Cyclooxygenase-2 in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer related mortality worldwide. The incidence of HCC is rising worldwide, especially in the United States. The overall survival of patients with HCC is grim and currently no efficient secondary prevention or systemic treatments are available. Recent evidence suggests that COX-2 signaling is implicated in hepatocarcinogenesis and COX-2 inhibitors prevent HCC cell growth in vitro and in animal models. However, given the recently reported side effect associated with some of the COX-2 inhibitors, it is imperative to develop chemotherapeutic strategy that simultaneously targets COX-2 and other related key molecules in hepatocarcinogenesis or to utilize agents inhibiting COX-2 signaling in conjunction with other standard chemotherapy or radiation therapy. Such combinational therapeutic approaches are expected to provide synergistic anti-tumor effect with lesser side effect. In this regard, the recently delineated interplay between COX-2-derived PG signaling and other growth-regulatory pathways such as EGFR, Met, iNOS, VEGF and n-3 polyunsaturated fatty acids is expected to provide important therapeutic implications. This review summarizes the recent advances in understanding the mechanisms for COX-2-derived PG signaling in hepatocarcinogenesis and focuses on the newly unveiled interactions between PG cascade and other key signaling pathways that coordinately regulate HCC growth. Understanding these mechanisms and interplays will facilitate the development of more effective chemopreventive and therapeutic strategies.     

Transplantation model of human hepatocellular carcinoma in nude mice. II. Establishment of the LTNM2 human liver cancer model in nude mice and observation on the growth of the transplanted tumor

LTNM2 model was established by the surgical specimen of a patient with recurrent hepatocellular carcinoma (HCC) with positive AFP. Human HCC was successfully transplanted subcutaneously into nude mice (Swiss nu/nu) following a latent period of 93 days with serial passages for 7 generations. Transplantability in nude mice was 72% (42/58). Based on the observation of 42 nude mice models, it was proved that the original properties of the human HCC, such as the morphological features, cell type and degree of differentiation and the functions, synthesis of AFP, were preserved. The tumor growth was progressive. The mean value of increased geometrical mean diameter tumor growth was progressive. The mean value of increased geometrical mean diameter (GMD) was 2.5 +/- 1.1 mm/week. Necrosis, ulceration and spontaneous regression was rarely observed. These results show that the transplanted tumor in nude mice bears a strong resemblance to the parent human HCC. LTNM2 model can be used not only for basic research of liver cancer but also for experimental therapeutic study.     

人肝癌裸鼠连续传代的病理变化特征

目的：探讨裸鼠人肝癌20年连续传代的病理变化特征。方法：裸鼠人肝癌组织模型（SMMU-LTNM）连续观察20年（1987—2007年），皮下移植瘤传至228代，建立腹腔移植瘤、肝原位移植瘤及NOD-SCID小鼠肝原位移植瘤的病理资料，经光镜、电镜、图像分析、染色体分析、周围血液AFP检测等方法分析病理变化特征。结果：（1）上述4种肿瘤模型的局部侵袭和转移均长期存在：皮下移植瘤的局部侵袭率为59．70％（40／67），肺内转移率为37．10％（23／62）；腹腔移植瘤的肺内转移率为59．02％（36／61）；肝原位移植瘤的肝内转移率为18．18％（4／22），肺内转移率为31．82％（7／22）；NOD—SCID小鼠肝原位移植瘤的肺内转移率为53．85％。（2）皮下移植瘤的组织学变化：第10代前的瘤细胞分化和组织结构与原人肝癌近似，以Ⅱ级分化、粗梁型为主；第11代至225代瘤细胞以分化Ⅲ级、团块型为主，电镜下亦证实瘤细胞分化更差。（3）AFP检测第32代前为92500μg／L，第33代至130代AFP下降为6729μg／L，220代AFP检测为1000—5000μg／L。（4）腹腔移植瘤的瘤细胞群体与肺转移瘤的瘤细胞群体DNA含量分布范围明显增宽，2C-6C不等，峰值明显右移，前者的分布范围比后者更宽；DNA含量分别为2．60±0．20和2．10±0．26。（5）染色体检测，第55—206代（相隔12年）部分瘤细胞染色体变为裸鼠染色体。结论：裸鼠皮下移植瘤可连续传代20年，局部侵袭及转移的恶性生物学行为不变；瘤细胞分化更差，AFP下降，部分瘤细胞染色体变为裸鼠染色体。这些病理变化可能与裸鼠内环境影响和瘤细胞的多潜能分化有关。     

