动脉内IL-12基因治疗联合化疗栓塞术治疗肝癌的实验研究
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摘要
目的
构建携带增强型绿色荧光蛋白(EGFP)和人白细胞介素12双亚基目的基因(hIL-12,P35,P40)的真核表达质粒pEGFP-C1_IL-12,研究其体外抗肿瘤作用。
分离、纯化白芨多糖,制备阳离子型白芨多糖,研究其表征,探讨其在体内外作为基因递送载体的可行性
研究动脉内白细胞介素12基因治疗联合化疗栓塞术治疗VX2肝癌的抗肿瘤及抗肿瘤血管生成的疗效,探讨其可能的机制。
材料与方法
提取脂多糖(LPS)诱导后的人脐带血淋巴细胞总RNA,RT-PCR法扩增人白细胞介素12的双亚基P35和P40的全长cDNA,采用重叠PCR法连接两个亚基,双酶切双亚基片段及载体pEGFP-C1,T4DNA连接酶连接,重组质粒转化大肠埃希菌,挑取阳性克隆,PCR、双酶切及测序鉴定。借助脂质体将重组质粒转染人肝癌细胞系HepG2,通过荧光显微镜检测报告基因的表达,RT-PCR及Western blot去检测目的基因的表达。MTT法检测肝癌细胞的生长情况,RT-PCR法检测肝癌细胞表达血管内皮生长因子(VEGF)的变化。
经热水抽提,乙醇沉淀,Sevag法脱蛋白,经阴离子交换纤维素柱(DE-52)和凝胶柱(Sephadex G-100)层析,分离纯化得白芨多糖,通过高碘酸钾氧化得到含醛基的还原性多糖,该还原性多糖与精胺在碱性条件下形成希夫碱式共轭物,经硼氢化钠还原得含伯胺基的阳离子型多糖,分别通过盐酸羟胺法和三硝基苯磺酸法测醛基与伯胺基的产量。考察氧化反应时间对反应产物的影响。运用琼脂糖凝胶电泳检测该阳离子型多糖对基因的结合与保护作用。将阳离子型白芨多糖载基因复合物与体外生长的肝癌细胞系HepG2共培养,研究转染效率。进一步通过介入途径经肝动脉导入复合物,以GFP作为报告基因检测复合物在体内对活体兔肝组织细胞的转染,同时检测其血清转氨酶水平及肾功能指标以评估体内毒性。
32只生长有VX2肝癌的新西兰大白兔随机分为四组,每组八只,开腹后使用自制穿刺针置入肝动脉行介入治疗。A组行生理盐水灌注(对照组),B组行常规化疗栓塞,C组行动脉内基因灌注治疗,D组行动脉内基因灌注治疗+化疗栓塞。治疗前及治疗后第14天行螺旋CT扫描检测肿瘤大小,计算肿瘤相对生长速率；于治疗前及治疗后第3、7、14天采静脉血检测循环血中IFN-γ的水平；于第14天处死所有实验兔,免疫组化法检测瘤组织VEGF表达水平、微血管密度(MVD值)及肿瘤细胞凋亡指数。
结果
PCR及测序鉴定证实重组质粒pEGFP-C1_IL-12构建成功,RT-PCR及Westernblot法证实重组质粒在HepG2细胞内正常表达。转染重组质粒后的肝癌细胞生长未受明显影响,表达VEGF能力无显著变化。
所提纯的白芨多糖为一种不含阳离子基团的非还原性多糖,通过胺化还原反应的方法可成功制备出含伯胺基的阳离子型多糖,红外光谱证实了多糖上伯胺基的存在。该阳离子型多糖可以结合并保护质粒DNA免受DNA酶的降解,体外实验证实该复合物可以转染入体外培养的肝癌细胞,以阳离子白芨多糖作为转染载体时转染效率要低于脂质体,差异具有统计学意义(28.87%±3.27% vs 36.64%±6.87%,t检验,P<0.05)。采用介入方法经肝动脉给药时复合物能靶向转染入活体兔肝细胞内并实现表达,阳离子白芨多糖未显示出明显体内毒性。
体内实验中,C、D组于第3、7天出现高水平IFN-γ的表达,明显高于治疗前水平及同期A、B组(Turkey HSD法方差分析,P<0.05),至第14天血清IFN-γ水平恢复至治疗前水平。两个基因治疗组(C组和D组)的瘤组织VEGF和MVD水平均下降,但单纯基因治疗组(C组)的肿瘤生长速度及肿瘤细胞凋亡率与对照组相比均无显著差异(Turkey HSD法方差分析,P>0.05),而基因治疗与化疗栓塞联合组(D组)肿瘤生长速度减慢,肿瘤细胞凋亡率增加,与对照组及化疗栓塞组相比均有显著差异。
结论
成功构建IL-12双亚基共表达质粒pEGFP-C1_IL-12,该质粒转染入肝癌细胞后,表达产物对体外培养的肝癌细胞的生长及表达VEGF的能力无显著影响。通过胺化还原法制备的阳离子型白芨多糖可以结合并保护质粒DNA,该阳离子白芨多糖能作为基因递送载体携载质粒pEGFP-C1_IL-12转染入体外培养的肝癌细胞及体内生长的肝细胞。经动脉IL-12基因治疗与化疗栓塞术联合应用能对VX2肝癌产生明显的抗肿瘤作用及抗肿瘤血管生成作用,联合应用的疗效明显优于化疗栓塞单独应用。
Objective
The first purpose of this study was to construct a recombinant eukaryotic expression plasmid pEGFP-C1_IL-12 containing report gene (EGFP) and recombinant human interleukin 12 double-submit(P40 and P35), and to research its anti-tumor effect in vitro. The second purpose was to prepare the cationic product of a polysaccharide isolated from Chinese medicinal herb Bletilla striata, and to investigate the characterization and the possibility of being a non-viral gene vector in vitro and in vivo. The third purpose was to evaluate the anti-tumor and anti-angiogenesis effect of intraarterial IL-12 gene therapy alone and in combination with transarterial chemoemboliztion (TACE) in a rabbit VX2 liver cancer model.
Methods and Materials
Total RNA was extracted from human umbilical cord blood lymphocytes, from which the total cDNA of human interleukin 12 double-submit was amplified by RT-PCR. The linkaged double-submit connected by overlap PCR was inserted into the MCS of vector pEGFP-C1 to construct a recombinant plasmid, which was identified by PCR and sequencing analysis. Then the recombinant plasmid was transfected into HepG2 cells lipidosome and its expression was detected by fluorescent microscopy, RT-PCR and Western blot.
Bletilla striata polysaccharide was prepared by ethanol precipitation followed the hot water extraction Bletilla striata stem and deproteinized with Sevag method. It was further isolated by ion-exchange chromatography on DE-52 column and gel filtrationon Sephadex G-100 column. Cationic polysaccharide was synthesized by conjugation of spermine to oxidized polysaccharide. The ability of the caionic polysaccharide to incorporate and protect plasmid DNA was measured. The ability of the BSP+/pDNA complex to transfect into HepG2 cells was measured. Then, we investigated the transfected effect of the BSP+/pDNA complex in vivo using green fluorescence protein (GFP) gene as a reporter gene administered through the hepatic artery.
Rabbits developed VX2 tumor in the liver were randomized into four groups, eight of each. After laparotomy and placement of a self-made 30-gauge needle into the proper liver artery, the following protocols of the interventional procedure were applied: 0.9% saline solution (group A), TACE (group B), intraarterial interlukin-12 gene infusion (group C) and intraarterial interlukin-12 gene infusion in combination with TACE (group D). Growth ratio was estimated by computed tomography. Interferon-gamma level of blood was analyzed by ELISA before and 3day,7day,14day after intervention. All animals were sacrificed 14day after procedure, and the tumor tissue were explanted to analyze vessel endothelial growth factor (VEGF), microvessel density (MVD) and apoptotic index of tumor tissues using immunohistochemistry.
Results
Identification of pEGFP-C1_IL-12 by PCR and sequencing analysis showed that the length, inserted location and direction was correct, and the expression of reported gene and target gene was observed by fluorescent microscopy, RT-PCR and Western blot.
There is no cationoid primary amine and reductive carbonyl in the polysaccharide isolated from the Chinese medicinal herb Bletilla striata. The structure of cationic Bletilla striata polysaccharide contained primary amine group was confirmed by FT-IR. The synthesized cationic product incorporated and protected plasmid DNA to avoidenzymolysis.
Tumor growth and angiogenesis were significantly suppressed in group D compared with other groups, characterized by lower tumor growth rate, VEGF, MVD, and higher apoptotic index of tumor cells. Interferon-gamma were higher in group C and group D 3day and 7day after intervention compared to group A and group B, but there is no significantly difference between group C and group D.
Conclusion
The cationic Bletilla striata polysaccharide synthesized by grafted spermine to the polysaccharide isolated from the Chinese medicinal herb Bletilla striata could incorporate and protect plasmid DNA, which could be an ideal non-viral gene vector in gene transduction. The BSP+/pDNA complex could target transfect into liver cell in vivo when administered through the hepatic artery using the interventional method, which could produce a marked effect as a new type polycation gene vector in gene therapy.
Intraarterial interlukin-12 encoded gene delivery could induce interferon-gamma expression, which may contributed to anti-angiogenesis effect of interlukin-12. Intraarterial interlukin-12 encoded gene delivery combined with chemoembolization could inhibit rabbit VX2 hepatocellular growth significantly, perhaps the anti-tumor and anti-angiogenesis effect were associated with high concentration IL-12 of tumor local when combined with chemoembolization.
