顺铂微球肝动脉栓塞术治疗原发性肝癌的临床应用

目的：总结分析顺铂微球肝动脉栓塞术治疗原发性肝癌的临床疗效。材料与方法：临床顺铂微球肝动脉栓塞治疗肝癌１８例，男１４例，女４例，经选择性肝动脉插管注入顺铂微球５０ｍｇ～１００ｍｇ至肿瘤供血动脉，１８例共栓塞治疗４１次，其中治疗３次８例，２次７例，１次３例。结果：栓塞后ＤＳＡ动脉造影表现为肿瘤血管明显减少，消失，肿瘤染色变浅，缩小，肿瘤供血动脉变细，其它部位出现新病灶，肝动脉－门静脉瘘，肝动脉血流重新分配，无侧支形成，综合评价，显效８例，有效７例，稳定３例，随访生存２年４例，１年半５例，１年４例，半年３例，失访２例，结论：顺铂微球栓塞于小动脉，且于局部缓释出顺铂并保持高浓度具有化疗性栓塞作用，治疗肝癌疗效明显     

磁性顺铂微球经大鼠肝动脉栓塞的靶向分布研究

从大鼠肝动脉注大３０～１２５μｍ大小的磁性顺铂微球（以下简称ＭＣ－ｍＳ）。顺铂剂量为４ｍｇ／ｋｇ。微球中含药量５０％，载磁材量１０％，高分子多糖材料４０％。体外用５２００ＧＳ磁场导向。术后２ｈ，２４ｈ，２７ｈ，１６８ｈ采用无火焰原子吸收光谱法分别测量靶区（左肝）及非靶区（右肝）的铂含量。结果各组铂含量经ｔ检验均有显著差异，尤其是术后１６８ｈ，靶区含量高于非靶区含量约一倍。证明磁性顺铂微球具有良好的     

去甲斑蝥素微球介入治疗对大鼠肝癌细胞凋亡和细胞增殖相关基因表达影响的研究

目的：探讨去甲斑蝥素微球介入治疗对大鼠肝癌细胞增殖和凋亡相关基因表达的影响。方法：89只肝癌大鼠随机分组后，分别经肝动脉注入生理盐水，去甲斑蝥素，空白微球，去甲斑蝥素加碘油，去甲斑蝥素微球。治疗后每组取8只观察生存时间，治疗后第8天处死余下大鼠，取肿瘤组织采用TUNEL标记法检测细胞凋亡指数，免疫组化SP法检测肝癌组织caspase-3，bcl-2，Ki67的表达。结果：治疗后N-MS（去甲斑蝥微球）组大鼠生存期明显长于其他各组（P〈0．01）。NMS组凋亡指数和caspase-3阳性率均高于其他各组（P〈0．01）；NMS组bcl-2阳性率和Ki67表达率低于其他各组（P〈0．01）。结论：去甲斑蝥素微球介入治疗能够延长肝癌大鼠的生存期；其介入治疗肝癌的机制与抑制Ki-67、bcl-2基因表达，上调caspase-3表达，从而抑制肝癌细胞增殖和促进细胞凋亡有关。     