Bevacizumab抑制高转移性人肝癌原位移植瘤的淋巴管形成

目的：探讨Bevacizumab抑制肝癌淋巴管形成及抑制肿瘤生长的作用。方法：建立LCI-D20高转移潜能肝癌组织原位移植裸鼠模型,给予治疗剂量的Bevacizumab并设对照组。28d后处死裸鼠,测量肿瘤负荷,免疫组织化学方法检测肿瘤组织微淋巴管密度(lymphatic microvessel density,LMVD)。结果：Bevacizumab治疗组肿瘤负荷低于对照组,统计学上具有显著性差异(P＜0.001)；Bevacizumab治疗组肿瘤内LMVD亦低于对照组,有统计学显著性意义(P＜0.001)。结论：动物实验中,Bevacizumab可有效地抑制肝癌细胞生长和淋巴管形成,为临床治疗肝癌治疗提供新的靶点。     

N-acetylglucosaminyltransferase V activity in metastatic models of human hepatocellular carcinoma in nude mice

N-linked beta 1-6 branched oligosaccharides may contribute directly to the malignant phenotype including metastatic potential of tumour cells. Increased beta 1-6 branching was associated with an increased level of N-acetylglucosaminyltransferase V (GnT V). In this report, the tissues from two metastatic models of human hepatocellular carcinoma (HCC) in nude mice were obtained. GnT V activity and mRNA level were determined. Results showed that GnT V activity in highly metastatic LCI-D20 models (Liver Cancer Institute, passage time: 20 days) (413.1+/-86.4U) was much higher than that in low metastatic LCI-D35 model (passage time 35 days) (155.3+/-31.9U). Northern blot showed that the mRNA level of GnT V in two models had no change. During the selection of a highly metastatic LCI-D20 model, GnT V activity increased from 301.6+/-57.3U to 413.1+/-86.4U while the highly metastatic LCI-D20 model acquired higher metastatic ability after selection. When highly metastatic LCI-D20 model tissues were implanted subcutaneously (s.c.), the GnT V activity decreased dramatically from 413.1+/-86.4U to 94.9U. This is the first report that GnT V activity increased in HCC during metastasis in vivo.     

Manumycin抗人肝癌细胞HepG2裸鼠移植瘤的作用及其对肿瘤血管生成的影响

背景与目的:法尼基转移酶抑制剂manumycin体内外抗胰腺癌、结肠癌和退行性甲状腺癌的研究已见报道。我们先前的体外研究发现,manumycin能抑制人肝癌HepG2细胞的增殖通路和生存通路。本研究拟探讨manumycin在裸小鼠体内的抗肝癌作用及其对肿瘤的血管生成的影响。方法:建立人肝癌HepG2细胞裸鼠移植瘤模型,接种后第8天按肿瘤大小随机分为5组:生理盐水对照组(20ml/kg)、阳性药对照组(CTX,25mg/kg)、0.1%Me2SO阴性对照组(20ml/kg)、manumycin低剂量组(2.5mg/kg)和高剂量组(5mg/kg)。测量各组肿瘤体积观察manumycin的体内抗瘤作用。采用免疫组化方法观察移植瘤的微血管密度(MVD),应用Westernblot法检测VEGF和b鄄FGF的蛋白水平变化,RT鄄PCR法检测VEGFmRNA的水平。结果:manumycin低剂量组和高剂量组的平均肿瘤体积比(V/V0)分别为0.68±0.09和0.59±0.04(n=5),与0.1%Me2SO阴性对照组(V/V0为1.38±0.21)相比,manumycin处理组肿瘤体积明显缩小(P<0.01)。与对照组相比较,manumycin处理组肿瘤组织MVD明显降低(P<0.01)。manumycin能明显抑制HepG2细胞及HepG2细胞裸鼠移植瘤VEGF蛋白的表达,而对b鄄FGF蛋白的表达影响不大。manumycin也明显抑制了HepG2细胞裸小鼠移植瘤VEGFmRNA的表达。结论:manumycin能明显抑制人肝癌HepG2细胞裸小鼠移植瘤的生长。下调VEGF表达,抑制肿瘤的血管生成可能是manumycin抗肿瘤作用的重要机理之一。     

