贞芪扶正胶囊对大鼠实验性肝癌发生发展的影响

目的：观察贞芪扶正胶囊在化学致癌剂二乙基亚硝胺（diethylnitrosamine,DENA)诱发大鼠肝癌过程中，对肝癌发生、发展的影响。方法；实验分为4组，除单纯致癌组（D组）外，其余各组大鼠均在给予致癌剂前（A组），同时（B组）或后（C组）加给贞芪扶正胶囊，在给予致癌剂20周后取肝脏作肉眼、光镜和电镜检查。结果：单纯致癌组大鼠均形成肝癌。服用贞芪扶正胶囊的各组情况则有较大差异，A组大鼠显示致癌剂对肝脏毒性损伤明显低于其他各组，并且当其他各组动物均已形成肝癌甚至已有转移时，此组中仅有少数大鼠形成肿瘤，多数大鼠则仅出现DENA毒性刺激而形成的细胞增生结节。结论：贞芪扶正胶囊有预防或延缓肝癌发生的作用。     

mFOLFOX-6方案联合贞芪扶正胶囊治疗转移性结直肠癌

目的:探讨mFOLFOX-6方案联合贞芪扶正胶囊治疗转移性结直肠癌的疗效和不良反应。方法:将61例转移性结直肠癌患者随机分为两组:A组30例采用mFOLFOX-6方案治疗,B组31例,采用mFOLFOX-6方案联合贞芪扶正胶囊治疗。治疗两个周期后进行评价,观察其近期有效率、QOL改善、KPS评分、骨髓抑制情况。结果:两组有效率无明显差异,两组最常见的不良反应为外周神经毒性、骨髓抑制、恶心、呕吐,但均以Ⅰ-Ⅱ度为主,B组骨髓抑制发生率明显少于A组。结论:mFOLFOX-6方案联合贞芪扶正胶囊治疗转移性结直肠癌疗效显著,贞芪扶正胶囊可预防化疗后骨髓抑制的发生。     

贞芪扶正胶囊预防化疗性浅表静脉炎的疗效观察

目的 :观察贞芪扶正胶囊预防化疗性浅表静脉炎的疗效。方法 :贞芪扶正胶囊 6粒口服 3次 /日 ,化疗前 7天开始至结束后 14天。结果 :应用贞芪扶正胶囊后 ,浅表静脉炎发生率明显下降 ,治疗组发生率 2 5 % ,对照组 6 3 33% ,有显著差异 (P <0 0 0 5 ) ,副作用小。结论 :贞芪扶正胶囊是预防化疗性浅表静脉炎的有效药物之一 ,疗效好 ,副作用少。     

贞芪扶正胶囊联合多西他赛加顺铂治疗中晚期非小细胞肺癌的临床观察

目的:观察贞芪扶正胶囊联合多西他赛加顺铂治疗中晚期非小细胞肺癌减毒增效、改善生存质量的效果.方法:58例中晚期非小细胞肺癌患者随机分为两组.中药加化疗组30例,给以贞芪扶正胶囊联合TP方案(多西他赛加顺铂)化疗.单纯化疗组28例,仅以TP方案化疗.均21天为1周期,至少化疗2周期.结果:58例患者均可评价疗效和不良反应,中药加化疗组1年生存率、生存质量改善情况明显优于单纯化疗组(73.3%Vs53.6% P<0.05),不良反应明显减轻(P<0.05).结论:多西他赛加顺铂辅以贞芪扶正胶囊治疗中晚期非小细胞肺癌方便易行,可以明显提高患者对化疗的耐受性和依从性,且疗效有所提高.     

贞芪扶正胶囊预防化疗性浅表静脉炎的疗效观察

目的:观察贞芪扶正胶囊预防化疗性浅表静脉炎的疗效.方法:贞芪扶正胶囊6粒口服3次/日,化疗前7天开始至结束后14天.结果:应用贞芪扶正胶囊后,浅表静脉炎发生率明显下降,治疗组发生率25%,对照组63.33%,有显著差异(P＜0.005),副作用小.结论:贞芪扶正胶囊是预防化疗性浅表静脉炎的有效药物之一,疗效好,副作用少.     