构建携带增强型绿色荧光蛋白(EGFP)和人白细胞介素12双亚基目的基因(hIL-12,P35,P40)的真核表达质粒pEGFP-C1_IL-12,研究其体外抗肿瘤作用。
分离、纯化白芨多糖,制备阳离子型白芨多糖,研究其表征,探讨其在体内外作为基因递送载体的可行性
研究动脉内白细胞介素12基因治疗联合化疗栓塞术治疗VX2肝癌的抗肿瘤及抗肿瘤血管生成的疗效,探讨其可能的机制。
材料与方法
提取脂多糖(LPS)诱导后的人脐带血淋巴细胞总RNA,RT-PCR法扩增人白细胞介素12的双亚基P35和P40的全长cDNA,采用重叠PCR法连接两个亚基,双酶切双亚基片段及载体pEGFP-C1,T4DNA连接酶连接,重组质粒转化大肠埃希菌,挑取阳性克隆,PCR、双酶切及测序鉴定。借助脂质体将重组质粒转染人肝癌细胞系HepG2,通过荧光显微镜检测报告基因的表达,RT-PCR及Western blot去检测目的基因的表达。MTT法检测肝癌细胞的生长情况,RT-PCR法检测肝癌细胞表达血管内皮生长因子(VEGF)的变化。
经热水抽提,乙醇沉淀,Sevag法脱蛋白,经阴离子交换纤维素柱(DE-52)和凝胶柱(Sephadex G-100)层析,分离纯化得白芨多糖,通过高碘酸钾氧化得到含醛基的还原性多糖,该还原性多糖与精胺在碱性条件下形成希夫碱式共轭物,经硼氢化钠还原得含伯胺基的阳离子型多糖,分别通过盐酸羟胺法和三硝基苯磺酸法测醛基与伯胺基的产量。考察氧化反应时间对反应产物的影响。运用琼脂糖凝胶电泳检测该阳离子型多糖对基因的结合与保护作用。将阳离子型白芨多糖载基因复合物与体外生长的肝癌细胞系HepG2共培养,研究转染效率。进一步通过介入途径经肝动脉导入复合物,以GFP作为报告基因检测复合物在体内对活体兔肝组织细胞的转染,同时检测其血清转氨酶水平及肾功能指标以评估体内毒性。
32只生长有VX2肝癌的新西兰大白兔随机分为四组,每组八只,开腹后使用自制穿刺针置入肝动脉行介入治疗。A组行生理盐水灌注(对照组),B组行常规化疗栓塞,C组行动脉内基因灌注治疗,D组行动脉内基因灌注治疗+化疗栓塞。治疗前及治疗后第14天行螺旋CT扫描检测肿瘤大小,计算肿瘤相对生长速率；于治疗前及治疗后第3、7、14天采静脉血检测循环血中IFN-γ的水平；于第14天处死所有实验兔,免疫组化法检测瘤组织VEGF表达水平、微血管密度(MVD值)及肿瘤细胞凋亡指数。
结果
PCR及测序鉴定证实重组质粒pEGFP-C1_IL-12构建成功,RT-PCR及Westernblot法证实重组质粒在HepG2细胞内正常表达。转染重组质粒后的肝癌细胞生长未受明显影响,表达VEGF能力无显著变化。
所提纯的白芨多糖为一种不含阳离子基团的非还原性多糖,通过胺化还原反应的方法可成功制备出含伯胺基的阳离子型多糖,红外光谱证实了多糖上伯胺基的存在。该阳离子型多糖可以结合并保护质粒DNA免受DNA酶的降解,体外实验证实该复合物可以转染入体外培养的肝癌细胞,以阳离子白芨多糖作为转染载体时转染效率要低于脂质体,差异具有统计学意义(28.87%±3.27% vs 36.64%±6.87%,t检验,P<0.05)。采用介入方法经肝动脉给药时复合物能靶向转染入活体兔肝细胞内并实现表达,阳离子白芨多糖未显示出明显体内毒性。
体内实验中,C、D组于第3、7天出现高水平IFN-γ的表达,明显高于治疗前水平及同期A、B组(Turkey HSD法方差分析,P<0.05),至第14天血清IFN-γ水平恢复至治疗前水平。两个基因治疗组(C组和D组)的瘤组织VEGF和MVD水平均下降,但单纯基因治疗组(C组)的肿瘤生长速度及肿瘤细胞凋亡率与对照组相比均无显著差异(Turkey HSD法方差分析,P>0.05),而基因治疗与化疗栓塞联合组(D组)肿瘤生长速度减慢,肿瘤细胞凋亡率增加,与对照组及化疗栓塞组相比均有显著差异。
结论
成功构建IL-12双亚基共表达质粒pEGFP-C1_IL-12,该质粒转染入肝癌细胞后,表达产物对体外培养的肝癌细胞的生长及表达VEGF的能力无显著影响。通过胺化还原法制备的阳离子型白芨多糖可以结合并保护质粒DNA,该阳离子白芨多糖能作为基因递送载体携载质粒pEGFP-C1_IL-12转染入体外培养的肝癌细胞及体内生长的肝细胞。经动脉IL-12基因治疗与化疗栓塞术联合应用能对VX2肝癌产生明显的抗肿瘤作用及抗肿瘤血管生成作用,联合应用的疗效明显优于化疗栓塞单独应用。
Objective
The first purpose of this study was to construct a recombinant eukaryotic expression plasmid pEGFP-C1_IL-12 containing report gene (EGFP) and recombinant human interleukin 12 double-submit(P40 and P35), and to research its anti-tumor effect in vitro. The second purpose was to prepare the cationic product of a polysaccharide isolated from Chinese medicinal herb Bletilla striata, and to investigate the characterization and the possibility of being a non-viral gene vector in vitro and in vivo. The third purpose was to evaluate the anti-tumor and anti-angiogenesis effect of intraarterial IL-12 gene therapy alone and in combination with transarterial chemoemboliztion (TACE) in a rabbit VX2 liver cancer model.
Methods and Materials
Total RNA was extracted from human umbilical cord blood lymphocytes, from which the total cDNA of human interleukin 12 double-submit was amplified by RT-PCR. The linkaged double-submit connected by overlap PCR was inserted into the MCS of vector pEGFP-C1 to construct a recombinant plasmid, which was identified by PCR and sequencing analysis. Then the recombinant plasmid was transfected into HepG2 cells lipidosome and its expression was detected by fluorescent microscopy, RT-PCR and Western blot.
Bletilla striata polysaccharide was prepared by ethanol precipitation followed the hot water extraction Bletilla striata stem and deproteinized with Sevag method. It was further isolated by ion-exchange chromatography on DE-52 column and gel filtrationon Sephadex G-100 column. Cationic polysaccharide was synthesized by conjugation of spermine to oxidized polysaccharide. The ability of the caionic polysaccharide to incorporate and protect plasmid DNA was measured. The ability of the BSP+/pDNA complex to transfect into HepG2 cells was measured. Then, we investigated the transfected effect of the BSP+/pDNA complex in vivo using green fluorescence protein (GFP) gene as a reporter gene administered through the hepatic artery.
Rabbits developed VX2 tumor in the liver were randomized into four groups, eight of each. After laparotomy and placement of a self-made 30-gauge needle into the proper liver artery, the following protocols of the interventional procedure were applied: 0.9% saline solution (group A), TACE (group B), intraarterial interlukin-12 gene infusion (group C) and intraarterial interlukin-12 gene infusion in combination with TACE (group D). Growth ratio was estimated by computed tomography. Interferon-gamma level of blood was analyzed by ELISA before and 3day,7day,14day after intervention. All animals were sacrificed 14day after procedure, and the tumor tissue were explanted to analyze vessel endothelial growth factor (VEGF), microvessel density (MVD) and apoptotic index of tumor tissues using immunohistochemistry.
Results
Identification of pEGFP-C1_IL-12 by PCR and sequencing analysis showed that the length, inserted location and direction was correct, and the expression of reported gene and target gene was observed by fluorescent microscopy, RT-PCR and Western blot.
There is no cationoid primary amine and reductive carbonyl in the polysaccharide isolated from the Chinese medicinal herb Bletilla striata. The structure of cationic Bletilla striata polysaccharide contained primary amine group was confirmed by FT-IR. The synthesized cationic product incorporated and protected plasmid DNA to avoidenzymolysis.
Tumor growth and angiogenesis were significantly suppressed in group D compared with other groups, characterized by lower tumor growth rate, VEGF, MVD, and higher apoptotic index of tumor cells. Interferon-gamma were higher in group C and group D 3day and 7day after intervention compared to group A and group B, but there is no significantly difference between group C and group D.
Conclusion
The cationic Bletilla striata polysaccharide synthesized by grafted spermine to the polysaccharide isolated from the Chinese medicinal herb Bletilla striata could incorporate and protect plasmid DNA, which could be an ideal non-viral gene vector in gene transduction. The BSP+/pDNA complex could target transfect into liver cell in vivo when administered through the hepatic artery using the interventional method, which could produce a marked effect as a new type polycation gene vector in gene therapy.
Intraarterial interlukin-12 encoded gene delivery could induce interferon-gamma expression, which may contributed to anti-angiogenesis effect of interlukin-12. Intraarterial interlukin-12 encoded gene delivery combined with chemoembolization could inhibit rabbit VX2 hepatocellular growth significantly, perhaps the anti-tumor and anti-angiogenesis effect were associated with high concentration IL-12 of tumor local when combined with chemoembolization.
引文
1. Simon MM, Hochgeschwender U, Brugger U, Landolfo S. Monoclonal antibodies to interferon-gamma inhibit interleukin 2-dependent induction of growth and maturation in lectin/antigen-reactive cytolytic T lymphocyte precursors. J Immunol.1986 Apr 15;136(8):2755-62.
2. Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med.1989 Sep 1;170(3):827-45.
3. Chizzonite R, Truitt T, Podlaski FJ, Wolitzky AG, Quinn PM, Nunes P, et al. IL-12:monoclonal antibodies specific for the 40-kDa subunit block receptor binding and biologic activity on activated human lymphoblasts. J Immunol.1991 Sep 1;147(5):1548-56.
4. Tone Y, Thompson SA, Babik JM, Nolan KF, Tone M, Raven C, et al. Structure and chromosomal location of the mouse interleukin-12 p35 and p40 subunit genes. Eur J Immunol.1996 Jun;26(6):1222-7.
5. Marchant A, Amedei A, Azzurri A, Vekemans J, Benagiano M, Tamburini C, et al. Polarization of PPD-specific T-cell response of patients with tuberculosis from ThO to Thl profile after successful antimycobacterial therapy or in vitro conditioning with interferon-alpha or interleukin-12. Am J Respir Cell Mol Biol.2001 Feb;24(2):187-94.
6. Sumimoto H, Tani K, Nakazaki Y, Tanabe T, Hibino H, Wu MS, et al. Superiority of interleukin-12-transduced murine lung cancer cells to GM-CSF or B7-1 (CD80) transfectants for therapeutic antitumor immunity in syngeneic immunocompetent mice. Cancer Gene Ther.1998 Jan-Feb;5(1):29-37.
7. Sgadari C, Angiolillo AL, Tosato G. Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood.1996 May 1;87(9):3877-82.
8. Sangro B, Melero I, Qian C, Prieto J. Gene therapy of cancer based on interleukin 12. Curr Gene Ther.2005 Dec;5(6):573-81.
9. Wang XH, Yang JM, Cui ZF, Wang WG, Wu MC, Qian QJ. [In vitro gene therapy of hepatocellular carcinoma using replication-defective and tumor-specific replication-competent adenovirus carrying interleukin-12 gene]. Zhonghua Zhong Liu Za Zhi.2004 Oct;26(10):581-4.