AFP介导慢病毒载体治疗荷人肝癌裸鼠移植瘤的实验研究

目的 构建甲胎蛋白（AFP）介导的以沉默胰岛素样生长因子1型受体（IGF1R）和表达野生型p53（Wtp53）的重组慢病毒,探讨该慢病毒载体对肝癌干细胞CD45-CD90+双靶点基因系统（IGF1R和Wtp53）和对体内肝癌生长的抑制作用。方法 从肝癌细胞Hep3B系中分离出肝癌干细胞CD45-CD90+细胞亚群,用携带AFP-Wtp53-pPRIME-miR30-shRNA-IGF1R融合基因的慢病毒进行体外转染。利用RT-PCR和Western blotting检测IGF1R、WtP53在细胞内的表达,将荷人肝癌的移植瘤裸鼠随机分为空白对照组（腋下接种未感染任何病毒的CD45-CD90+细胞）、空载体对照组（腋下接种感染空载体慢病毒pPRIME的CD45-CD90+细胞）和实验组（腋下接种感染空载体慢病毒AFP-WtP53-pPRIME-miR30-shRNA-IGF1R的CD45-CD90+细胞）,检测各组的IGF1R表达,微血管密度和细胞凋亡程度。结果 成功构建anti-AFP介导的慢病毒;qRT-PCR和Western blotting检测显示,anti-AFP介导的慢病毒能表达Wtp53并同时干扰IGF1R的表达。体内实验显示,与空白对照组和空载体对照组相比,实验组肿瘤的潜伏期较长,肿瘤体积较小,瘤组织的IGF1R水平、微血管密度较低,但凋亡指数较高,差异有统计学意义（P＜0.05）。结论 anti-AFP介导的慢病毒可高效特异性转染肝癌干细胞CD45-CD90+ 双靶点基因系统,起到杀伤肝癌干细胞及抑制肝癌体内生长的作用。     

