2-Acetylaminofluorene ; Angiogenesis Inhibitors ; pharmacology ; Animals ; Carcinoma, Hepatocellular ; chemically induced ; metabolism ; pathology ; Immunohistochemistry ; Liver ; drug effects ; metabolism ; pathology ; Liver Neoplasms, Experimental ; chemically induced ; metabolism ; pathology ; Male ; NF-kappa B ; antagonists & inhibitors ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Thalidomide ; pharmacology

Anticarcinogenic effect of red ginseng (Panax ginseng C.A. Meyer cultivated in JiLin, China) on the development of liver cancer induced by diethylnitrosamine (DEN) in rats was studied, especially in preventive and curative groups. In the preventive group, the rats were given with DEN concomitantly with red ginseng fluid, and in the curative group, the rats were administered with red ginseng fluid after they developed liver cancer nodules induced by DEN. The result of the preventive group revealed that the developmental rate of liver cancer in the experimental group was 14.3%, while 100% in the control group, with the difference being statistically significant. DNA, RNA, glycogen, gamma-GT, SDH, and 5'-NT were maintained at relatively normal level in experimental group, and decreased or increased in the control group. The result of curative group showed that hepatoma nodules of the DEN-red ginseng group I were smaller than those of control group I, the structure of hepatic tissue was well preserved, the area with gamma-GT positive was smaller, and the ultrastructure of hepatocytes was normal. The average life span the DEN-red ginseng group II and the DEN control group II were 72.8 and 42.3 days, respectively. To sum up, all findings on preventive and curative groups had clearly proved that the red ginseng had the anticarcinogenic effect on the development of liver cancer induced by DEN in rats.
Animal ; Anticarcinogenic Agents/*pharmacology ; Carcinoma, Hepatocellular/chemically induced/*pathology ; Data Interpretation, Statistical ; Diethylnitrosamine/adverse effects ; Liver/pathology/ultrastructure ; Liver Neoplasms, Experimental/chemically induced/*pathology ; Male ; *Panax ; Plant Extracts/pharmacology ; Rats ; Rats, Wistar

Aflatoxin B1 ; toxicity ; Animals ; Carcinoma, Hepatocellular ; chemically induced ; metabolism ; Cell Transformation, Neoplastic ; Liver ; pathology ; Male ; Rats ; Rats, Sprague-Dawley ; beta Catenin ; metabolism

To investigate the influence of bear bile on rat hepatocarcinoma induced by diethylnitrosamine (DEN), a total of 40 rats were randomly divided into 4 groups: normal control group, model group, and two bear bile treatment groups. The rat liver cancer model was induced by breeding with water containing 100 mg x L(-1) DEN for 14 weeks. The rats of the bear bile groups received bear bile powder (200 or 400 mg x kg(-1)) orally 5 times per week for 18 weeks. The general condition and the body weight of rats were examined every day. After 18 weeks the activities of serum alanine transaminase (ALT), aspartate transaminase (AST) and total bilirubin (TBIL) were detected. Meanwhile, the pathological changes of liver tissues were observed after H&E staining. The expression of proliferative cell nuclear antigen (PCNA) and a-smooth muscle actin (alpha-SMA) in liver tissue were detected by immunohistochemical method. After 4 weeks the body weights of rats in normal group were significantly more than that in other groups (P < 0.05); and that in the two bile groups was significantly more than that in the model group. Compared with normal group, the level of serum glutamic-pyruvic transaminase and total bilirubin increased significantly in other groups; compared with model group, these two indexes decreased significantly in two bile groups. Hepatocellular carcinoma occurred in all rats except for normal group; there were classic cirrhosis and cancer in model group while there were mild cirrhosis and high differentiation in two bile groups. There were almost no expressions of PCNA and alpha-SMA in normal group while there were high expressions in model group; the two bile groups had some expressions but were inferior to the model group, and alpha-SMA reduced markedly. It indicated that bear bile restrained the development of liver cancer during DEN inducing rat hepatocarcinoma, which may be related to its depressing hepatic stellate cell activation and relieving hepatic lesion and cirrhosis.
Actins ; metabolism ; Alanine Transaminase ; blood ; Animals ; Antineoplastic Agents ; pharmacology ; Aspartate Aminotransferases ; blood ; Bile ; chemistry ; Bilirubin ; blood ; Body Weight ; drug effects ; Carcinoma, Hepatocellular ; blood ; chemically induced ; pathology ; Diethylnitrosamine ; Liver ; metabolism ; pathology ; Liver Cirrhosis ; chemically induced ; pathology ; Liver Neoplasms, Experimental ; blood ; chemically induced ; pathology ; Male ; Powders ; pharmacology ; Proliferating Cell Nuclear Antigen ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Ursidae

