝炎病毒（HCV）核心蛋白可诱导对抗癌药物的耐受。干扰素（IFN）是众所周知的，以减少HCV的病毒载量。经皮隔离肝灌注（PIHP）是一种高剂量的肝脏化疗，同时减少了细胞毒性药物的全身暴露。目的探讨干扰素预处理联合PIHP肝内化疗治疗丙型肝炎合并肝癌的疗效。（A）基础研究1）抗肿瘤药物耐受性获得的机制分析我们将HCV核心蛋白表达细胞和对照细胞分别培养在含有放线菌素D（Act.D）或阿霉素（Doxo）的培养基中。P-糖蛋白抑制剂环孢菌素A可抑制HCV核心蛋白表达细胞的存活（Act.D ; 151%→ 10.2%，Doxo ; 86%→2.4%）。P-糖蛋白是HCV核心蛋白表达细胞获得抗癌药物耐受机制的相关介质之一。（B）临床研究1）回顾性研究：根据HCV RNA水平将接受PIHP治疗的HCC伴HCV患者分为两组。I组：HCV-RNA<3x10^2Kcopy/ml，II组：HCV-RNA <3x10^2Kcopy/ml。我们比较了I组和II组的肿瘤效应。与II组相比，I组的局部肿瘤控制显著有效。CR+PR ; 2）前瞻性研究：我们制定了IFN-α预处理方案（IFN-α 300 × 10^4 IU/d，每日1次，共1周）。2例在IFN预处理后行PIHP。这2例患者在PIHP治疗1个月后部分缓解。基于这些结果，IFN预处理增加了HCV感染的HCC患者对抗肿瘤药物的敏感性，但IFN的副作用全血细胞减少是最需要改善的问题。

项目成果

Ku Y., Tominaga M., Iwasaki T., Fukumoto T., Kuroda Y.: "Isolated hepatic perfusion chemotherapy for unresectable malignant hepatic tumors"Int J Clin Oncol. 7. 82-90 (2002)

Ku Y.、Tominaga M.、Iwasaki T.、Fukumoto T.、Kuroda Y.：“不可切除的恶性肝肿瘤的隔离肝灌注化疗”Int J Clin Oncol。

具 英成: "進行多発肝細胞癌に対する減量切除と経皮的肝灌流(PIHP)の合併療法による新治療体系の確立"消化器科. 37. 419-426 (2003)

Eisei Gu：“采用减瘤切除和经皮肝灌注（PIHP）联合疗法治疗晚期多发性肝细胞癌的新治疗系统的建立”消化内科 37. 419-426（2003）。

富永正寛: "切除不能肝細胞癌に対する減量肝切除と経皮的肝再灌流による集学的治療"臨床外科. 59. 293-301 (2004)

Masahiro Tominaga：“使用减灭性肝脏切除和经皮肝脏再灌注治疗不可切除的肝细胞癌的多学科治疗”《临床外科》59. 293-301 (2004)。

Ku Y, Tominaga M, Iwasaki T, Fukumoto T, Kusunoki N, Ogata S, Kuroda Y: "Regional treatment for unresectable malignant hepatic tumors : An overview of isolated hepatic perfusion"Chir Gastroenterol. 19. 370-376 (2003)

Ku Y、Tominaga M、Iwasaki T、Fukumoto T、Kusunoki N、Ogata S、Kuroda Y：“不可切除的恶性肝肿瘤的区域治疗：离体肝灌注概述”Chir Gastroenterol。