蜂毒素对人肝癌BEL-7402细胞裸鼠皮下移植瘤生长及肿瘤血管生成的影响

背景与目的:蜂毒素体外抗骨肉瘤、白血病及宫颈癌的研究已有报道.我们先前的实验发现蜂毒素能够抑制人肝癌细胞株BEL-7402细胞增殖,并诱导其凋亡.本研究拟探讨蜂毒素在裸小鼠体内的抗肝癌作用及其对肿瘤血管生成的影响.方法:建立人肝癌BEL-7402细胞裸鼠皮下移植瘤模型,随机分为5组:生理盐水对照组(10 ml/kg)、阳性对照组(沙利度胺,200 mg/kg)、蜂毒素低剂量组(40 μg/kg)、蜂毒素中剂量组(60 μg/kg)和蜂毒素高剂量组(80 μg/kg).测量各组裸鼠肿瘤体积,观察蜂毒素的体内抗肿瘤作用.光镜下观察肿瘤组织及瘤内血管形态.采用免疫组织化学SABC法检测微血管密度(microvessel density,MVD)及血管内皮细胞生长因子(vascular endothelial growth factor,VEGF)、碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)和核转录因子κB(nuclear factor κB,NF-κB)蛋白表达.应用实时荧光定量PCR法检测BEL-7402细胞VEGF mRNA和bFGF mRNA的表达.结果:蜂毒素低、中、高剂量组裸鼠肿瘤相对体积(V/V0)分别为4.42±0.58、3.47±0.97和3.06±1.23,与生理盐水对照组(V/V0为9.06±1.45)相比,蜂毒素处理组肿瘤体积明显缩小(P＜0.01).与生理盐水对照组MVD(16.50±2.35)比较,蜂毒素低、中、高剂量组肿瘤组织MVD(11.33±1.86、9.17±1.17和6.67±1.21)明显降低(P＜0.01).显微镜下可见蜂毒素各剂量组肿瘤组织呈片状坏死,肿瘤间质内可见肿瘤血管,并有血管破坏现象.蜂毒素低、中、高剂量组肿瘤组织VEGF(2.59±0.27、2.61±0.17和1.55±0.22)、bFGF(2.45±0.78、2.27±0.36和2.10±0.27)及NF-κB(2.79±0.29、2.71±0.66和2.26±0.56)阳性表达指数均低于生理盐水对照组(3.80±0.60、4.43±0.34和4.98±0.63)(P＜0.01).实时荧光定量PCR检测显示,蜂毒素能够抑制BEL-7402细胞VEGF mRNA和bFGF mRNA的表达.结论:蜂毒素能够明显抑制人肝癌BEL-7402细胞裸鼠移植瘤的生长,影响NF-κB表达、下调VEGF和bFGF的表达、抑制肝癌血管生成可能是其抗肿瘤作用的重要机理之一.     

抗肝癌重组免疫毒素对荷人肝癌裸鼠移植瘤生长的抑制作用

目的:观察二硫键稳定人源化抗肝癌单链抗体(humanized disulfide stabilization single chain antibody,hdsFv)融合牛蛙核糖核酸酶(rana catesbeiana ribonuclease,RC-RNase)重组免疫毒素(hdsFv-RC-RN-ase)对荷人肝癌裸鼠移植瘤生长的抑制作用。方法:将人肝癌细胞系SMMC-7721细胞接种于裸鼠皮下,建立荷人肝癌裸鼠移植瘤动物模型,随机分为3组,分别经尾静脉注射给予生理盐水、盐酸多柔比星和抗肝癌hdsFv-RC-RNase治疗,疗程为2周。通过测量各实验组裸鼠肿瘤体积及瘤质量变化,绘制肿瘤生长曲线并计算抑瘤率。治疗结束后取各组裸鼠肿瘤组织及重要器官HE染色,光学显微镜下观察。结果:治疗后hdsFv-RC-RNase组与空白对照组相比较,荷人肝癌裸鼠移植瘤生长速度显著减慢,肿瘤体积和瘤质量明显减小,P<0·01;同样,与盐酸多柔比星组相比较差异有统计学意义,P<0·01。hdsFv-RC-RNase组和盐酸多柔比星组抑瘤率分别为(78·9±4·1)%和(70·3±6·6)%,P<0·01。光学显微镜下观察hdsFv-RC-RNase组和盐酸多柔比星组肿瘤组织出现明显坏死,尤以前者更为显著。各实验组裸鼠重要器官未见明显异常。结论:抗肝癌hdsFv-RC-RNase重组免疫毒素对荷人肝癌裸鼠移植瘤生长具有良好的抑制作用。     

Isomalto oligosaccharide sulfate inhibits tumor growth and metastasis of hepatocellular carcinoma in nude mice

Background  

Hepatocellular carcinoma (HCC) usually has a dismal prognosis because of its limited response to current pharmacotherapy and high metastatic rate. Sulfated oligosaccharide has been confirmed as having potent antitumor activities against solid tumors. Here, we explored the preclinical effects and molecular mechanisms of isomalto oligosaccharide sulfate (IMOS), another novel sulfated oligosaccharide, in HCC cell lines and a xenograft model.     