磁流体对肝癌细胞的凋亡诱导研究及联合紫杉醇对大鼠肝癌的抑制作用

不同浓度的磁性纳米颗粒作用于肝癌HepG2细胞后,检测其凋亡情况,并电镜观察细胞形态变化。制备抗肿瘤靶向药物紫杉醇白蛋白磁性纳米颗粒（MAG-TAX-NP）,将其联合碘化油治疗大鼠肝癌,观察治疗效果。方法：化学共沉淀法制备磁流体,将其作用于HepG2细胞,流式细胞仪检测细胞凋亡情况。电镜观察磁微球作用于肝癌HepG2细胞后的形态学变化。用乳化-超声-加热固化法制备紫杉醇磁性纳米颗粒。建立大鼠肝癌模型,将荷瘤大鼠30只随机分为5组,除空白对照组外,分别将碘化油﹑碘化油紫杉醇﹑碘化油纳米磁流体、碘化油紫杉醇白蛋白磁性纳米颗粒各0.2 mL注入其余4组大鼠肝固有动脉内。紫杉醇用量为5mg/kg体重,肝肿瘤区外加磁场,14d后处死大鼠,取肝肿瘤组织称重,计算各组抑瘤率。结果：证实了磁流体可诱导肝癌HepG2细胞凋亡。电镜下可见肿瘤细胞吞噬磁流体后细胞内形成凋亡小体,细胞裂解增加。大鼠肝癌模型中除空白对照组外,其余各组的抑瘤率分别为43.2%、51%、57.4%、87.4%。结论：磁微球可诱导肝癌HepG2细胞凋亡。碘化油紫杉醇白蛋白磁性纳米颗粒局部栓塞可抑制肿瘤生长,较其他组具有更强的抑瘤效果。随着深入研究,磁流体有望成为治疗肿瘤的方法,紫杉醇白蛋白磁性纳米颗粒可作为临床紫杉醇药物治疗肝癌的新剂型。     

化疗激素治疗不能手术切除的肝细胞癌

研究肝癌组织存在雌激素受体的新近进展提示使用激素治疗肝细胞癌的可能性。肝动脉灌注阿霉素、顺铂治疗不能切除的肝癌已广泛应用,但很少有联合使用性激素和化疗治疗肝癌的报告。 1987年4月至1988年8月,30例(男23例,女7例)原发或复发性不能切除的肝癌,随机分为2组。A组:联合使用化疗、激素治疗。B组:单独使用化疗。导管置入肝动脉内并与植于皮下的输注器相连。A组在置管第15天注入顺铂60mg/m~2;第1,8天注入阿霉素13mg/m~2,同时每日口服 5-FU150     

吡柔比星联合用药肝动脉化疗栓塞治疗中晚期肝癌近期临床疗效分析

观察吡柔比星联合用药与丝裂霉素联合用药肝动脉灌注化疗栓塞治疗中期期直癌的疗效与毒副反应。方法治疗组：吡柔比星,羟基喜树碱,５氟尿嘧啶,顺铂,治疗４８例肝癌。对照组：丝裂霉素,５ＦＵ,ＯＰＴ,ＤＤＰ,治疗３６例肝癌,直动脉灌注化疗栓塞共８４例中晚期肝癌。     

对不能切除的原发性肝癌综合治疗的临床研究

目的 比较术中肝动脉检塞化疗加超分割放射治疗与单纯肝动脉栓塞治疗不能切除的原发性肝癌的疗效。方法 对９１例手术探查不能切除的原发性肝癌随机分为２个组;术中肝动脉栓塞加超分割放射治疗组（ＩＨＡＥ＋ＨＲ）４３例,单纯术中肝动脉栓塞组（ＩＨＡＥ）４８例。肝动脉化疗选用４０％碘化油≤２０ｍＬ＋顺铂２０～４０ｍｇ、阿霉素４０～８０ｍｇ、丝裂霉素１０～２０ｍｇ、氟尿嘧啶１０００～１５００ｍｇ。栓塞选用注入明胶     

夹心式32磷-玻璃微球经肝动脉介入治疗中晚期肝癌的临床观察(附27例报告)

目的：探讨^32磷－玻璃微球经肝动脉介入治疗肝癌的疗效。方法：采用Seldinger技术将导管选择性地插到肝固有动脉或肝左、右动脉，按夹心式给药方法注入^32磷－玻璃微球碘油混悬液和化疗药。结果：治疗中晚期肝癌27例，治疗后患者临床症状、体征改善，3、6、12个月生存率分别为96.3%、71.1%、63.0%，中位生存期13个月；而对照组分别为77.8%、37.0%、18.5%和4个月。结论：^32磷－玻璃微球是治疗中晚期肝癌的一种有效的内照射核素和末梢栓塞剂。     