二乙基亚硝胺诱发大鼠肝癌过程中的病理形态观察

 恶性肿瘤的病因和细胞癌变的规律至今尚不完全清楚。我们以往曾对肝癌和皮肤癌进行过初步的实验研究,认为癌变的发生可能与细胞的增生与分化间的平衡失常有关。为了进一步研究癌变的原理,本实验进行了二乙基亚硝胺(DENA)诱发大鼠肝癌过程中肝脏病理形态观察和生化改变的研究。DENA在自然界比较广泛地存在于食物中,可诱发多种动物肿瘤。     

Smo、Gli1在大鼠肝癌中的表达及维生素D3对Smo、Gli1的抑制

背景与目的:研究表明Sonic Hedgehog(Shh)信号通路与肿瘤的发生有重要联系,本实验通过检测大鼠肝癌模型中Smo、Gli1的表达,探讨其与肝癌发生发展的关系,了解维生素D3(Vitamin D3,VitD3)对Smo、Gli1的作用.方法:取48只5～6周龄的健康雄性SD大鼠,并随机分组.对照组:一般饲养的8只大鼠;DEN组:二乙基亚硝胺(diethylnirtosamine,DEN)诱癌的20只大鼠;DEN+VitD3组:DEN+VitD3干预的20只大鼠;分别于实验12周和20周处死各组一半数量的大鼠,采用Western blot检测大鼠肝脏中Smo、Gli1蛋白的表达,实时荧光定量PCR检测两种蛋白mRNA的表达.结果:对照组中12周和20周大鼠肝脏的Smo、Gli1的mRNA及蛋白的表达差异无统计学意义(P＞0.05);DEN组或DEN+VitD3组中20周的Smo、Gli1表达高于12周(P＜0.05);相同实验周期:DEN的Smo、Gli1表达高于VitD3组(P＜0.05);与其他两组相比,对照组表达最低(P＜0.01).结论:Smo、Gli1可能参与肝癌的发生发展,VitD3对Smo、Gli1具有一定抑制作用.     

柴胡皂甙-d对DEN致大鼠实验性肝癌形成的影响

目的:研究柴胡皂甙d(saikosaponin-d,SSd)对二乙基亚硝胺(diethylnitrosamine,DEN)致大鼠实验性肝癌形成的影响.方法:清洁级雄性SD大鼠90只,随机分为5组:模型组(n=20),对照组(n=10)与SSd大、中、小剂量治疗组(各组n=20).对照组给予等量生理盐水灌胃,其余各组大鼠均给予2g/L二乙基亚硝胺(DEN,10 mg/kg)灌胃,每周5次,同时各治疗组每天腹腔注射不同浓度SSd(2.0,1.5,1.0 mg/kg),至16 周停药.分别于第6、12、16周处死大鼠,自动生化分析仪测定血清总胆红素(total bilirubin,TBIL)、丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天门冬氨酸氨基转移酶(aspartate amino transferase,AST)和白蛋白(albumin,ALB)含量的变化,HE染色观察实验大鼠各期肝组织病理学结构的改变.结果:SSd各治疗组与模型组相比,SSd能够改善大鼠血清各项肝功指标,增加体重,明显减轻大鼠肝细胞的变性坏死,降低死亡率,并且有统计学差异(P＜0.05).病理学检查发现SSd各治疗组大鼠癌结节数及灶的大小均小于模型组,镜下单纯造模组癌细胞呈多形性,异形性明显;相反,SSd各干预组癌细胞分化程度高,异形性较低.结论:SSd对实验性大鼠肝癌的形成有一定的抑制作用.     

扶正固本为主联合化疗治疗晚期非小细胞肺癌的临床研究

目的:观察扶正固本为主联合化疗治疗晚期非小细胞肺癌(NSCLC)的临床疗效.方法: 189例晚期NSCLC住院患者随机平均分为中西药组(化疗加口服扶正固本为主中药治疗)63例、中药组(单纯口服扶正固本为主中药治疗)63例和单纯化疗组63例,治疗期为3个月,并比较3组进行临床疗效、生存质量、不良反应和体重等.结果: 中西药组、中药组、单纯化疗组近期有效率(CR PR)分别为17.5%、3.1%和7.8%,中西药组疗效优于中药组和单纯化疗组(P<0.05),且中西药组、中药组患者在临床症状变化、生活质量方面均优于单纯化疗组(P<0.05);治疗后体重均有下降,中西药组、中药组下降低于单纯化疗组(P<0.05); 中西药组的化疗毒性发生率及毒性程度均较单纯化疗组明显减轻(P<0.05).结论: 扶正固本为主联合化疗治疗NSCLC具有较好作用,能提高患者的生活质量、近期有效率、体重,具有减毒增效作用.     