低分子肝素对肝癌血管抑制作用的实验研究

目的研究低分子肝素对肝癌血管形成的抑制作用.方法采用人肝癌裸鼠转移模型(LCI-D20).40只模型鼠随机分成4组即对照组(生理盐水)、化疗组(顺铂 氟尿嘧啶)、肝素组(法安明)、联合组(顺铂、氟尿嘧啶与法安明).观察肿瘤大小和转移、抑瘤率、测血清AFP、肿瘤微血管密度(MVD)和血管内皮生长因子(VEGF)的表达.结果对照组、化疗组、低分子肝素组、联合组的肿瘤体积分别为25245±13367 mm3、2610±1217 mm3、5883±3131 mm3和5556±2570 mm3;抑瘤率为0%、93.62%、76.70%和77.99%;MVD为20.67±6.80、18.17±2.64、4.83±1.83和6.50±2.35;VEGF阳性率为90%、80%、30%和30%;AFP为121.80±31.34 ng/ml、21.45±13.29 ng/ml、75.60±29.74 ng/ml和55.82±37.98 mg/ml;肝转移率分别为80%、70%、20%和10%;肺转移率为70%、60%、20%和10%;腹壁转移率为90%、60%、40%和40%;腹水形成率为20%、10%、0%和0%.低分子肝素组、联合组分别与对照组比较,对肝癌生长的抑制作用有显著差异(P＜0.05),低分子肝素对肝癌血管形成和转移有良好的抑制作用,与对照组及单纯化疗组比较有统计学意义(P＜0.05).结论低分子肝素通过抗肿瘤血管形成,对肝癌的生长与转移有抑制作用.     

反义端粒酶RNA基因对裸鼠肝癌移植瘤的抑制作用

目的:研究反义人端粒酶RNA基因(human telomerase RNA ,hTR)在裸鼠体内对肝癌移植瘤的抑制作用。方法： BALB/c裸鼠前肢腋窝皮下注射HepG2肝癌细胞构建移植瘤模型,以携反义hTR逆转录病毒质粒PLXSNhTRBamHⅠ瘤体内注射治疗（每次0.2 ml,共5次）,以注射正义hTR逆转录病毒质粒PLXSNhTREcoRⅠ和生理盐水为对照,测量肿瘤体积,计算抑瘤率;HE染色观察瘤组织病理变化; TUNEL法检测肿瘤组织细胞的凋亡。结果：反义hTR治疗组肿瘤生长较正义hTR治疗组及生理盐水组明显减慢,反义hTR组抑瘤率为26.78%,明显高于正义hTR组的1.93%（P< 0.01）。反义hTR治疗组较正义hTR治疗组及生理盐水组瘤组织坏死面积、肿瘤细胞凋亡率均明显增加（均P< 0.01）。结论：反义hTR在裸鼠体内能够显著抑制肝癌移植瘤的生长,促进肿瘤细胞的凋亡。     

Antitumor effect of deferoxamine on human hepatocellular carcinoma growing in athymic nude mice.

BACKGROUND. Iron is essential for the growth of all living cells. One of the important intracellular roles for iron is in the activation of ribonucleotide reductase, the enzyme that catalyzes the first step in DNA synthesis. Thus, the intracellular iron level may serve as a regulator of cell growth. The authors tested the hypothesis that lowering body iron concentration inhibits the growth of human-derived hepatocellular carcinoma (HCC) cells by depleting these cells of iron. Deferoxamine (DFO), an iron-chelating agent, was used to lower intracellular iron level. METHODS. HCC cells, PLC/PRF/5 (7 x 10(6) cells/mouse), were transplanted subcutaneously into athymic nude mice. When tumors reached 200-300 microliters in size, mice with comparable tumor sizes were paired; one was treated with DFO (300 mg/kg body weight/day, 5 days/week) intraperitoneally while the other received no treatment. RESULTS. Eight pairs of mice with HCC were observed for 5-18 weeks. Mean tumor growth rates (TGR) (mean +/- standard error) for the untreated and treated mice were 30.5 +/- 3.7 microliters/week and 11.9 +/- 1.5 microliters/week. The difference was significant (P < 0.02). In the second set of studies, DFO treatment was begun when the tumor size was smaller (100-200 microliters). Four pairs of mice were observed for 4-15 weeks; mean TGR for the four untreated mice was 18.1 +/- 5.1 microliters/week. In two mice treated with DFO, tumors regressed completely by the seventh week after initiation of treatment. The two remaining mice on DFO therapy had much slower growing tumors, with a mean TGR of 1.8 +/- 0.5 microliters/week. CONCLUSIONS. Thus, our results suggest that (1) reduction of intracellular iron concentration by DFO may be useful as antitumor therapy in HCC and (2) the favorable effects of DFO treatment are best seen when treatment is begun when the tumor is small.     