BACKGROUND/AIMS: ErbB receptor proteins are transmembrane tyrosine kinase receptors; when they are activated by interaction with ligands, they generate diverse cellular responses, especially during lesion development and progression to cancer. In this study the expression of ErbB receptors and TGF-alpha were investigated using an experimental cirrhosis rat model giving rise to hepatocellular neoplasms, similar to human liver diseases. METHODS: Fifty three male rats received intraperitoneal injection of diethylnitrosamine (DEN, 50 mg/kg), weekly for 18 weeks. Until the eighth week, two rats were sacrificed every two weeks and from the tenth to the eighteenth week, five rats were sacrificed weekly. Grossly, dyschromatic and dysmorphic nodules were counted and categorized into three groups: N1/N2/N3: 3 mm < or = x < 5 mm/5 mm < or = x < 10 mm/x > or = 10 mm in diameter. All nodules were examined, histologically. Antibodies for GSTp, TGF-alpha, EGF-R, ErbB2, ErbB3 and ErbB4 were used for immunohistochemistry. RESULTS: The onset of cirrhoses was noted from the twelfth week. Preneoplastic foci, hepatocellular adenomas (HCA) and hepatocellular carcinomas (HCC) were noted from the second, eleventh and fifteenth week, respectively. The nodules (N1/N2/N3: 397/258/64) included regenerating nodule; RN (N1/N2/N3: 72.3%/15.9%/0%), HCA (N1/N2/N3: 27.2%/82.2%/7.6%) and HCC (N1/N2/N3: 0.5%/ 1.9%/92.4%). EGF-R was expressed in 12.5% of RN, 64.7% HCA and 75.2% HCC. TGF-alpha was expressed in 92.4% of RN, 91.3% HCA and 93.2% HCC. Sixty eight percent of TGF-alpha expressing nodules showed concurrent EGF-R expression. ErbB2 was expressed in 83.6% of RN, 72.9% HCA and 88.7% HCC. ErbB4 was expressed in 95.2% of RN, 86.3% HCA and 62.5% HCC. CONCLUSIONS: Increased expression of EGF-R and decreased expression of ErbB4, might be related with tumor progression during DEN-induced hepatocarcinogenesis.
Adenoma, Liver Cell/chemically induced/metabolism/pathology ; Animals ; Carcinoma, Hepatocellular/chemically induced/*metabolism/pathology ; Diethylnitrosamine ; Glutathione Transferase/metabolism ; Immunohistochemistry ; Liver Neoplasms, Experimental/chemically induced/*metabolism/pathology ; Male ; Rats ; Rats, Wistar ; Receptor, Epidermal Growth Factor/*metabolism ; Receptor, erbB-2/*metabolism ; Transforming Growth Factor alpha/*metabolism

BACKGROUND/AIMS: We investigated the effects of sorafenib monotherapy on advanced hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT) in a clinical setting. METHODS: In total, 143 consecutive patients with unresectable HCC were treated with sorafenib. Among these patients, 30 patients with advanced HCC and PVTT (Vp3 or 4) were treated with sorafenib monotherapy. RESULTS: All patients had a performance status of 1 to 2 (Eastern Cooperative Oncology Group 1/2, 20/10) and Child-Pugh class A or B (A/B, 17/13). Eleven patients had modified Union for International Cancer Control stage IVA tumors, whereas 19 had stage IVB tumors. All patients had PVTT (Vp3, 6; Vp4, 24). Following sorafenib monotherapy, three patients (10.0%) had a partial response with PVTT revascularization, and nine (30.0%) had stable disease, with a disease control rate of 33.3%. The median overall survival was 3.1 months (95% confidence interval [CI], 2.70 to 3.50), and the median progression-free survival was 2.0 months (95% CI, 1.96 to 2.05). Fatigue and hand-foot skin reactions were the most troublesome side effects. CONCLUSIONS: A limited proportion of patients with advanced HCC and PVTT exhibited a remarkable outcome after sorafenib monotherapy, although the treatment results in this type of patient is extremely poor. Further studies to predict good responders to personalized therapy are warranted.
Adult ; Aged ; Aged, 80 and over ; Anorexia/chemically induced ; Antineoplastic Agents/adverse effects/*therapeutic use ; Carcinoma, Hepatocellular/*drug therapy/pathology ; Diarrhea/chemically induced ; Disease-Free Survival ; Fatigue/chemically induced ; Female ; Hand-Foot Syndrome/etiology ; Humans ; Kaplan-Meier Estimate ; Liver Neoplasms/*drug therapy/pathology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Nausea/chemically induced ; Neoplasm Invasiveness ; Niacinamide/adverse effects/*analogs & derivatives/therapeutic use ; Phenylurea Compounds/adverse effects/*therapeutic use ; Portal Vein/*pathology ; Proportional Hazards Models ; Tomography, Spiral Computed ; Venous Thrombosis/*drug therapy/pathology

OBJECTIVETo screen the differentially expressed proteins especially at the precancerous stage of diethylnitrosamine (DEN) induced hepatocarcinogenesis by comparative proteome research.