BALB/c小鼠肝癌模型建立及其形态学特征分析

目的:建立BALB/c小鼠肝癌动物模型,并研究其超微结构的特点,为开展肝细胞癌相关实验研究奠定基础。方法:66只正常雄性成年BALB/c小鼠完全随机分为5组,即实验A、B、C、D组和对照组,实验组每组14只,对照组10只。采用二乙基亚硝胺(DEN)/四氯化碳(CCl4)/乙醇的联合诱导方式喂养实验组小鼠;于给药后第60、90、120和150天,分别取实验A、B、C和D组小鼠肝脏组织;于给药后第150天取对照组小鼠肝脏组织。观察小鼠肝脏病变的发生情况及其超微结构的改变,并利用RT-PCR检测病变肝脏组织不同时期小鼠甲胎蛋白(mAFP)的变化情况。结果:对小鼠肝脏组织行病理学检查发现,对照组肝脏未见异常,给药后第60天实验A组小鼠肝脏炎症发生率为64.28%(9/12),第90天实验B组小鼠肝脏轻度纤维化发生率为64.28%(9/12),第120天实验C组小鼠肝硬化发生率为71.43%(10/12),第150天实验D组小鼠肝脏肿瘤性病变发生率为64.28%(9/12);以上时间点各实验组小鼠肝脏病变发生率均明显高于对照组,P<0.05。mAFP阳性表达在给药60d后出现;第150天时透射电镜下观察到的形态特征符合肝癌。结论:利用化学致癌剂和肿瘤促进剂,成功建立了甲胎蛋白分泌型BALB/c小鼠肝癌动物模型,该方法诱导时间相对较短,病变过程和超微结构的改变均与人类肝癌发病特点类同,是研究肝癌发生发展的理想实验动物模型。     

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。     

Anti-tumor effects of cimetidine on hepatocellular carcinomas in diethylnitrosamine-treated rats

Cimetidine is known to have an anti-tumor effect on certain types of malignancies, though on hepatocellular carcinomas (HCCs), its effect remains unclear. We studied the anti-tumor effects of cimetidine on chemically-induced HCCs in rats. Four-week-old male Wistar rats (n=105) were divided into 4 groups. Those in groups A and B were administered diethylnitrosamine (DEN) intraperitoneally at 100 mg/kg body weight every week for 6 weeks, during which rats in group A were given tap water and those in group B received cimetidine (100 mg/kg/day) in their drinking water. Rats in groups C and D were administered saline instead of DEN and given tap water with 100 mg/kg/day of cimetidine, respectively. The animals were sacrificed at 7, 12, 22 and 32 weeks after the first administration of drugs and examined. Liver nodules were observed only in groups A and B, with the number of nodules, maximum diameter of the largest nodule, and liver weight significantly lower in group B. Immunohistochemistry findings showed that glutathione S-transferase placental-positive preneoplastic foci were significantly decreased in group B. Cimetidine treatment decreased the number of proliferating cell nuclear antigen-positive hepatocytes and tended to enhance natural killer (NK) cell activity in splenic lymphocytes. In addition, flow cytometry revealed that the proportion of NK cells among total splenic lymphocytes was not affected by cimetidine treatment. Our results showed that cimetidine has an inhibiting effect on hepatocarcinogenesis.     

Modification of diethylnitrosamine liver carcinogenesis with phenobarbital but not with immunosuppression.

Administration of 40 ppm diethylnitrosamine (DENA) in the drinking water for 10 weeks to male Fischer rats led to hepatocellular carcinoma in 100 percent with metastasis to the lung in 40 percent, of the animals living for the full experimental period of 20 weeks. Concurrent feeding of phenobarbital and DENA for 10 weeks produced cancer of the liver in 77 percent of the animals, but only 9 percent had metastases in the lung. A brief regimen of DENA for 4 weeks, followed by 16 weeks of observation, induced cancer of the liver in only 13 percent of the rats. Administration of phenobarbital, begun 1 week after cessation of DENA intake and terminated at week 20, led to liver cancer in 64 percent of the rodents. Hydroxyurea had no effect on this enhancement. Treatment with a purified gamma fraction of antilymphocytic serum after the DENA did not influence the outcome. Thus phenobarbital given together with DENA reduced the severity of the carcinogenic process, but when it was given after the hepatocarcinogen, it increased the effect.     