肝癌治疗的新途径——应用碘油、顺铂、明胶海绵的化学栓塞疗法

经导管的动脉栓塞疗法已被认为是治疗原发性肝癌的有效手段。此疗法对主要癌结节相当有效,但对其余小癌结节(小的肝内转移)、门静脉癌栓和肝包膜内浸润则几乎无效,因而不是一种根治性疗法。本文作者采用碘油、顺铂(CDDP)和明胶海绵进行肝动脉化学栓塞洽疗肝癌,并通过组织学检查估测了其     

碘化油十顺铂肝动脉注入治疗肝癌1例

碘化油十顺铂肝动脉注入治疗肝癌１例辜天慧四川巴中市人民医院（６３５５００）碘化油能选择性的存留于肝癌组织中，时间为数周至１年，它起到微栓塞物作用，还可作抗癌药物的载体，将药物导向肿瘤，缓慢而持久地发挥其作用，我院施行１例，报道于下：患者男，５５岁，农...     

Targeting liver tumors with hyperthermia: ferromagnetic embolization in a rabbit liver tumor model

BACKGROUND AND OBJECTIVES: Ferromagnetic embolization hyperthermia (FEH) consists of arterially embolizing liver tumors with ferromagnetic particles, and then applying an external alternating magnetic field to generate hysteretic heating within the embolized particles. The objective of this study was to assess the ability of FEH to selectively target liver tumors with hyperthermia. METHODS: Twenty rabbits containing hepatic VX2 carcinomas were arterially infused with ferromagnetic particles suspended in lipiodol, and then exposed to an external alternating magnetic field. Temperatures in the tumor, normal hepatic parenchyma (NHP), and rectum were recorded. Tumour and NHP were chemically analyzed for iron content, which was then correlated with the observed heating rates. RESULTS: The mean tumor-to-NHP iron concentration ratio was 5.3:1 (P < 0.001, N = 20). The mean tumor heating rates were 3.0-11.5 times greater than those in the NHP (P < 0.001, N = 20). After 5 min of heating, the greatest increase in mean tumor temperature was 11.0 degrees C and the greatest increase in mean NHP temperature was 1.3 degrees C. There was a positive relationship between tumor iron concentration and heating rate (correlation coefficient = 0.82, P < 0.001, N = 20). A tumor iron concentration of 2-3 mg/g resulted in tumor heating rates of 0.5-1.0 degrees C/min. CONCLUSIONS: Hepatic arterial infusion of lipiodol containing ferromagnetic particles can result in excellent targeting of liver tumors with hyperthermia on the subsequent application of an external alternating magnetic field. The promising results of this study warrant further investigation of FEH as a potential treatment for advanced liver cancer.     

Preparation of carboplatin-Fe@C-loaded chitosan nanoparticles and study on hyperthermia combined with pharmacotherapy for liver cancer

Background: Magnetic fluid hyperthermia is a kind of technology for treating tumors based on nanotechnology. It is suitable to various types of tumors. The purpose of this study was to prepare carboplatin-Fe@C-loaded chitosan nanoparticles with Fe@C as a magnetic core and to investigate efficacy of hyperthermia combined with chemotherapy for transplanted liver cancer in rats.

Methods: Fe@C nanopowder was treated with dilute hydrochloric acid to prepare Fe@C nanocage. Carboplatin-Fe@C-loaded chitosan nanoparticles were prepared by reverse microemulsion method with the nanocages as the magnetic cores, chitosan as the matrix. The shape, size, drug-loading rate, and in vitro cumulative release of the nanoparticles were observed and heat product under high frequency alternating electromagnetic field in vitro was explored. Eighty rats with transplanted liver cancer were randomly divided into 4 groups (group A: control group, group B: free carboplatin group, group C: nanoparticles with static magnetic field group, and group D: nanoparticles with static field and alternating magnetic field). Drug was injected into the hepatic artery. The therapeutic effect of hyperthermia combined with chemotherapy for tumor, toxicity and rat survival time were observed.