10. Goto T, Nishi T, Kobayashi O, Tamura T, Dev SB, Takeshima H, et al. Combination electro-gene therapy using herpes virus thymidine kinase and interleukin-12 expression plasmids is highly efficient against murine carcinomas in vivo. Mol Ther.2004 Nov;10(5):929-37.
11.羊东晔,卢放根,汤熙翔等.人白细胞介素12双亚基共表达载体的构建及表达.中国免疫学杂志.2004；20(2)：79-82.
12.羊东晔,卢放根,赵水平等.人白细胞介素12双亚基共表达真核载体的构建.湖南医科大学学报.2003；28(4)：338-42.
13. Arai K, Ohkuma S, Matsukawa T, Kato S. A simple estimation of peroxisomal degradation with green fluorescent protein-an application for cell cycle analysis. FEBS Lett.2001 Oct 26;507(2):181-6.
14. Tomohide Tatsumi, Tetsuo Takehara, Tatsuya Kanto, et al. Administration of Interleukin-12 Enhances the Therapeutic Efficacy of Dendritic Cell-based Tumor Vaccines in Mouse Hepatocellular carcinoma. Cancer Research.2001; 61:7563-7567.
15. Hideo Komita, Sadamu Hommal, Hideo Saotome, Mikio Zeniya, Tsuneya Ohnol, Gotaro Toda. Interferon-gamma produced by interleukin-12-activated tumor infiltrating CD8+T cells directly induces apoptosis of mouse hepatocellular carcinoma. Journal of Hepatology.2006;45:662-672
1 ZHENG CS,FENG GS,ZHANG YF. Bletilla colloid as a vascular embolization agent:experimental studies[J]. Chin J Radiol(中华放射学杂志),1998,32(3):188-191.
2 LI WY,FENG GS,ZHENG CS. Pharmacokinetics of 5-Fu Bletilla Microspheres Following Renal Arterial Embolization in Rabbits[J]. Acta Universitatis Medictnae Tongjil(同济医科大学学报),2001,30(5)：501-503.
3 FENG GS,LI X,ZHENG CS,et al. Mechanism of inhibition of tumor angiogenesis by Bletilla colloid: an experimental study[J]. Natl Med J China(中华医学杂志),2003,83(5)：412-416.
4 WANG CM, SUN JT,LUO Y. A polysaccharide isolated from the medicinal herb Bletilla striata induces endothelial cells proliferation and vascular endothelial growth factor expression in vitro[J]. Biotechnology Letters,2006,28(8):539-543.
5 Tony Azzam,Hagit Eliyahu,Libi Shapira. Polysaccharide-Oligoamine Based Conjugates for Gene Delivery[J]. J Med Chem,2002,45(9):1817-1824.
6 I YUDOVIN-FARBER, AJ DOMB. Cationic polysaccharides for gene delivery[J]. Materials Science and Engineering,2007.595-598.
7 Snyder S. L,Sobocinski, P. Z. An improved 2,4,6-trinitrobenzenesulfonic acid method for the determination of amines[J]. Anal Biochem,1975,64(1):284-288.
8 RUI HY,WU GR,CHEN JY. Isolation,Purification and Structural Characterizationof Neutral Heteropolysaccharide from Bletilla striata[J]. Journal of Anhui Agricultural University(安徽农业大学学报),2004,31(1)：30-33.
9 Park IK,IhmJE,Park YH, et al. Galactosylated chitosan (GC)-graft-poly(viny pyrrolidone) as hepatocyte-targeting DNA carrier preparation and physiochemical characterization of (GC)-graft-PVP/ DNA complex[J]. J Controlled Release,2003,86(2):349-359.
10 Anderson, W. F. Human gene therapy[J]. Science,1992,256(5058):808-813.
11 Aoki K,Yoshida T,Sugimura T,Terada. Liposome-mediated in vivo gene transfer
of antisence K-ras construct inhibits pancreatic tumor dissemination in the murine peritoneal cavity[J]. Cancer Res,1995,55(9):3810-3816.
12 Saleh M,Wiegmans A,Malone Q,Stylli S S,Kaye A H. Effect of in situ Retroviral Interleukin-4 Transfer on Established Intracranial Tumors [J]. J Natl Cancer Inst, 1999,91(5):438-445.
13 De Smedt SC,Demeester J,Hennink WE. Cationic polymer based gene delivery systems[J]. Pharm Res,2000,17(2):113-125.
1. Bozorgzadeh A, Orloff M, Abt P, Tsoulfas G, Younan D, Kashyap R, et al. Survival outcomes in liver transplantation for hepatocellular carcinoma, comparing impact of hepatitis C versus other etiology of cirrhosis. Liver Transpl. 2007 Jun;13(6):807-13.
2. Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta LA. Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci.2002 Jun;963:13-20.
3. Yu AS, Keeffe EB. Management of hepatocellular carcinoma. Rev Gastroenterol Disord.2003 Winter;3(1):8-24.
4. Alsowmely AM, Hodgson HJ. Non-surgical treatment of hepatocellular carcinoma. Aliment Pharmacol Ther.2002 Jan;16(1):1-15.
5. Maataoui A, Qian J, Vossoughi D, Khan MF, Oppermann E, Bechstein WO, et al. Transarterial chemoembolization alone and in combination with other therapies:a comparative study in an animal HCC model. Eur Radiol.2005 Jan;15(1):127-33.
6. Doyon D, Mouzon A, Jourde AM, Regensberg C, Frileux C. [Hepatic, arterial embolization in patients with malignant liver tumours (author's transl)]. Ann Radiol (Paris).1974 Oct;17(6):593-603.
7. Achenbach T, Seifert JK, Pitton MB, Schunk K, Junginger T. Chemoembolization for primary liver cancer. Eur J Surg Oncol.2002 Feb;28(1):37-41.
8. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma:a randomised controlled trial. Lancet.2002 May 18;359(9319):1734-9.
9. Qian C, Drozdzik M, Caselmann WH, Prieto J. The potential of gene therapy in the treatment of hepatocellular carcinoma. J Hepatol.2000 Feb;32(2):344-51.
10. Stefani AL, Barzon L, Castagliuolo I, Guido M, Pacenti M, Parolin C, et al. Systemic efficacy of combined suicide/cytokine gene therapy in a murine model of hepatocellular carcinoma. J Hepatol.2005 May;42(5):728-35.
11. Xia Xiangwen LX, Feng Gansheng et al Construction and Expression of a Human Interleukin 12 Double-submit Co-expressing Eukarya Plasmid pEGFP-C1_IL-12. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong.2009(1).
12. XIA Xiang-wen LX, FENG Gan-sheng et al. Preparation and Characterization of a Non-viral Gene Vector from a Polysaccharide Isolated from the Chinese Medicinal Herb Bletilla striata. Chinese Pharmaceutical Journal.2008(18).
13. Xiang-Wen Xia XL, Gan-Sheng Feng et al. Feasibility of a polysaccharide isolated from Bletilla striata used as a gene vector administered through an interventional pathway. World Chinese Journal of Digestology.2009(18).
14. Park YN, Kim YB, Yang KM, Park C. Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis. Arch Pathol Lab Med.2000 Jul;124(7):1061-5.
15. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med.1991 Jan 3;324(1):1-8.
16. Katiyar SK. Interleukin-12 and photocarcinogenesis. Toxicol Appl Pharmacol.2007 Nov 1;224(3):220-7.
17. Kanagawa N, Gao JQ, Motomura Y, Yanagawa T, Mukai Y, Yoshioka Y, et al. Antitumor mechanism of intratumoral injection with IL-12-expressing adenoviral vector against IL-12-unresponsive tumor. Biochem Biophys Res Commun.2008 Aug 8;372(4):821-5.
18. Barajas M, Mazzolini G, Genove G, Bilbao R, Narvaiza I, Schmitz V, et al. Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12. Hepatology.2001 Jan;33(1):52-61.
19. Otani T, Nakamura S, Toki M, Motoda R, Kurimoto M, Orita K. Identification of IFN-gamma-producing cells in IL-12/IL-18-treated mice. Cell Immunol.1999 Dec 15;198(2):111-9.
20. Imagawa Y, Satake K, Kato Y, Tahara H, Tsukuda M. Antitumor and antiangiogenic effects of interleukin 12 gene therapy in murine head and neck carcinoma model. Auris Nasus Larynx.2004 Sep;31(3):239-45.
21. Yao L, Sgadari C, Furuke K, Bloom ET, Teruya-Feldstein J, Tosato G Contribution of natural killer cells to inhibition of angiogenesis by interleukin-12. Blood.1999 Mar 1;93(5):1612-21.
22. Zabala M, Lasarte JJ, Perret C, Sola J, Berraondo P, Alfaro M, et al. Induction of immunosuppressive molecules and regulatory T cells counteracts the antitumor effect of interleukin-12-based gene therapy in a transgenic mouse model of liver cancer. J Hepatol.2007 Dec;47(6):807-15.
23. Leonard JP, Sherman ML, Fisher GL, Buchanan LJ, Larsen G, Atkins MB, et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood.1997 Oct 1;90(7):2541-8.
24. Chen L, Chen D, Block E, O'Donnell M, Kufe DW, Clinton SK. Eradication of murine bladder carcinoma by intratumor injection of a bicistronic adenoviral vector carrying cDNAs for the IL-12 heterodimer and its inhibition by the IL-12 p40 subunit homodimer. J Immunol.1997 Jul 1;159(1):351-9.
25. Kim YI, Chung JW, Park JH, Han JK, Hong JW, Chung H. Intraarterial gene delivery in rabbit hepatic tumors:transfection with nonviral vector by using iodized oil emulsion. Radiology.2006 Sep;240(3):771-7.
26. Zheng F, Shi XW, Yang GF, Gong LL, Yuan HY, Cui YJ, et al. Chitosan nanoparticle as gene therapy vector via gastrointestinal mucosa administration: results of an in vitro and in vivo study. Life Sci.2007 Jan 2;80(4):388-96.
27. Hattori Y, Ding WX, Maitani Y. Highly efficient cationic hydroxyethylated cholesterol-based nanoparticle-mediated gene transfer in vivo and in vitro in prostate carcinoma PC-3 cells. J Control Release.2007 Jul 16;120(1-2):122-30.
28. Chen J, Tian B, Yin X, Zhang Y, Hu D, Hu Z, et al. Preparation, characterization and transfection efficiency of cationic PEGylated PLA nanoparticles as gene delivery systems. J Biotechnol.2007 Jun 15;130(2):107-13.