Targeting study of human hepatocellular carcinoma (HCC) using human HCC model in nude mice

Fifty-three nude mice bearing human HCC were used for targeting study of HCC using 131I-antihuman HCC isoferritin IgG. Of these mice, 17 were used for radioimaging with 131I-labeled IgG, 131I-labeled albumin and 131NaI. In labeled IgG group, all tumors were positively visualized by gamma camera with the best imaging on the 7th day after injection of labeled IgG (200 microCi, ip), the tumor/liver radioactivity ratio being 2.7. The dose of tumor radioactivity at the 7th day was 7-10 times higher than that in labeled albumin group. Thirty-six mice were used for the study of radioimmunotherapy with 131I-labeled IgG, 131NaI and IgG (n = 9, 300 microCi/50 micrograms, ip). The tumor inhibition rate in the labeled IgG group at 4th week after treatment was significantly higher than those of the other groups (81%, 60% and 18%, respectively, P less than 0.05). Tumor cell DNA analysis showed that the tumor cells were inhibited in S stage of the cell cycle. In the same way, five kinds of substances with affinity to HCC were studied in this animal model. The result indicates that the transplantable nude mice-human HCC model is acceptable for targeting study of HCC.     

Radioimmunotherapy combined with chemotherapy and immunotherapy for nude mice bearing human hepatocellular carcinoma

A comparative study of multiple modalities, radioimmunotherapy combined with cisplatin and MBV was made. The tumor size and macrophage activity (acid phosphatase) were measured after treatment. The results showed that the tumor inhibition rates were 48, 55, 74, 76, 79% in radioimmunotherapy, cisplatin, radioimmunotherapy + MBV, radioimmunotherapy + cisplatin and radioimmunotherapy + MBV + cisplatin groups, respectively. Radioimmunotherapy was effective in controlling tumor growth, especially in sequential treatment by two injections. Both cisplatin and MBV could increase therapeutic effect of radioimmunotherapy. Therefore, combination of the three modalities is the best choice for tumor growth control. The effectiveness of MBV may be related to the increase of macrophage activity. Preliminary clinical results were satisfactory. Decline in serum AFP level and shrinkage of tumor were observed in 80% (12/15) and 65% (13/20) of the patients. It is suggested that combination of multiple treatment modalities may provide an important approach to treat moderately advanced liver cancer.     

Radiotherapy alternated with chemotherapy and immunotherapy on nude mice bearing human hepatocellular carcinoma

A comparative study of multiple modalities of multiple fractions of external radiation per day (MFD), routine radiation (RD), cisplatin (CDDP), mixed bacterial vaccine (MBV), MFD + CDDP. MFD + MBV, MFD + CDDP + MBV on nude mice bearing human hepatocellular carcinoma (HCC) were investigated. The tumor size and serum alpha fetoprotein (AFP) level were measured. The results showed that the tumor inhibition rates were 97%, 94%, 79%, 2% for the MFD, RD, CDDP, and MBV groups, respectively. No tumor disappeared (complete regression) in single modality groups. When MFD was used in combination with CDDP and/or MBV, the tumor cure rates were remarkably increased. The tumor inhibition rate was 99% in the MFD + MBV group, in which two tumors disappeared, 99% in the MFD + CDDP group as well, in which five tumors disappeared. The greatest effectiveness was observed in the MFD + MBV + CDDP group with tumor inhibition rate of 100%, in which eight tumors disappeared. In all these groups, the AFP level was decreased as the tumor size reduced. Preliminary clinical results were satisfactory, the decrease of the serum AFP level and shrinkage of tumor were observed in 88% (7/8) and 91% (10/11) of patients, respectively.     