Results: Carboplatin-Fe@C-loaded chitosan nanoparticles were spherical in shape with an average size of (207 ± 21) nm and high saturation magnetization. The drug-loading rate of the nanoparticles was 11.0 ± 1.1%. The cumulative release percentage of carboplatin-Fe@C-loaded chitosan nanoparticles in vitro at different point time phase of 24 h, 48 h, 72 h, 96 h and 120 h were 51%, 68%, 80%, 87% and 91%, respectively. With an increase in carboplatin-Fe@C-loaded chitosan nanoparticle concentration and magnetic field strength, the heating rate and constant temperature of carboplatin-Fe@C-loaded chitosan nanoparticles dispersed in physiological saline were increased in an alternating magnetic field. In vivo experiments showed that after particle injection, tumor temperature reached 42.6° ± 0.2°C within 10 min in the alternating magnetic field; and the temperatures in the right hepatic lobes and the rectum were significantly lower than in the tumor and the constant temperature could last up to 30 min. The inhibition ratio of tumor weight in group D was significantly enhanced, no obviously toxic and side-effect occurred and survival time was prolonged.

Conclusion: Carboplatin-Fe@C-loaded chitosan nanoparticles possess good magnetic targeting and heat production properties. They can target liver cancer tissue by static magnetic field, and with the application of alternating magnetic field, effectively raise tumor tissue temperature and facilitate tumor apoptosis. The combination of chemotherapy and magnetic materials into nanoparticles as described herein demonstrates promising efficacy.     

卡铂碳铁纳米球对大鼠移植性肝癌的靶向性研究

目的:观察卡铂碳铁纳米球(C-C&Fe-N)经肝动脉注射,结合体外磁场引导下,在移植性肝癌大鼠体内的靶向分布情况.方法:移植性肝癌大鼠40只为A组,健康大鼠40只为B组.肝动脉插管,注入C-C&Fe-N,以肿瘤(A组)或肝左叶(B组)为靶区,施加磁场30 min(5 000 Gs).分别于相应时间点,采集肿瘤或靶区肝、非靶区肝、肾、脾、肺和心组织标本,测定卡铂浓度,显微镜观察C-C&Fe-N在各脏器沉积情况.结果:A组靶区肿瘤组织卡铂峰浓度(Cmax)65.21μg/g,为B组靶区肝组织38.47 μg/g的1.7倍,为A组非靶区肝组织14.36 μg/g的4.5倍.48 h时A组靶区肿瘤组织卡铂浓度7.27 μg/g,为B组靶区肝组织3.11μg/g的2.3倍,为A组非靶区肝组织0.32 μg/g的22.7倍.各时间点,A组肿瘤组织药物浓度均成倍高于B组靶区肝组织和两组非靶区肝组织,差异有统计学意义,P<0.05.A组靶区肿瘤组织卡铂AUC是906(μg·h)/g,为B组靶区肝组织421.34(μg·h)/g的2.2倍,为A组非靶区肝组织86.47(μg·h)/g的10.5倍.结论:C-C& Fe-N在体内显示出良好的磁靶向性和药物缓释性,并且对肿瘤组织具有更强的靶向性,能成倍提高肿瘤组织中的药物浓度,延长维持时间.     

Targeting behavior of hepatic artery injected temperature sensitive liposomal adriamycin on tumor-bearing rats

Temperature sensitive liposomal Adriamycin (LADM) was injected into the hepatic artery of rats bearing implanted hepatic tumors. Two hours after the injection, the liver was heated at 42 degrees C and maintained for six minutes at that temperature using local hyperthermia. Blood samples were taken at regular intervals until 8 hours after injection, at which time the animals were sacrificed and the drug distribution in the tissues was examined. Results indicate that the Adriamycin was released from the liposome, with the drug concentration in circulation peaking at 30 minutes after heating. High drug levels (25.2 micrograms/g of wet tissue) in the tumor and high tumor/liver Adriamycin level ratios (TLAR; 4.1) were found. The drug levels and the TLAR of the liposomal Adriamycin injection combined with heating (LADM H) were significantly different from those of the same dose of aqueous Adriamycin with heating (ADM H) or aqueous Adriamycin (ADM) and LADM without heating. The experiment shows that the LADM is cleared from the liver slowly, and when hyperthermia treatment at phase-transition temperature of the liposome is performed, the drug level in an implanted hepatic tumor is increased, and in the parenchyma is decreased. The results imply that targeting the hepatic tumor in this way may be an effective therapeutic method, and the drug release from the liposome may be controlled externally. This method appears promising for clinical practice.     