29. Yoo HS, Lee JE, Chung H, Kwon IC, Jeong SY. Self-assembled nanoparticles containing hydrophobically modified glycol chitosan for gene delivery. J Control Release.2005 Mar 2;103(1):235-43.
30. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology.2002 May;35(5):1164-71.
31. Andrews KJ, Ribas A, Butterfield LH, Vollmer CM, Eilber FC, Dissette VB, et al. Adenovirus-interleukin-12-mediated tumor regression in a murine hepatocellular carcinoma model is not dependent on CDl-restricted natural killer T cells. Cancer Res.2000 Nov 15;60(22):6457-64.
32. Uehara K, Ichida T, Sugahara S, Ishikawa T, Yamagiwa S, Yoshida Y, et al. Systemic administration of liposome-encapsulated OK-432 prolongs the survival of rats with hepatocellular carcinoma through the induction of IFN-gamma-producing hepatic lymphocytes. J Gastroenterol Hepatol.2002 Jan;17(1):81-90.
33. Oka M, Hazama S, Yoshino S, Shimoda K, Suzuki M, Shimizu R, et al. Intraarterial combined immunochemotherapy for unresectable hepatocellular carcinoma:preliminary results. Cancer Immunol Immunother.1994 Mar;38(3):194-200.
34. Nio Y, Nagami H, Tamura K, Tsubono M, Nio M, Sato M, et al. Multi-institutional randomized clinical study on the comparative effects of intracavital chemotherapy alone versus immunotherapy alone versus immunochemotherapy for malignant effusion. Br J Cancer.1999 May;80(5-6):775-85.
1.李玉林等.病理学(第六版)；2004.
2. Bozorgzadeh A, Orloff M, Abt P, Tsoulfas G, Younan D, Kashyap R, et al. Survival outcomes in liver transplantation for hepatocellular carcinoma, comparing impact of hepatitis C versus other etiology of cirrhosis. Liver Transpl. 2007 Jun;13(6):807-13.
3. Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta LA. Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci.2002 Jun;963:13-20.
4. Tang ZY. A new concept on the natural course of hepatocellular carcinoma. Chin Med J (Engl).1981 Sep;94(9):585-8.
5. Sheu JC, Sung JL, Chen DS, Yang PM, Lai MY, Lee CS, et al. Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications. Gastroenterology.1985 Aug;89(2):259-66.
6.廖彩霞.原发性肝癌的自然病程观察.肝胆外科杂志.1997；5(4)：236-8.
7. Bober J, Samek P. Surgery of the tumours of the liver. Bratisl Lek Listy. 2002;103(11):403-7.
8. Yu AS, Keeffe EB. Management of hepatocellular carcinoma. Rev Gastroenterol Disord.2003 Winter;3(1):8-24.
9.钦伦秀,孙惠川,汤钊猷.原发性肝癌研究进展—2006沪港国际肝病大会纪要.中华外科杂志.2006；44(15)：1070-5.
10.汤钊猷.从肝癌看癌症临床研究.癌症.2009；29(1)：1-4.
11.吴孟超.肝癌外科治疗的现状和前景.中华肝胆外科杂志.2006；12(1)：1-4.
12. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med.2006 Aug;12(8):939-44.
13. Nieters A, Yuan JM, Sun CL, Zhang ZQ, Stoehlmacher J, Govindarajan S, et al. Effect of cytokine genotypes on the hepatitis B virus-hepatocellular carcinoma association. Cancer.2005 Feb 15;103(4):740-8.
14. Sun HC, Zhang W, Qin LX, Zhang BH, Ye QH, Wang L, et al. Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol.2007 Nov;47(5):684-90.
15.陈孝平,裘法祖,吴在德.原发性肝癌要按个体化采用以手术为主的综合治疗.中华外科杂志.2003；41(3)：161-2.
16. Doyon D, Mouzon A, Jourde AM, Regensberg C, Frileux C. [Hepatic, arterial embolization in patients with malignant liver tumours (author's transl)]. Ann Radiol (Paris).1974 Oct;17(6):593-603.
17. Maataoui A, Qian J, Vossoughi D, Khan MF, Oppermann E, Bechstein WO, et al. Transarterial chemoembolization alone and in combination with other therapies:a comparative study in an animal HCC model. Eur Radiol.2005 Jan;15(1):127-33.
18. Achenbach T, Seifert JK, Pitton MB, Schunk K, Junginger T. Chemoembolization for primary liver cancer. Eur J Surg Oncol.2002 Feb;28(1):37-41.
19. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma:a randomised controlled trial. Lancet.2002 May 18;359(9319):1734-9.
20. Breedis C, Young G The blood supply of neoplasms in the liver. Am J Pathol. 1954 Sep-Oct;30(5):969-77.
21. Trevisani F, D'Intino PE, Caraceni P, Pizzo M, Stefanini GF, Mazziotti A, et al. Etiologic factors and clinical presentation of hepatocellular carcinoma. Differences between cirrhotic and noncirrhotic Italian patients. Cancer.1995 May 1;75(9):2220-32.
22. Ramsey DE, Kernagis LY, Soulen MC, Geschwind JF. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol.2002 Sep;13(9 Pt 2):S211-21.
23. Matsui O, Kadoya M, Yoshikawa J, Gabata T, Takashima T, Demachi H. Subsegmental transcatheter arterial embolization for small hepatocellular carcinomas:local therapeutic effect and 5-year survival rate. Cancer Chemother Pharmacol.1994;33 Suppl:S84-8.
24. Eurvilaichit C. Outcome of transcatheter oily chemoembolization in patients with hepatocellular carcinoma. Hepatogastroenterology.2004 Jan-Feb;51(55):20-4.
25. Lau WY, Yu SC, Lai EC, Leung TW. Transarterial chemoembolization for hepatocellular carcinoma. J Am Coll Surg.2006 Jan;202(1):155-68.
26. Li C, Shi Z, Hao Y. [Combined percutaneous ethanol injection through liver puncture and transcatheter hepatic arterial chemoembolization for hepatocellular carcinoma]. Zhonghua Zhong Liu Za Zhi.2001 Nov;23(6):490-2.
27. Kamada K, Kitamoto M, Aikata H, Kawakami Y, Kono H, Imamura M, et al. Combination of transcatheter arterial chemoembolization using cisplatin-lipiodol suspension and percutaneous ethanol injection for treatment of advanced small hepatocellular carcinoma. Am J Surg.2002 Sep;184(3):284-90.
28.曹海利,孟巍,白彬.肝癌基因治疗研究新进展.介入放射学杂志.2008；17(5)：375-8.
29. Xu GW, Sun ZT, Forrester K, Wang XW, Coursen J, Harris CC. Tissue-specific growth suppression and chemosensitivity promotion in human hepatocellular carcinoma cells by retroviral-mediated transfer of the wild-type p53 gene. Hepatology.1996 Nov;24(5):1264-8.
30. Cheng J, Leng X, Peng J. [Construction of a hepatoma-targeting vector of adeno-associated virus containing human alpha-fetoprotein promoter and wild p53 gene in gene therapy of liver cancer]. Zhonghua Yi Xue Za Zhi.2000 Jun;80(6):461-3.
31. Okimoto T, Yahata H, Itou H, Shinozaki K, Tanji H, Sakaguchi T, et al. Safety and growth suppressive effect of intra-hepatic arterial injection of AdCMV-p53 combined with CDDP to rat liver metastatic tumors. J Exp Clin Cancer Res.2003 Sep;22(3):399-406.
32. Moolten FL. Drug sensitivity ("suicide") genes for selective cancer chemotherapy. Cancer Gene Ther.1994 Dec;1(4):279-87.
33. Qian C, Bilbao R, Bruna O, Prieto J. Induction of sensitivity to ganciclovir in human hepatocellular carcinoma cells by adenovirus-mediated gene transfer of herpes simplex virus thymidine kinase. Hepatology.1995 Jul;22(1):118-23.
34. Qian C, Idoate M, Bilbao R, Sangro B, Bruna O, Vazquez J, et al. Gene transfer and therapy with adenoviral vector in rats with diethylnitrosamine-induced hepatocellular carcinoma. Hum Gene Ther.1997 Feb 10;8(3):349-58.
35. Brand K, Arnold W, Bartels T, Lieber A, Kay MA, Strauss M, et al. Liver-associated toxicity of the HSV-tk/GCV approach and adenoviral vectors. Cancer Gene Ther.1997 Jan-Feb;4(1):9-16.
36. Huber BE, Richards CA, Krenitsky TA. Retroviral-mediated gene therapy for the treatment of hepatocellular carcinoma:an innovative approach for cancer therapy. Proc Natl Acad Sci U S A.1991 Sep 15;88(18):8039-43.
37. Lu SQ, Liu YS, Yang H. [Effects of CD/5-FC suicide gene therapy system on human malignant glioma cells in vitro]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2004 Apr;29(2):174-6,80.
38. Xie Y, Gilbert JD, Kim JH, Freytag SO. Efficacy of adenovirus-mediated CD/5-FC and HSV-1 thymidine kinase/ganciclovir suicide gene therapies concomitant with p53 gene therapy. Clin Cancer Res.1999 Dec;5(12):4224-32.
39. Huang XM, Wei SG, Wang LF. [Reversal of malignant phenotype of human hepatoma cells by antisense c-ets-2, c-myc and N-ras]. Zhonghua Zhong Liu Za Zhi.1994 Jul;16(4):243-6.
40. Maret A, Galy B, Arnaud E, Bayard F, Prats H. Inhibition of fibroblast growth factor 2 expression by antisense RNA induced a loss of the transformed phenotype in a human hepatoma cell line. Cancer Res.1995 Nov 1;55(21):5075-9.
41. Taouis M, Dupont J, Gillet A, Derouet M, Simon J. Insulin receptor substrate 1 antisense expression in an hepatoma cell line reduces cell proliferation and induces overexpression of the Src homology 2 domain and collagen protein (SHC). Mol Cell Endocrinol.1998 Feb;137(2):177-86.
42. Mercola D, Cohen JS. Antisense approaches to cancer gene therapy. Cancer Gene Ther.1995 Mar;2(1):47-59.
43. Ellouk-Achard S, Djenabi S, De Oliveira GA, Desauty G, Duc HT, Zohair M, et al. Induction of apoptosis in rat hepatocarcinoma cells by expression of IGF-I antisense c-DNA. J Hepatol.1998 Nov;29(5):807-18.