METHODSRats were divided into normal and DEN groups and sacrificed periodically. The liver samples were stained with gamma-glutamyl transpeptidase (GGT) and HE to distinguish the preneoplastic lesion (pre-HCC) from the normal and HCC tissues. The two-dimensional electrophoresis (2-DE) and mass spectrometry (MALDI-TOF-MS/MS) were then applied to analyze the differentially expressed protein between pre-HCC and normal tissues, pre-HCC and HCC, as well as HCC and normal tissues. A few of the candidate proteins such as laminin receptor 1 (67LR) and agmatinase were validated by Western blot and RT-PCR.

RESULTSTotally, there were 82 proteins that differentially expressed two fold or more in one kind of tissues sample than the other, 47 of which occurred in the pre-HCC tissues. Eight proteins including 67LR were consistently up-regulated from normal tissue to pre-HCC and then to HCC tissues, while 22 proteins including agmatinase showed progressively down-regulated in these tissues samples.

CONCLUSIONThe protein expression profiles are different during the process of hepatocarcinogenesis. Further study on the differentially expressed protein, especially these upregulated in the precancerous stage such as 67LR and agmatinase, might contribute to prevention and early diagnosis of human HCC.

Animals ; Blotting, Western ; Carcinoma, Hepatocellular ; chemically induced ; metabolism ; pathology ; Diethylnitrosamine ; Liver ; metabolism ; pathology ; Liver Neoplasms, Experimental ; chemically induced ; metabolism ; pathology ; Male ; Neoplasm Proteins ; metabolism ; Precancerous Conditions ; metabolism ; pathology ; Proteins ; metabolism ; Proteome ; Rats ; Rats, Wistar ; Receptors, Laminin ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Ureohydrolases ; metabolism ; gamma-Glutamyltransferase

Although continuous low-dose (metronomic [MET]) therapy exerts anti-cancer efficacy in various cancer models, the effect of long-term MET therapy for hepatocellular carcinoma (HCC) remains unknown. This study assessed the long-term efficacy of MET on suppression of tumor growth and spontaneous metastasis in a rat model of HCC induced by administration of diethylnitrosamine for 16 wk. The rats were divided into 3 groups: MTD group received intraperitoneal (i.p.) injections of 40 mg/kg cyclophosphamide on days 1, 3, and 5 of a 21-day cycle; Control and MET groups received i.p. injections of saline and 20 mg/kg cyclophosphamide twice a week, respectively. Anti-tumor and anti-angiogenic effects and anti-metastatic mechanisms including matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were evaluated. Twelve wk of MET therapy resulted in a significant reduction in intrahepatic tumors than control or MTD therapy. The MET group had fewer proliferating cell nuclear antigen-positive cells and decreased hypoxia-inducible factor-1alpha levels and microvessel density. Lung metastases were detected in 100%, 80%, and 42.9% in the control, MTD, and MET groups, respectively. MET therapy significantly decreased expression of TIMP-1, MMP-2 and -9. For mediators of pro-MMP-2 activation, MET therapy induced significant suppression in the TIMP-2 and MMP-14 level. The survival in the MET group was significantly prolonged compared to the control and MTD groups. Long-term MET scheduling suppresses tumor growth and metastasis via its potent anti-angiogenic properties and a decrease in MMPs and TIMPs activities. These results provide a rationale for long-term MET dosing in future clinical trials of HCC treatment.
Animals ; Antineoplastic Agents/*administration & dosage/*pharmacology ; Carcinoma, Hepatocellular/chemically induced/*drug therapy/mortality/pathology ; Cell Proliferation/drug effects ; Cyclophosphamide/*administration & dosage/*pharmacology ; Diethylnitrosamine ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic/*drug effects ; Liver Cirrhosis/chemically induced ; Liver Neoplasms/chemically induced/*drug therapy/mortality/pathology ; Lung Neoplasms/drug therapy/pathology/secondary ; Male ; Matrix Metalloproteinases/metabolism ; Neovascularization, Pathologic/enzymology/physiopathology ; Rats ; Rats, Sprague-Dawley ; Survival Analysis ; Tissue Inhibitor of Metalloproteinases/metabolism ; Tumor Burden/drug effects

OBJECTIVETo observe the efficacy and safety of sorafenib monotherapy in Chinese patients with advanced hepatocellular carcinoma (HCC).

