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.

我们检测了丙型肝炎病毒（HCV）核心蛋白诱导的对抗癌药物的耐受性。众所周知，干扰素（IFN）可以降低HCV病毒载量。经皮离体肝灌注（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。我们研究了肝细胞癌（HCC）合并HCV患者使用PIHP联合IFN预处理对肝脏的化疗效果。(A)基础研究1)抗癌药物耐受性获得的机制分析。我们在含放线菌素D （Act.D）或多柔比星（Doxo）的培养基中培养HCV核心蛋白表达细胞和对照细胞。CyclosporinA是一种p糖蛋白抑制剂，可抑制HCV核心蛋白表达细胞的存活。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性机制相关的介质之一。(B)临床研究1)回顾性研究：采用PIHP治疗的HCC合并HCV患者根据HCV- rna水平分为两组。第一组；HCV-RNA<3x10^2Kcopy/ml, GroupII；HCV-RNA≧3 x10 ^ 2 kcopy /毫升。比较I组和II组的肿瘤效果。与II组相比，I组局部肿瘤控制明显有效。CR +公关;2)前瞻性研究：我们制定了IFN-α预处理方案（IFN-α 300 × 10^4 IU/天，每天，1周）。2例经IFN预处理后行PIHP。这2例患者在PIHP治疗1个月后出现部分缓解。基于这些结果，IFN预处理可提高HCC合并HCV患者抗肿瘤药物的敏感性，但IFN的副作用全细胞减少是目前亟待改善的问题。

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.