44. Chouaib S, Asselin-Paturel C, Mami-Chouaib F, Caignard A, Blay JY. The host-tumor immune conflict:from immunosuppression to resistance and destruction. Immunol Today.1997 Oct;18(10):493-7.
45. Komita H, Homma S, Saotome H, Zeniya M, Ohno T, Toda G Interferon-gamma produced by interleukin-12-activated tumor infiltrating CD8+T cells directly induces apoptosis of mouse hepatocellular carcinoma. J Hepatol. 2006 Nov;45(5):662-72.
46. Nishi N, van der Vliet HJ, Koezuka Y, von Blomberg BM, Scheper RJ, Pinedo HM, et al. Synergistic effect of KRN7000 with interleukin-15,-7, and -2 on the expansion of human V alpha 24+V beta 11+ T cells in vitro. Hum Immunol.2000 Apr;61(4):357-65.
47. Sangro B, Melero I, Qian C, Prieto J. Gene therapy of cancer based on interleukin 12. Curr Gene Ther.2005 Dec;5(6):573-81.
48. Chang CM, Lo CH, Shih YM, Chen Y, Wu PY, Tsuneyama K, et al. Treatment of Metastatic Hepatocellular Carcinoma by Adeno-associated Virus Encoding Interleukin-15 Superagonist. Hum Gene Ther.2010 Jan 11.
49. Robertson MJ, Mier JW, Logan T, Atkins M, Koon H, Koch KM, et al. Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin Cancer Res.2006 Jul 15;12(14 Pt 1):4265-73.
50. Kishida T, Asada H, Itokawa Y, Cui FD, Shin-Ya M, Gojo S, et al. Interleukin (IL)-21 and IL-15 genetic transfer synergistically augments therapeutic antitumor immunity and promotes regression of metastatic Iymphoma. Mol Ther.2003 Oct;8(4):552-8.
51. Reay J, Kim SH, Lockhart E, Kolls J, Robbins PD. Adenoviral-mediated, intratumor gene transfer of interleukin 23 induces a therapeutic antitumor response. Cancer Gene Ther. 2009 Oct;16(10):776-85.
52. Zhang KJ, Wang YG, Cao X, Zhong SY, Wei RC, Wu YM, et al. Potent antitumor effect of interleukin-24 gene in the survivin promoter and retinoblastoma double-regulated oncolytic adenovirus. Hum Gene Ther.2009 Aug;20(8):818-30.
53. Mushinski JF, Nguyen P, Stevens LM, Khanna C, Lee S, Chung EJ, et al. Inhibition of tumor cell motility by the interferon-inducible GTPase MxA. J Biol Chem.2009 May 29;284(22):15206-14.
54. Yano H. Inhibitory function of interferon on hepatocarcinogenesis. Oncology. 2008;75 Suppl 1:22-9.
55. Zhu Y, Tibensky I, Schmidt J, Ryschich E, Marten A. Interferon-alpha enhances antitumor effect of chemotherapy in an orthotopic mouse model for pancreatic adenocarcinoma. J Immunother.2008 Sep;31(7):599-606.
56. Kohashi S, Sato Y, Fukushima T, Shomura H, Oshima T, Bairun S, et al. Interferon-beta inhibits liver metastases from murine colon 26 carcinoma and its highly metastatic variant. Surg Today.2007;37(6):474-81.
57. Lejeune FJ, Lienard D, Matter M, Ruegg C. Efficiency of recombinant human TNF in human cancer therapy. Cancer Immun.2006;6:6.
58. Chen XP, He SQ, Wang HP, Zhao YZ, Zhang WG Expression of TNF-related apoptosis-inducing Ligand receptors and antitumor tumor effects of TNF-related apoptosis-inducing Ligand in human hepatocellular carcinoma. World J Gastroenterol.2003 Nov;9(11):2433-40.
59. Chang CJ, Chen YH, Huang KW, Cheng HW, Chan SF, Tai KF, et al. Combined GM-CSF and IL-12 gene therapy synergistically suppresses the growth of orthotopic liver tumors. Hepatology.2007 Mar;45(3):746-54.
60. Berraondo P, Prieto J, Gonzalez-Aseguinolaza G Advances in interleukin-12 gene therapy for acquired liver diseases. Curr Gene Ther.2009 Apr;9(2):62-71.
61. Tatsumi T, Takehara T, Kanto T, Miyagi T, Kuzushita N, Sugimoto Y, et al. Administration of interleukin-12 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines in mouse hepatocellular carcinoma. Cancer Res.2001 Oct 15;61(20):7563-7.
62. Peng LS, Penichet ML, Dela Cruz JS, Sampogna SL, Morrison SL. Mechanism of antitumor activity of a single-chain interleukin-12 IgG3 antibody fusion protein (mscIL-12.her2.IgG3). J Interferon Cytokine Res.2001 Sep;21(9):709-20.
63. Sumimoto H, Tani K, Nakazaki Y, Tanabe T, Hibino H, Wu MS, et al. Superiority of interleukin-12-transduced murine lung cancer cells to GM-CSF or B7-1 (CD80) transfectants for therapeutic antitumor immunity in syngeneic immunocompetent mice. Cancer Gene Then 1998 Jan-Feb;5(1):29-37.
64. Sgadari C, Angiolillo AL, Tosato G Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood.1996 May 1;87(9):3877-82.
65. Coca S, Enrech S, Moreno Garcia V, Saez MA, Gutierrez C, Colmenarejo A, et al. Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1,2 dimethyl-hydrazine (DMH). Rev Esp Enferm Dig.2005 Sep;97(9):619-28.
66. Del Vecchio M, Bajetta E, Canova S, Lotze MT, Wesa A, Parmiani G, et al. Interleukin-12:biological properties and clinical application. Clin Cancer Res. 2007 Aug 15;13(16):4677-85.
67. Duda DG, Sunamura M, Lozonschi L, Kodama T, Egawa S, Matsumoto G, et al. Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12. Cancer Res.2000 Feb 15;60(4):1111-6.
68. Waehler R, Ittrich H, Mueller L, Krupski G, Ameis D, Schnieders F. Low-dose adenoviral immunotherapy of rat hepatocellular carcinoma using single-chain interleukin-12. Hum Gene Ther.2005 Mar;16(3):307-17.
69. Schirrmacher V, Fournier P. Newcastle disease virus:a promising vector for viral therapy, immune therapy, and gene therapy of cancer. Methods Mol Biol. 2009;542:565-605.
70. Liu JY, Zhu Q, Li J, Zhao S, Li L. The retrovirus-mediated antisense human telomerase RNA (hTR) gene limits the growth of hepatocellular carcinoma growth in cell culture and animals. Dig Dis Sci.2008 Apr;53(4):1122-30.
71. Mao CY, Hua HJ, Chen P, Yu DC, Cao J, Teng LS. Combined use of chemotherapeutics and oncolytic adenovirus in treatment of AFP-expressing hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int.2009 Jun;8(3):282-7.
72. Evans RK, Nawrocki DK, Isopi LA, Williams DM, Casimiro DR, Chin S, et al. Development of stable liquid formulations for adenovirus-based vaccines. J Pharm Sci.2004 Oct;93(10):2458-75.
73. Ferrari FK, Samulski T, Shenk T, Samulski RJ. Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J Virol.1996 May;70(5):3227-34.
74. Chai N, Chang HE, Nicolas E, Gudima S, Chang J, Taylor J. Assembly of hepatitis B virus envelope proteins onto a lentivirus pseudotype that infects primary human hepatocytes. J Virol.2007 Oct;81(20):10897-904.
75. Topf N, Worgall S, Hackett NR, Crystal RG. Regional 'pro-drug' gene therapy:intravenous administration of an adenoviral vector expressing the E. coli cytosine deaminase gene and systemic administration of 5-fluorocytosine suppresses growth of hepatic metastasis of colon carcinoma. Gene Ther.1998 Apr;5(4):507-13.
76. Atkins MB, Robertson MJ, Gordon M, Lotze MT, DeCoste M, DuBois JS, et al. Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res.1997 Mar;3(3):409-17.
77. Wang L, Hernandez-Alcoceba R, Shankar V, Zabala M, Kochanek S, Sangro B, et al. Prolonged and inducible transgene expression in the liver using gutless adenovirus:a potential therapy for liver cancer. Gastroenterology.2004 Jan;126(1):278-89.
78. Shiotani M, Ku Y, Kusunoki N, Kitagawa T, Maeda I, Tominaga M, et al. [Pharmacokinetic comparison of intraarterial and intraportal infusion of adriamycin in regional chemotherapy of the liver]. Gan To Kagaku Ryoho.1995 Sep;22(11):1560-2.
79. Anderson SC, Johnson DE, Harris MP, Engler H, Hancock W, Huang WM, et al. p53 gene therapy in a rat model of hepatocellular carcinoma:intra-arterial delivery of a recombinant adenovirus. Clin Cancer Res.1998 Jul;4(7):1649-59.
80. Kim YI, Chung JW, Park JH, Han JK, Hong JW, Chung H. Intraarterial gene delivery in rabbit hepatic tumors:transfection with nonviral vector by using iodized oil emulsion. Radiology.2006 Sep;240(3):771-7.
81. Ma H, Liu YX, Liu SL, Xu RA, Zheng DX. [Expression of TRAIL(114-281) mediated by adeno-associated virus and its tumoricidal activity]. Zhonghua Yi Xue Za Zhi.2004 Oct 2;84(19):1635-41.
82. Jiang YF, Ma J, He Y, Zhang YH, Xu Y, Gong GZ. Cationic liposome-mediated transfection of CD40 ligand gene inhibits hepatic tumor growth of hepatocellular carcinoma in mice. J Zhejiang Univ Sci B.2009 Jan;10(1):7-13.
2. Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med.1989 Sep 1;170(3):827-45.
3. Chizzonite R, Truitt T, Podlaski FJ, Wolitzky AG, Quinn PM, Nunes P, et al. IL-12:monoclonal antibodies specific for the 40-kDa subunit block receptor binding and biologic activity on activated human lymphoblasts. J Immunol.1991 Sep 1;147(5):1548-56.
4. Tone Y, Thompson SA, Babik JM, Nolan KF, Tone M, Raven C, et al. Structure and chromosomal location of the mouse interleukin-12 p35 and p40 subunit genes. Eur J Immunol.1996 Jun;26(6):1222-7.
5. Marchant A, Amedei A, Azzurri A, Vekemans J, Benagiano M, Tamburini C, et al. Polarization of PPD-specific T-cell response of patients with tuberculosis from ThO to Thl profile after successful antimycobacterial therapy or in vitro conditioning with interferon-alpha or interleukin-12. Am J Respir Cell Mol Biol.2001 Feb;24(2):187-94.