夏枯草及抗炎一号注射液经肝动脉联合灌注治疗大鼠肝癌作用机制的初步探讨

目的:探讨夏枯草及抗炎一号注射液经肝动脉联合灌注治疗大鼠肝癌的作用机制。方法:建立30只二乙基亚硝胺(DEN)诱发大鼠晚期原发性肝癌模型,随机分为中药组、化疗组和盐水组,每组各10只。经胃十二指肠动脉至肝固有动脉分别灌注生理盐水0.5ml、夏枯草注射液0.6g/kg 抗炎一号注射液0.45g/kg、顺铂(DDP)4mg/kg 羟基喜树碱(HCPT)1.5mg/kg 5-氟尿嘧啶(5-FU)34mg/kg。应用流式细胞仪(FCM)检测治疗后各组大鼠肝癌细胞的凋亡情况。结果:盐水组、化疗组和中药组均存在不同程度的细胞凋亡现象,与盐水组比较,中药组和化疗组肝癌细胞凋亡百分率均显著增高(P<0.01),但化疗组和中药组之间无显著性差异(P>0.05)。结论:夏枯草与抗炎一号注射液可诱导大鼠肝癌细胞凋亡,其程度与化疗药物相似。     

Increased uptake of 5-FU in experimental liver tumours by simultnaeous infusion of norepinephrine

The effect of the simultaneous administration of norepinephrine and 5-fluorouracil (5-FU) on the uptake of radiolabelled 5-FU by liver tumours was studied in rats. Three different concentrations of 5-FU were used (15, 1.5 and 0.15 μg/g body weight). The drugs were infused over a 30 min period via the hepatic artery, following cannulation of the gastroduodenal artery. The radioactivity in liver tumour, normal liver, lungs and intestines was estimated by liquid scintillation counting. At all concentrtions tested, an increased uptake of radioactive 5-FU was found in the tumour when norepinephrine was infused. Tumour/liver ratios also increased significantly in all these cases. No significant differences were noted between norepinephrine infused and control animals in the radioactivity in normal liver, lungs and intestines. The effects noted were possibly due to changes in blood flow within the liver, but the possibility of a direct effect of norepinephrine on DNA metabolism is discussed.     

Effect of hepatic artery ligation on the incorporation of 3H-orotic acid into an adenocarcinoma transplanted to rat liver

In the model of secondary liver cancer in Wistar rats a study was made of the influence of hepatic artery ligation (HAL) on the amount of nucleotides and RNA in tumor and liver tissue and on the uptake of 3H-orotic acid into these compounds and DNA after labelling for 90 minutes. Ten days after inoculation with tumor cells into the central liver lobe, a catheter was placed into the portal vein in all rats and in half of them the hepatic artery was ligated. On days one, three, five or ten, rats were given 3H-orotic acid through the catheter. On day ten 3H-orotic acid was also infused via the femoral vein or intraperitoneally. After HAL there was a decrease in the nucleotide and RNA content of the tumor cells after one, three and five days. There was no such decrease in the liver cells. In all HAL rats there was an increase in the nucleotide and RNA content of the tumor cells at day ten compared to day five. The ratio of RNA to acid soluble fraction labelling in tumors was also increased on day ten in all groups compared to HAL rats at day five. The increased uptake of 3H-orotic acid into tumour RNA at day ten after HAL strongly suggests rearterialization. There was no support for an increased vascularization of the tumor from the portal vein on day three or five. In the liver tissue, HAL had no influence. This experimental study gives no support for the use of hepatic dearterialization followed by intraportal infusion av cytostatic agents in clinical settings.     