Hepatoprotective Effects of Curcumin Against Diethyl Nitrosamine Induced Hepatotoxicity in Albino Rats

Curcumin is widely used as a traditional medicine. This work was aimed to investigate its possible protectiveeffect against chemically induced hepatocellular carcinoma (HCC) in rats. Fifty male albino rats were dividedinto five groups (n=10, each). The control group received a single dose of normal saline, the diethylnitrosamine(DENA) group received a single intra-peritoneal dose at 200mg/kg body weight, and the 3rd, 4th and 5th groupswere given DENA and daily administrated curcunine (CUR) via intra-gastric intubation in doses of 300,200and 100 mg/kg b.wt. respectively for 20 weeks. Serum, and liver samples were used for determination of alphafeto-protein (AFP), interleukin-2 (IL-2), interleukine-6 (IL-6), serum liver enzymes (AST, ALT, ALP and GGT)levels as well the activities and gene expression of glutathione peroxidise (GPx), glutathione reductase (GR),catalase (CAT) and super oxide dismutase (SOD). Curcumin significantly lowered the serum levels of AFP,IL-2 and IL-6, ALT, ALT, and malondialdehyde (MDA) as well gene expression of IL-2 and IL-6. In contrast itincreased the gene expression and activities of Gpx, GRD, CAT and SOD. The protective effect of CUR againstDEN-induced hepatocarcinogenesis in albino rats was proven.     

Inhibitory effect of UFT on rat hepatocarcinogenesis induced by 3'-methyl-4-dimethylaminoazobenzene and phenobarbital promotion]

Inhibitory effect of UFT on hepatocarcinogenesis in rats induced by 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB) and phenobarbital (PB) promotion was studied. Donryu male rats were divided into four groups. Group A was fed a diet containing 0.06% 3'-MeDAB for 3, 5, or 7 weeks, and then fed normal diet for 2 weeks, subsequently received a diet containing 0.05% PB. Group B was given UFT (20 mg/kg/5 days a week) simultaneously with feeding 3'-MeDAB. Group C was given UFT simultaneously with feeding PB. Group D was given 3'-MeDAB alone. In all groups, the development of hepatocellular carcinoma was investigated 37 weeks later and the number and area per mm2 of induced glutathione S-transferase placental form (GST-P) positive foci were measured using an image processor. The number and area of GST-P positive foci in group B and group C were markedly decreased as compared with those in group A. These results seem to show that the administration of UFT inhibited the production of GST-P positive foci and that stronger inhibitory effect of UFT was observed by simultaneous administration of an initiator than by that of a promoter.     

Dose-response relationship of phenobarbital promotion of diethylnitrosamine initiated tumors in rat liver

The dose-response relationship was determined in rats for the enhancement by phenobarbital of diethylnitrosamine (DENA)-initiated neoplastic nodules and hepatocellular carcinomas. Male Sprague-Dawley rats received a single oral dose of either 80 mg/kg DENA or water. Seven days later, the animals were divided into groups that started to receive 0, 62.5, 125, 250, 500 or 1000 ppm sodium phenobarbital in the drinking water. Animals from each group were killed at 48 and 70 weeks after the DENA. No significant difference was observed in the low response of neoplastic nodules among the DENA-initiated groups. The incidence of DENA-initiated hepatocellular carcinoma was enhanced at 70 weeks by 250, 500 and 1000 ppm sodium phenobarbital but not by 62.5 or 125 ppm sodium phenobarbital. Equal enhancement of the incidence of hepatocellular carcinomas was obtained with 250, 500 and 1000 ppm sodium phenobarbital. In non-DENA-initiated rats, phenobarbital did not induce neoplastic nodules or hepatocellular carcinomas. Our results suggest that a daily dose of at least 250 ppm sodium phenobarbital is required in order for it to exert tumor promoting activity.     