6. Sumimoto H, Tani K, Nakazaki Y, Tanabe T, Hibino H, Wu MS, et al. Superiority of interleukin-12-transduced murine lung cancer cells to GM-CSF or B7-1 (CD80) transfectants for therapeutic antitumor immunity in syngeneic immunocompetent mice. Cancer Gene Ther.1998 Jan-Feb;5(1):29-37.
7. Sgadari C, Angiolillo AL, Tosato G. Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood.1996 May 1;87(9):3877-82.
8. Sangro B, Melero I, Qian C, Prieto J. Gene therapy of cancer based on interleukin 12. Curr Gene Ther.2005 Dec;5(6):573-81.
9. Wang XH, Yang JM, Cui ZF, Wang WG, Wu MC, Qian QJ. [In vitro gene therapy of hepatocellular carcinoma using replication-defective and tumor-specific replication-competent adenovirus carrying interleukin-12 gene]. Zhonghua Zhong Liu Za Zhi.2004 Oct;26(10):581-4.
10. Goto T, Nishi T, Kobayashi O, Tamura T, Dev SB, Takeshima H, et al. Combination electro-gene therapy using herpes virus thymidine kinase and interleukin-12 expression plasmids is highly efficient against murine carcinomas in vivo. Mol Ther.2004 Nov;10(5):929-37.
11.羊东晔,卢放根,汤熙翔等.人白细胞介素12双亚基共表达载体的构建及表达.中国免疫学杂志.2004；20(2)：79-82.
12.羊东晔,卢放根,赵水平等.人白细胞介素12双亚基共表达真核载体的构建.湖南医科大学学报.2003；28(4)：338-42.
13. Arai K, Ohkuma S, Matsukawa T, Kato S. A simple estimation of peroxisomal degradation with green fluorescent protein-an application for cell cycle analysis. FEBS Lett.2001 Oct 26;507(2):181-6.
14. Tomohide Tatsumi, Tetsuo Takehara, Tatsuya Kanto, et al. Administration of Interleukin-12 Enhances the Therapeutic Efficacy of Dendritic Cell-based Tumor Vaccines in Mouse Hepatocellular carcinoma. Cancer Research.2001; 61:7563-7567.
15. Hideo Komita, Sadamu Hommal, Hideo Saotome, Mikio Zeniya, Tsuneya Ohnol, Gotaro Toda. Interferon-gamma produced by interleukin-12-activated tumor infiltrating CD8+T cells directly induces apoptosis of mouse hepatocellular carcinoma. Journal of Hepatology.2006;45:662-672
1 ZHENG CS,FENG GS,ZHANG YF. Bletilla colloid as a vascular embolization agent:experimental studies[J]. Chin J Radiol(中华放射学杂志),1998,32(3):188-191.
2 LI WY,FENG GS,ZHENG CS. Pharmacokinetics of 5-Fu Bletilla Microspheres Following Renal Arterial Embolization in Rabbits[J]. Acta Universitatis Medictnae Tongjil(同济医科大学学报),2001,30(5)：501-503.
3 FENG GS,LI X,ZHENG CS,et al. Mechanism of inhibition of tumor angiogenesis by Bletilla colloid: an experimental study[J]. Natl Med J China(中华医学杂志),2003,83(5)：412-416.
4 WANG CM, SUN JT,LUO Y. A polysaccharide isolated from the medicinal herb Bletilla striata induces endothelial cells proliferation and vascular endothelial growth factor expression in vitro[J]. Biotechnology Letters,2006,28(8):539-543.
5 Tony Azzam,Hagit Eliyahu,Libi Shapira. Polysaccharide-Oligoamine Based Conjugates for Gene Delivery[J]. J Med Chem,2002,45(9):1817-1824.
6 I YUDOVIN-FARBER, AJ DOMB. Cationic polysaccharides for gene delivery[J]. Materials Science and Engineering,2007.595-598.
7 Snyder S. L,Sobocinski, P. Z. An improved 2,4,6-trinitrobenzenesulfonic acid method for the determination of amines[J]. Anal Biochem,1975,64(1):284-288.
8 RUI HY,WU GR,CHEN JY. Isolation,Purification and Structural Characterizationof Neutral Heteropolysaccharide from Bletilla striata[J]. Journal of Anhui Agricultural University(安徽农业大学学报),2004,31(1)：30-33.
9 Park IK,IhmJE,Park YH, et al. Galactosylated chitosan (GC)-graft-poly(viny pyrrolidone) as hepatocyte-targeting DNA carrier preparation and physiochemical characterization of (GC)-graft-PVP/ DNA complex[J]. J Controlled Release,2003,86(2):349-359.
10 Anderson, W. F. Human gene therapy[J]. Science,1992,256(5058):808-813.
11 Aoki K,Yoshida T,Sugimura T,Terada. Liposome-mediated in vivo gene transfer
of antisence K-ras construct inhibits pancreatic tumor dissemination in the murine peritoneal cavity[J]. Cancer Res,1995,55(9):3810-3816.
12 Saleh M,Wiegmans A,Malone Q,Stylli S S,Kaye A H. Effect of in situ Retroviral Interleukin-4 Transfer on Established Intracranial Tumors [J]. J Natl Cancer Inst, 1999,91(5):438-445.
13 De Smedt SC,Demeester J,Hennink WE. Cationic polymer based gene delivery systems[J]. Pharm Res,2000,17(2):113-125.
1. Bozorgzadeh A, Orloff M, Abt P, Tsoulfas G, Younan D, Kashyap R, et al. Survival outcomes in liver transplantation for hepatocellular carcinoma, comparing impact of hepatitis C versus other etiology of cirrhosis. Liver Transpl. 2007 Jun;13(6):807-13.
2. Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta LA. Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci.2002 Jun;963:13-20.
3. Yu AS, Keeffe EB. Management of hepatocellular carcinoma. Rev Gastroenterol Disord.2003 Winter;3(1):8-24.
4. Alsowmely AM, Hodgson HJ. Non-surgical treatment of hepatocellular carcinoma. Aliment Pharmacol Ther.2002 Jan;16(1):1-15.
5. Maataoui A, Qian J, Vossoughi D, Khan MF, Oppermann E, Bechstein WO, et al. Transarterial chemoembolization alone and in combination with other therapies:a comparative study in an animal HCC model. Eur Radiol.2005 Jan;15(1):127-33.
6. Doyon D, Mouzon A, Jourde AM, Regensberg C, Frileux C. [Hepatic, arterial embolization in patients with malignant liver tumours (author's transl)]. Ann Radiol (Paris).1974 Oct;17(6):593-603.
7. Achenbach T, Seifert JK, Pitton MB, Schunk K, Junginger T. Chemoembolization for primary liver cancer. Eur J Surg Oncol.2002 Feb;28(1):37-41.
8. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma:a randomised controlled trial. Lancet.2002 May 18;359(9319):1734-9.
9. Qian C, Drozdzik M, Caselmann WH, Prieto J. The potential of gene therapy in the treatment of hepatocellular carcinoma. J Hepatol.2000 Feb;32(2):344-51.
10. Stefani AL, Barzon L, Castagliuolo I, Guido M, Pacenti M, Parolin C, et al. Systemic efficacy of combined suicide/cytokine gene therapy in a murine model of hepatocellular carcinoma. J Hepatol.2005 May;42(5):728-35.
11. Xia Xiangwen LX, Feng Gansheng et al Construction and Expression of a Human Interleukin 12 Double-submit Co-expressing Eukarya Plasmid pEGFP-C1_IL-12. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong.2009(1).
12. XIA Xiang-wen LX, FENG Gan-sheng et al. Preparation and Characterization of a Non-viral Gene Vector from a Polysaccharide Isolated from the Chinese Medicinal Herb Bletilla striata. Chinese Pharmaceutical Journal.2008(18).
13. Xiang-Wen Xia XL, Gan-Sheng Feng et al. Feasibility of a polysaccharide isolated from Bletilla striata used as a gene vector administered through an interventional pathway. World Chinese Journal of Digestology.2009(18).
14. Park YN, Kim YB, Yang KM, Park C. Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis. Arch Pathol Lab Med.2000 Jul;124(7):1061-5.
15. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med.1991 Jan 3;324(1):1-8.
16. Katiyar SK. Interleukin-12 and photocarcinogenesis. Toxicol Appl Pharmacol.2007 Nov 1;224(3):220-7.
17. Kanagawa N, Gao JQ, Motomura Y, Yanagawa T, Mukai Y, Yoshioka Y, et al. Antitumor mechanism of intratumoral injection with IL-12-expressing adenoviral vector against IL-12-unresponsive tumor. Biochem Biophys Res Commun.2008 Aug 8;372(4):821-5.
18. Barajas M, Mazzolini G, Genove G, Bilbao R, Narvaiza I, Schmitz V, et al. Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12. Hepatology.2001 Jan;33(1):52-61.
19. Otani T, Nakamura S, Toki M, Motoda R, Kurimoto M, Orita K. Identification of IFN-gamma-producing cells in IL-12/IL-18-treated mice. Cell Immunol.1999 Dec 15;198(2):111-9.
20. Imagawa Y, Satake K, Kato Y, Tahara H, Tsukuda M. Antitumor and antiangiogenic effects of interleukin 12 gene therapy in murine head and neck carcinoma model. Auris Nasus Larynx.2004 Sep;31(3):239-45.
21. Yao L, Sgadari C, Furuke K, Bloom ET, Teruya-Feldstein J, Tosato G Contribution of natural killer cells to inhibition of angiogenesis by interleukin-12. Blood.1999 Mar 1;93(5):1612-21.
22. Zabala M, Lasarte JJ, Perret C, Sola J, Berraondo P, Alfaro M, et al. Induction of immunosuppressive molecules and regulatory T cells counteracts the antitumor effect of interleukin-12-based gene therapy in a transgenic mouse model of liver cancer. J Hepatol.2007 Dec;47(6):807-15.
23. Leonard JP, Sherman ML, Fisher GL, Buchanan LJ, Larsen G, Atkins MB, et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood.1997 Oct 1;90(7):2541-8.
24. Chen L, Chen D, Block E, O'Donnell M, Kufe DW, Clinton SK. Eradication of murine bladder carcinoma by intratumor injection of a bicistronic adenoviral vector carrying cDNAs for the IL-12 heterodimer and its inhibition by the IL-12 p40 subunit homodimer. J Immunol.1997 Jul 1;159(1):351-9.