姜黄素对化学诱导大鼠肝癌缺氧模型血管生成的影响

目的:探讨姜黄素对二乙基亚硝胺( diethylnitrosamine, DEN)诱发大鼠肝细胞癌（hepatocellular carcinoma, HCC）缺氧后血管形成的影响。方法: 采用DEN诱发大鼠HCC,结扎肝动脉并构建大鼠HCC缺氧模型。将HCC模型大鼠按照数字表法随机分为单纯碘化油栓塞组（A组）、碘化油联合姜黄素栓塞组（B组）、碘化油联合肝周包膜组（C组）、碘化油联合姜黄素及肝周包膜组（D组）,每组10 只。比较各组大鼠相应治疗后HCC细胞及组织VEGF、微血管密度（microvessel density,MVD）及大鼠中位生存时间（median survival time,MST）。结果：B组与D组的VEGF蛋白表达及MVD均比A组显著降低（P<0.01）,而C组上述指标则与A组无显著变化（P>0.05）。B、C、D组比A组大鼠MST均显著延长（P<0.05）,D组大鼠的MST高于B、C组（P<0.05）。结论：姜黄素可抑制HCC缺氧大鼠肿瘤血管的生成,可降低VEGF表达及MVD,起到延长大鼠生存期的作用。     

Inhibitory effect of 2-deoxy-D-glucose on liver tumor growth in rats.

Since tumor cells are more dependent on glycolysis for energy supply than other cells, we tested whether its inhibition by 2-deoxy-D-glucose (2-DG) affects tumor growth. Male Wistar rats were inoculated in the liver with tumor cells from a chemically induced colonic adenocarcinoma. From day 5 after inoculation 2-DG (400 mg/kg/24 h) was continuously infused into the hepatic artery for 5 days; controls received saline in the same fashion. Seven days after the end of infusion, the animals were sacrificed. A second experimental group of rats was treated with isolated liver perfusion for 30 min with oxygenated blood through the portal vein and hepatic artery simultaneously. In the perfusate, 400 mg/kg 2-DG were added, and the rats were sacrificed at 10 days after perfusion. A first control group underwent perfusion without 2-DG, and a second control group received i.v. infusion of 2-DG (400 mg/kg/30 min) for 30 min over 5 days. A nontreated control group was also added. All animals survived the procedures. The concentration of blood glucose increased in the rats receiving 2-DG i.v. and intraarterially but was unchanged in the other groups. The tumor growth was significantly reduced by 2-DG in all experimental groups, with no difference between the groups. It is therefore concluded that 2-DG is of potential interest in the treatment of malignancies. Since local application of 2-DG avoids the risk for systemic side effects, this approach should be explored further.     

Potent antitumor effects of intra-arterial injection of fibroblasts genetically engineered to express IL-12 in liver metastasis model of rat: no additional benefit of using retroviral producer cell

Interleukin-12 (IL-12) mediates significant antitumor effects in animal models but associated with dose-dependent toxicity in human. To achieve local expression of IL-12 at the tumor site without systemic toxicity, we performed intra-arterial administration of fibroblasts genetically engineered to produce IL-12 protein with or without retrovirus (CRIP- IL-12 or 3T3-IL-12) in liver metastasis model. Rat breast cancer cells ( MADB - 106) were injected into the portal vein of syngeneic Fisher rats on day 0, and fibroblasts were injected into the hepatic artery on day 7. On day 21, liver weight and number of liver tumors were examined. As controls, CRIP cells expressing retrovirus carrying lacZ marker gene (CRIP-lacZ) or saline (Hanks balanced salt solution, HBSS) were injected. Administration of CRIP-IL-12 significantly reduced tumor metastasis in liver measured by number of foci (CRIP- IL-12: 45.2 +/- 36.7, CRIP-lacZ: >250, HBSS: >250, P<.05) and by liver weight (CRIP-IL-12: 13.0+/-2.5 g, CRIP-lacZ: 30.4+/-8.5 g, HBSS: 26.0+/-7.6 g, P<.05). 3T3-IL-12, which produced only IL-12 protein but not IL-12 retrovirus, also had significant antitumor effects equivalent to CRIP-IL-12. Intra-arterial injection of IL-12--producing fibroblasts into the liver may be an effective therapy for liver tumors reducing systemic toxicity, and could be developed for clinical application.