Cessation of Long-term Alcohol Administration and Two-day Cycling of Exposure Respectively Promote and Inhibit Hepatocarcinogenesis in Rats

The effects of different patterns of alcohol administration on hepatocarcinogenesis induced by diethylnitrosamine ‍(DEN) in male Wistar rats were assessed using a modified Ito’s medium-term bioassay system. Carcinogenic potential ‍was scored by comparing numbers and areas of glutathione S transferase placental form (GST-P)-positive foci. The ‍activity of ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine synthesis, was also measured as ‍a parameter of cell proliferation. Rats were given a single i.p. injection of DEN (200 mg/kg body weight), maintained ‍on basal solid diet for two weeks, then divided into five groups: group A maintained on liquid diet in which 36% of ‍total calories were provided by ethanol (diet Al) for 24 weeks; group B maintained on diet Al for 12 weeks and ‍subsequently on control diet (diet C) for 12 weeks; group C maintained on diet C for 24 weeks; group D maintained ‍on a cycle of two days on diet Al followed by two days on diet C; group E maintained on another liquid diet in which ‍18% of total calories were provided by ethanol for 24 weeks. The numbers and areas per cm2 of GST-P positive foci ‍in group B were highest and in group D were the lowest among the five groups. ODC activities in groups A and E ‍were significantly lower than in group C, that for group B was intermediate. These results suggest that the intermittent ‍intake of alcohol exerts preventive potential on hepatocellular lesion development, and that interruption of longterm ‍alcohol administration enhances hepatocarcinogenesis. ‍     

Suppressive Effects of S-Methyl Methanethiosulfonate on Promotion Stage of Diethylnitrosamine-initiated and Phenobarbital-promoted Hepatocarcinogenesis Model

Modifying effects of S-methyl methanethiosulfonate (MMTS) on diethylnitrosamine (DEN)-initiated and phenobarbital (PB)-promoted hepatocarcinogenesis were examined in rats. Five-week-old male F344 rats were divided into 8 groups. After a week, groups 1–5 were given DEN (100 mg/kg body weight, i.p.) once a week for 3 weeks, whereas groups 6–8 received vehicle treatment. Group 2 was given 100 ppm MMTS containing diet in the initiation phase. From 4 weeks after the start of experiment, groups 3 and 5 were fed MMTS, and groups 1–3 and 7 received drinking water containing 500 ppm PB. Group 6 was given MMTS diet alone throughout the experiment (24 weeks). The incidences of hepatocellular adenoma and total liver tumors were significantly smaller in group 3 than those of group 1. The average numbers of hepatocellular adenoma, carcinoma and total tumors in group 3 were significantly smaller than in group 1. Glutathione, S-transferase placental form-positive foci were also significantly decreased by MMTS treatment in the promotion phase. MMTS treatment in the initiation or promotion phase reduced ornithine decarboxylase activity in the liver of rats given DEN. The antioxidant activity against lipid peroxidation of MMTS was confirmed in tests with rabbit erythrocyte membrane ghosts or rat hepatocytes. These results suggest that MMTS is a promising chemopreventive agent for liver neoplasia when concurrently administered with PB.     

Induction of gamma-glutamyltransferase-positive and nonspecific esterase-positive foci in rat liver by partial hepatectomy following single injection of N-nitrosodiethylamine

The effect of partial hepatectomy (PH) on alteration of liver foci induced by N-nitrosodiethylamine (DENA) was studied in inbred F344 male rats. As early as 2 weeks after PH was performed 6 hours after an injection of 100 mg DENA/kg, gamma-glutamyltransferase-positive hepatocellular foci were induced, whereas DENA alone induced no foci until 12 weeks after PH. The focus counts of the group with PH performed 6 hours after an injection of 100 mg DENA/kg were consistently greater than those of a group with PH performed at 24 hours following DENA injection. At 3 and 6 weeks after PH was done at 12 weeks following treatment with 100 or 200 mg DENA/kg, the focus count was significantly increased compared with that in nonhepatectomized groups. The results indicate that increased liver cell proliferation resulting from PH enhances the conversion of persisting DNA damage to a permanent alteration in DNA. The effect at 12 weeks after exposure supports the concept that DNA damage in hepatocytes is highly persistent.     

Anticancer effects of Huaier are associated with down-regulation of P53

This study was designed to explore the mechanism of Huaier anticancer effects on experimental hepatocellular cancer (HCC) development. Seventy five rats were divided into 5 groups, administered N-nitrosodiethylamine (groups B, C, D and E) or natural saline (group A). Rats in group C and E were also given Huaier. At the 15 week sacrifice point, the HCC incidence of group C was lower than group correlating with serum AFP. The serum ALT concentration (98.9% greater) and P53 mRNA levels (23.2%) were higher in Group B than group C. Longer term survival rates between group D and E were not significantly different. Huaier can protect liver from chemical injury and furthermore HCC development, possibly with involvement of down-regulation of P53.