25. Kim YI, Chung JW, Park JH, Han JK, Hong JW, Chung H. Intraarterial gene delivery in rabbit hepatic tumors:transfection with nonviral vector by using iodized oil emulsion. Radiology.2006 Sep;240(3):771-7.
26. Zheng F, Shi XW, Yang GF, Gong LL, Yuan HY, Cui YJ, et al. Chitosan nanoparticle as gene therapy vector via gastrointestinal mucosa administration: results of an in vitro and in vivo study. Life Sci.2007 Jan 2;80(4):388-96.
27. Hattori Y, Ding WX, Maitani Y. Highly efficient cationic hydroxyethylated cholesterol-based nanoparticle-mediated gene transfer in vivo and in vitro in prostate carcinoma PC-3 cells. J Control Release.2007 Jul 16;120(1-2):122-30.
28. Chen J, Tian B, Yin X, Zhang Y, Hu D, Hu Z, et al. Preparation, characterization and transfection efficiency of cationic PEGylated PLA nanoparticles as gene delivery systems. J Biotechnol.2007 Jun 15;130(2):107-13.
29. Yoo HS, Lee JE, Chung H, Kwon IC, Jeong SY. Self-assembled nanoparticles containing hydrophobically modified glycol chitosan for gene delivery. J Control Release.2005 Mar 2;103(1):235-43.
30. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology.2002 May;35(5):1164-71.
31. Andrews KJ, Ribas A, Butterfield LH, Vollmer CM, Eilber FC, Dissette VB, et al. Adenovirus-interleukin-12-mediated tumor regression in a murine hepatocellular carcinoma model is not dependent on CDl-restricted natural killer T cells. Cancer Res.2000 Nov 15;60(22):6457-64.
32. Uehara K, Ichida T, Sugahara S, Ishikawa T, Yamagiwa S, Yoshida Y, et al. Systemic administration of liposome-encapsulated OK-432 prolongs the survival of rats with hepatocellular carcinoma through the induction of IFN-gamma-producing hepatic lymphocytes. J Gastroenterol Hepatol.2002 Jan;17(1):81-90.
33. Oka M, Hazama S, Yoshino S, Shimoda K, Suzuki M, Shimizu R, et al. Intraarterial combined immunochemotherapy for unresectable hepatocellular carcinoma:preliminary results. Cancer Immunol Immunother.1994 Mar;38(3):194-200.
34. Nio Y, Nagami H, Tamura K, Tsubono M, Nio M, Sato M, et al. Multi-institutional randomized clinical study on the comparative effects of intracavital chemotherapy alone versus immunotherapy alone versus immunochemotherapy for malignant effusion. Br J Cancer.1999 May;80(5-6):775-85.
1.李玉林等.病理学(第六版)；2004.
2. Bozorgzadeh A, Orloff M, Abt P, Tsoulfas G, Younan D, Kashyap R, et al. Survival outcomes in liver transplantation for hepatocellular carcinoma, comparing impact of hepatitis C versus other etiology of cirrhosis. Liver Transpl. 2007 Jun;13(6):807-13.
3. Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta LA. Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci.2002 Jun;963:13-20.
4. Tang ZY. A new concept on the natural course of hepatocellular carcinoma. Chin Med J (Engl).1981 Sep;94(9):585-8.
5. Sheu JC, Sung JL, Chen DS, Yang PM, Lai MY, Lee CS, et al. Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications. Gastroenterology.1985 Aug;89(2):259-66.
6.廖彩霞.原发性肝癌的自然病程观察.肝胆外科杂志.1997；5(4)：236-8.
7. Bober J, Samek P. Surgery of the tumours of the liver. Bratisl Lek Listy. 2002;103(11):403-7.
8. Yu AS, Keeffe EB. Management of hepatocellular carcinoma. Rev Gastroenterol Disord.2003 Winter;3(1):8-24.
9.钦伦秀,孙惠川,汤钊猷.原发性肝癌研究进展—2006沪港国际肝病大会纪要.中华外科杂志.2006；44(15)：1070-5.
10.汤钊猷.从肝癌看癌症临床研究.癌症.2009；29(1)：1-4.
11.吴孟超.肝癌外科治疗的现状和前景.中华肝胆外科杂志.2006；12(1)：1-4.
12. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med.2006 Aug;12(8):939-44.
13. Nieters A, Yuan JM, Sun CL, Zhang ZQ, Stoehlmacher J, Govindarajan S, et al. Effect of cytokine genotypes on the hepatitis B virus-hepatocellular carcinoma association. Cancer.2005 Feb 15;103(4):740-8.
14. Sun HC, Zhang W, Qin LX, Zhang BH, Ye QH, Wang L, et al. Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol.2007 Nov;47(5):684-90.
15.陈孝平,裘法祖,吴在德.原发性肝癌要按个体化采用以手术为主的综合治疗.中华外科杂志.2003；41(3)：161-2.
16. Doyon D, Mouzon A, Jourde AM, Regensberg C, Frileux C. [Hepatic, arterial embolization in patients with malignant liver tumours (author's transl)]. Ann Radiol (Paris).1974 Oct;17(6):593-603.
17. Maataoui A, Qian J, Vossoughi D, Khan MF, Oppermann E, Bechstein WO, et al. Transarterial chemoembolization alone and in combination with other therapies:a comparative study in an animal HCC model. Eur Radiol.2005 Jan;15(1):127-33.
18. Achenbach T, Seifert JK, Pitton MB, Schunk K, Junginger T. Chemoembolization for primary liver cancer. Eur J Surg Oncol.2002 Feb;28(1):37-41.
19. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma:a randomised controlled trial. Lancet.2002 May 18;359(9319):1734-9.
20. Breedis C, Young G The blood supply of neoplasms in the liver. Am J Pathol. 1954 Sep-Oct;30(5):969-77.
21. Trevisani F, D'Intino PE, Caraceni P, Pizzo M, Stefanini GF, Mazziotti A, et al. Etiologic factors and clinical presentation of hepatocellular carcinoma. Differences between cirrhotic and noncirrhotic Italian patients. Cancer.1995 May 1;75(9):2220-32.
22. Ramsey DE, Kernagis LY, Soulen MC, Geschwind JF. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol.2002 Sep;13(9 Pt 2):S211-21.
23. Matsui O, Kadoya M, Yoshikawa J, Gabata T, Takashima T, Demachi H. Subsegmental transcatheter arterial embolization for small hepatocellular carcinomas:local therapeutic effect and 5-year survival rate. Cancer Chemother Pharmacol.1994;33 Suppl:S84-8.
24. Eurvilaichit C. Outcome of transcatheter oily chemoembolization in patients with hepatocellular carcinoma. Hepatogastroenterology.2004 Jan-Feb;51(55):20-4.
25. Lau WY, Yu SC, Lai EC, Leung TW. Transarterial chemoembolization for hepatocellular carcinoma. J Am Coll Surg.2006 Jan;202(1):155-68.
26. Li C, Shi Z, Hao Y. [Combined percutaneous ethanol injection through liver puncture and transcatheter hepatic arterial chemoembolization for hepatocellular carcinoma]. Zhonghua Zhong Liu Za Zhi.2001 Nov;23(6):490-2.
27. Kamada K, Kitamoto M, Aikata H, Kawakami Y, Kono H, Imamura M, et al. Combination of transcatheter arterial chemoembolization using cisplatin-lipiodol suspension and percutaneous ethanol injection for treatment of advanced small hepatocellular carcinoma. Am J Surg.2002 Sep;184(3):284-90.
28.曹海利,孟巍,白彬.肝癌基因治疗研究新进展.介入放射学杂志.2008；17(5)：375-8.
29. Xu GW, Sun ZT, Forrester K, Wang XW, Coursen J, Harris CC. Tissue-specific growth suppression and chemosensitivity promotion in human hepatocellular carcinoma cells by retroviral-mediated transfer of the wild-type p53 gene. Hepatology.1996 Nov;24(5):1264-8.
30. Cheng J, Leng X, Peng J. [Construction of a hepatoma-targeting vector of adeno-associated virus containing human alpha-fetoprotein promoter and wild p53 gene in gene therapy of liver cancer]. Zhonghua Yi Xue Za Zhi.2000 Jun;80(6):461-3.
31. Okimoto T, Yahata H, Itou H, Shinozaki K, Tanji H, Sakaguchi T, et al. Safety and growth suppressive effect of intra-hepatic arterial injection of AdCMV-p53 combined with CDDP to rat liver metastatic tumors. J Exp Clin Cancer Res.2003 Sep;22(3):399-406.
32. Moolten FL. Drug sensitivity ("suicide") genes for selective cancer chemotherapy. Cancer Gene Ther.1994 Dec;1(4):279-87.
33. Qian C, Bilbao R, Bruna O, Prieto J. Induction of sensitivity to ganciclovir in human hepatocellular carcinoma cells by adenovirus-mediated gene transfer of herpes simplex virus thymidine kinase. Hepatology.1995 Jul;22(1):118-23.
34. Qian C, Idoate M, Bilbao R, Sangro B, Bruna O, Vazquez J, et al. Gene transfer and therapy with adenoviral vector in rats with diethylnitrosamine-induced hepatocellular carcinoma. Hum Gene Ther.1997 Feb 10;8(3):349-58.
35. Brand K, Arnold W, Bartels T, Lieber A, Kay MA, Strauss M, et al. Liver-associated toxicity of the HSV-tk/GCV approach and adenoviral vectors. Cancer Gene Ther.1997 Jan-Feb;4(1):9-16.
36. Huber BE, Richards CA, Krenitsky TA. Retroviral-mediated gene therapy for the treatment of hepatocellular carcinoma:an innovative approach for cancer therapy. Proc Natl Acad Sci U S A.1991 Sep 15;88(18):8039-43.
37. Lu SQ, Liu YS, Yang H. [Effects of CD/5-FC suicide gene therapy system on human malignant glioma cells in vitro]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2004 Apr;29(2):174-6,80.
38. Xie Y, Gilbert JD, Kim JH, Freytag SO. Efficacy of adenovirus-mediated CD/5-FC and HSV-1 thymidine kinase/ganciclovir suicide gene therapies concomitant with p53 gene therapy. Clin Cancer Res.1999 Dec;5(12):4224-32.
39. Huang XM, Wei SG, Wang LF. [Reversal of malignant phenotype of human hepatoma cells by antisense c-ets-2, c-myc and N-ras]. Zhonghua Zhong Liu Za Zhi.1994 Jul;16(4):243-6.
40. Maret A, Galy B, Arnaud E, Bayard F, Prats H. Inhibition of fibroblast growth factor 2 expression by antisense RNA induced a loss of the transformed phenotype in a human hepatoma cell line. Cancer Res.1995 Nov 1;55(21):5075-9.