METHODSThirty-eight patients with advanced HCC of Child-Pugh status A or B were included in this study. Patients received orally administered sorafenib at a dose of 400 mg twice a day on a continuous schedule. Adverse events were documented. The efficacy and safety were evaluated every four to six weeks.

RESULTSDuring the treatment, partial response (PR) was observed in 1 patient (2.6%), minor response (MR) in 5 (13.2%), stable disease (SD) in 16 (42.1%), and progressive disease (PD) in 16 (42.1%), respectively. The median oral administration time of sorafenib was 180 days (range, 15-550 d), and the mean overall survival was 370 days (range, 42-562 days). The median response duration was 169 days (range, 42-426 days). The mean overall survival of 22 patients with controlled disease (PR + MR + SD) was 428 days (95% CI 330-526 days). The most frequent adverse events were dermal reaction (27 cases, 71.1%), gastrointestinal reaction (25 cases, 65.8%), and constitutional symptoms (14 cases, 36.8%). Most of the drug related adverse events were mild and easily to manage and reversible.

CONCLUSIONSorafenib monotherapy is effective and tolerable in a part of Chinese patients with advanced hepatocellular carcinoma and liver function of Child-Pugh A or B, and may prolong their survival.

Adult ; Aged ; Antineoplastic Agents ; adverse effects ; therapeutic use ; Benzenesulfonates ; adverse effects ; therapeutic use ; Carcinoma, Hepatocellular ; drug therapy ; pathology ; Diarrhea ; chemically induced ; Female ; Foot Dermatoses ; chemically induced ; Hand Dermatoses ; chemically induced ; Humans ; Liver Neoplasms ; drug therapy ; pathology ; Male ; Middle Aged ; Neoplasm Staging ; Niacinamide ; analogs & derivatives ; Phenylurea Compounds ; Protein Kinase Inhibitors ; adverse effects ; therapeutic use ; Pyridines ; adverse effects ; therapeutic use ; Remission Induction ; Survival Rate ; Syndrome ; Young Adult

OBJECTIVETo evaluate the effect and adverse effects of arsenic trioxide (As2O3) in the treatment of primary hepatocarcinoma patients, and conduct the pharmacokinetics study.

METHODSA total of one hundred and eleven advanced primary hepatocarcinoma patients in five centers were treated with As2O3 injection 7 - 8 mg/m(2) i.v. qd for 14 days and was repeated after 7 - 14 days. Evaluation of the clinical response and adverse effects was conducted after two cycles of treatment. The patient who had reached partial PR and SD was treated continuously until disease progression or intolerance.

RESULTSAmong the 102 patients evaluable for clinical efficacy analysis, there were 7 PR, 71 SD and 24 PD, the response rate was 6.9% and the clinical benefit rate was 76.5%. The quality of life was improved in 22.5% of patients. The pain relief rate was 71.7%, time to progress (TTP) was 97 days, and the median survival time (MST) was 195 days. The major adverse effects were reversible WHO I-II grade gastrointestinal reactions and bone marrow suppression. The results of pharmacokinetic study showed that the distribution and elimination characteristics in vivo was found to be a two-compartment model. The plasma elimination half-life was (23.94 ± 18.39) h.

CONCLUSIONSAs2O3 is effective in the management of primary hepatocarcinoma, with a significant analgesic effect. To some extent, it can extend TTP and MST in advanced liver cancer patients, while the treatment is well tolerated in the majority of patients.

Adult ; Aged ; Antineoplastic Agents ; administration & dosage ; adverse effects ; pharmacokinetics ; therapeutic use ; Arsenicals ; administration & dosage ; adverse effects ; pharmacokinetics ; therapeutic use ; Carcinoma, Hepatocellular ; blood ; drug therapy ; pathology ; Disease Progression ; Female ; Follow-Up Studies ; Half-Life ; Humans ; Injections ; Leukopenia ; chemically induced ; Liver Neoplasms ; blood ; drug therapy ; pathology ; Lung Neoplasms ; drug therapy ; secondary ; Lymphatic Metastasis ; Male ; Middle Aged ; Nausea ; chemically induced ; Neoplasm Staging ; Oxides ; administration & dosage ; adverse effects ; pharmacokinetics ; therapeutic use ; Quality of Life ; Remission Induction ; Survival Rate ; Vomiting ; chemically induced