裸鼠中人肝细胞癌转铁蛋白受体的分子显像研究

目的探讨~(99m)Tc-转铁蛋白(Tf)对肝细胞癌的诊断价值。方法以~(99m)Tc标记Tf进行Balb/c小鼠体内生物分布,对Tf受体阻断前后的Balb/c人肝癌细胞系SMMC-7721nu/nu裸鼠进行显像研究,测定SMMC-7721细胞膜Tf受体数及125I-Tf与Tf受体的解离常数(Kd)。结果~(99m)Tc-Tf主要分布于肝、血及肾脏。荷人肝癌SMMC-7721裸鼠注入~(99m)Tc-Tf后18h,肿瘤/血、肿瘤/肝及肿瘤/肌肉的比值分别为24.2、1.7和35.5,非标记Tf抑制前后小鼠肿瘤摄取率的比值为16.3。人肝癌SMMC-7721细胞膜Tf受体数为2.4×105/细胞,Kd为4.46nmol/L。结论~(99m)Tc-Tf在高表达Tf受体的肿瘤病变部位特异性聚积,~(99m)Tc-Tf有望用于肝细胞癌Tf受体显像。     

Human ferritins present in the sera of nude mice transplanted with human neuroblastoma or hepatocellular carcinoma

Fifteen nude mice were inoculated with a human neuroblastoma cell line and 14 with a human primary hepatocellular carcinoma cell line. Human ferritins were detected in the sera of the mice which developed tumors. Of 14 mice bearing human neuroblastoma, 12 had human liver-type ferritin (8 to 52 ng/ml) in their sera, and three of these also had HeLa-type ferritin (acidic ferritin) (29 to 40 ng/ml). Of 10 nude mice bearing human primary hepatocellular carcinoma, eight had human liver-type ferritin (10 to 820 ng/ml), and one of these had HeLa-type ferritin at a level of 43 ng/ml. Since the ferritins in the sera of these mice were produced by the human tumor cells, these observations support the hypothesis that the elevated ferritins often found in the serum of patients with cancer are, in part, derived from their tumors.     

环氧合酶-2及其抑制剂与子宫内膜癌

环氧合酶-2(COX-2)参与子宫内膜癌的发生、发展,可能影响其预后.COX-2在子宫内膜癌中的表达诱导肿瘤细胞增殖,抑制细胞凋亡,促进肿瘤细胞侵袭和转移.因此,COX-2抑制剂有望成为子宫内膜癌新的防治方法.     

Mebendazole inhibits growth of human adrenocortical carcinoma cell lines implanted in nude mice

Adrenocortical carcinoma is a rare tumor of the adrenal gland which requires new therapeutic approaches as its early diagnosis is difficult and prognosis poor despite therapies used. Recently, mebendazole has been proved to be effective against different cancers. The aim of our study was to evaluate whether mebendazole may result therapeutically useful in the treatment of human adrenocortical carcinoma. We analyzed the effect of mebendazole on human adrenocortical carcinoma cells in vitro and after implantation in nude mice. In order to clarify mechanisms of mebendazole action, metastases formation, apoptosis and angiogenesis were also investigated. Mebendazole significantly inhibited cancer cells growth, both in vitro and in vivo, the effects being due to the induction of apoptosis. Moreover, mebendazole inhibited invasion and migration of cancer cells in vitro, and metastases formation in vivo. Overall, these data suggest that treatment with mebendazole, also in combination with standard therapies, could provide a new protocol for the inhibition of adrenocortical carcinoma growth.