41. Taouis M, Dupont J, Gillet A, Derouet M, Simon J. Insulin receptor substrate 1 antisense expression in an hepatoma cell line reduces cell proliferation and induces overexpression of the Src homology 2 domain and collagen protein (SHC). Mol Cell Endocrinol.1998 Feb;137(2):177-86.
42. Mercola D, Cohen JS. Antisense approaches to cancer gene therapy. Cancer Gene Ther.1995 Mar;2(1):47-59.
43. Ellouk-Achard S, Djenabi S, De Oliveira GA, Desauty G, Duc HT, Zohair M, et al. Induction of apoptosis in rat hepatocarcinoma cells by expression of IGF-I antisense c-DNA. J Hepatol.1998 Nov;29(5):807-18.
44. Chouaib S, Asselin-Paturel C, Mami-Chouaib F, Caignard A, Blay JY. The host-tumor immune conflict:from immunosuppression to resistance and destruction. Immunol Today.1997 Oct;18(10):493-7.
45. Komita H, Homma S, Saotome H, Zeniya M, Ohno T, Toda G Interferon-gamma produced by interleukin-12-activated tumor infiltrating CD8+T cells directly induces apoptosis of mouse hepatocellular carcinoma. J Hepatol. 2006 Nov;45(5):662-72.
46. Nishi N, van der Vliet HJ, Koezuka Y, von Blomberg BM, Scheper RJ, Pinedo HM, et al. Synergistic effect of KRN7000 with interleukin-15,-7, and -2 on the expansion of human V alpha 24+V beta 11+ T cells in vitro. Hum Immunol.2000 Apr;61(4):357-65.
47. Sangro B, Melero I, Qian C, Prieto J. Gene therapy of cancer based on interleukin 12. Curr Gene Ther.2005 Dec;5(6):573-81.
48. Chang CM, Lo CH, Shih YM, Chen Y, Wu PY, Tsuneyama K, et al. Treatment of Metastatic Hepatocellular Carcinoma by Adeno-associated Virus Encoding Interleukin-15 Superagonist. Hum Gene Ther.2010 Jan 11.
49. Robertson MJ, Mier JW, Logan T, Atkins M, Koon H, Koch KM, et al. Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin Cancer Res.2006 Jul 15;12(14 Pt 1):4265-73.
50. Kishida T, Asada H, Itokawa Y, Cui FD, Shin-Ya M, Gojo S, et al. Interleukin (IL)-21 and IL-15 genetic transfer synergistically augments therapeutic antitumor immunity and promotes regression of metastatic Iymphoma. Mol Ther.2003 Oct;8(4):552-8.
51. Reay J, Kim SH, Lockhart E, Kolls J, Robbins PD. Adenoviral-mediated, intratumor gene transfer of interleukin 23 induces a therapeutic antitumor response. Cancer Gene Ther. 2009 Oct;16(10):776-85.
52. Zhang KJ, Wang YG, Cao X, Zhong SY, Wei RC, Wu YM, et al. Potent antitumor effect of interleukin-24 gene in the survivin promoter and retinoblastoma double-regulated oncolytic adenovirus. Hum Gene Ther.2009 Aug;20(8):818-30.
53. Mushinski JF, Nguyen P, Stevens LM, Khanna C, Lee S, Chung EJ, et al. Inhibition of tumor cell motility by the interferon-inducible GTPase MxA. J Biol Chem.2009 May 29;284(22):15206-14.
54. Yano H. Inhibitory function of interferon on hepatocarcinogenesis. Oncology. 2008;75 Suppl 1:22-9.
55. Zhu Y, Tibensky I, Schmidt J, Ryschich E, Marten A. Interferon-alpha enhances antitumor effect of chemotherapy in an orthotopic mouse model for pancreatic adenocarcinoma. J Immunother.2008 Sep;31(7):599-606.
56. Kohashi S, Sato Y, Fukushima T, Shomura H, Oshima T, Bairun S, et al. Interferon-beta inhibits liver metastases from murine colon 26 carcinoma and its highly metastatic variant. Surg Today.2007;37(6):474-81.
57. Lejeune FJ, Lienard D, Matter M, Ruegg C. Efficiency of recombinant human TNF in human cancer therapy. Cancer Immun.2006;6:6.
58. Chen XP, He SQ, Wang HP, Zhao YZ, Zhang WG Expression of TNF-related apoptosis-inducing Ligand receptors and antitumor tumor effects of TNF-related apoptosis-inducing Ligand in human hepatocellular carcinoma. World J Gastroenterol.2003 Nov;9(11):2433-40.
59. Chang CJ, Chen YH, Huang KW, Cheng HW, Chan SF, Tai KF, et al. Combined GM-CSF and IL-12 gene therapy synergistically suppresses the growth of orthotopic liver tumors. Hepatology.2007 Mar;45(3):746-54.
60. Berraondo P, Prieto J, Gonzalez-Aseguinolaza G Advances in interleukin-12 gene therapy for acquired liver diseases. Curr Gene Ther.2009 Apr;9(2):62-71.
61. Tatsumi T, Takehara T, Kanto T, Miyagi T, Kuzushita N, Sugimoto Y, et al. Administration of interleukin-12 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines in mouse hepatocellular carcinoma. Cancer Res.2001 Oct 15;61(20):7563-7.
62. Peng LS, Penichet ML, Dela Cruz JS, Sampogna SL, Morrison SL. Mechanism of antitumor activity of a single-chain interleukin-12 IgG3 antibody fusion protein (mscIL-12.her2.IgG3). J Interferon Cytokine Res.2001 Sep;21(9):709-20.
63. Sumimoto H, Tani K, Nakazaki Y, Tanabe T, Hibino H, Wu MS, et al. Superiority of interleukin-12-transduced murine lung cancer cells to GM-CSF or B7-1 (CD80) transfectants for therapeutic antitumor immunity in syngeneic immunocompetent mice. Cancer Gene Then 1998 Jan-Feb;5(1):29-37.
64. Sgadari C, Angiolillo AL, Tosato G Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood.1996 May 1;87(9):3877-82.
65. Coca S, Enrech S, Moreno Garcia V, Saez MA, Gutierrez C, Colmenarejo A, et al. Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1,2 dimethyl-hydrazine (DMH). Rev Esp Enferm Dig.2005 Sep;97(9):619-28.
66. Del Vecchio M, Bajetta E, Canova S, Lotze MT, Wesa A, Parmiani G, et al. Interleukin-12:biological properties and clinical application. Clin Cancer Res. 2007 Aug 15;13(16):4677-85.
67. Duda DG, Sunamura M, Lozonschi L, Kodama T, Egawa S, Matsumoto G, et al. Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12. Cancer Res.2000 Feb 15;60(4):1111-6.
68. Waehler R, Ittrich H, Mueller L, Krupski G, Ameis D, Schnieders F. Low-dose adenoviral immunotherapy of rat hepatocellular carcinoma using single-chain interleukin-12. Hum Gene Ther.2005 Mar;16(3):307-17.
69. Schirrmacher V, Fournier P. Newcastle disease virus:a promising vector for viral therapy, immune therapy, and gene therapy of cancer. Methods Mol Biol. 2009;542:565-605.
70. Liu JY, Zhu Q, Li J, Zhao S, Li L. The retrovirus-mediated antisense human telomerase RNA (hTR) gene limits the growth of hepatocellular carcinoma growth in cell culture and animals. Dig Dis Sci.2008 Apr;53(4):1122-30.
71. Mao CY, Hua HJ, Chen P, Yu DC, Cao J, Teng LS. Combined use of chemotherapeutics and oncolytic adenovirus in treatment of AFP-expressing hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int.2009 Jun;8(3):282-7.
72. Evans RK, Nawrocki DK, Isopi LA, Williams DM, Casimiro DR, Chin S, et al. Development of stable liquid formulations for adenovirus-based vaccines. J Pharm Sci.2004 Oct;93(10):2458-75.
73. Ferrari FK, Samulski T, Shenk T, Samulski RJ. Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J Virol.1996 May;70(5):3227-34.
74. Chai N, Chang HE, Nicolas E, Gudima S, Chang J, Taylor J. Assembly of hepatitis B virus envelope proteins onto a lentivirus pseudotype that infects primary human hepatocytes. J Virol.2007 Oct;81(20):10897-904.
75. Topf N, Worgall S, Hackett NR, Crystal RG. Regional 'pro-drug' gene therapy:intravenous administration of an adenoviral vector expressing the E. coli cytosine deaminase gene and systemic administration of 5-fluorocytosine suppresses growth of hepatic metastasis of colon carcinoma. Gene Ther.1998 Apr;5(4):507-13.
76. Atkins MB, Robertson MJ, Gordon M, Lotze MT, DeCoste M, DuBois JS, et al. Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res.1997 Mar;3(3):409-17.
77. Wang L, Hernandez-Alcoceba R, Shankar V, Zabala M, Kochanek S, Sangro B, et al. Prolonged and inducible transgene expression in the liver using gutless adenovirus:a potential therapy for liver cancer. Gastroenterology.2004 Jan;126(1):278-89.
78. Shiotani M, Ku Y, Kusunoki N, Kitagawa T, Maeda I, Tominaga M, et al. [Pharmacokinetic comparison of intraarterial and intraportal infusion of adriamycin in regional chemotherapy of the liver]. Gan To Kagaku Ryoho.1995 Sep;22(11):1560-2.
79. Anderson SC, Johnson DE, Harris MP, Engler H, Hancock W, Huang WM, et al. p53 gene therapy in a rat model of hepatocellular carcinoma:intra-arterial delivery of a recombinant adenovirus. Clin Cancer Res.1998 Jul;4(7):1649-59.
80. Kim YI, Chung JW, Park JH, Han JK, Hong JW, Chung H. Intraarterial gene delivery in rabbit hepatic tumors:transfection with nonviral vector by using iodized oil emulsion. Radiology.2006 Sep;240(3):771-7.
81. Ma H, Liu YX, Liu SL, Xu RA, Zheng DX. [Expression of TRAIL(114-281) mediated by adeno-associated virus and its tumoricidal activity]. Zhonghua Yi Xue Za Zhi.2004 Oct 2;84(19):1635-41.
82. Jiang YF, Ma J, He Y, Zhang YH, Xu Y, Gong GZ. Cationic liposome-mediated transfection of CD40 ligand gene inhibits hepatic tumor growth of hepatocellular carcinoma in mice. J Zhejiang Univ Sci B.2009 Jan;10(1):7-13.
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