Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of cycloprodigiosin hydrochloride (cPrG-HCl), a new H(+)/Cl(-) symporter, were examined in liver cancer cell lines in vitro and in vivo. In the in vitro MTT assay, cPrG-HCl inhibited the growth of 6 liver cancer cell lines (Huh-7, HCC-M, HCC-T, dRLh-84, and H-35, hepatocellular carcinoma; HepG2, hepatoblastoma) in a dose- and time-dependent manner. The 50% inhibitory concentrations (IC(50)) at 72 hours' treatment for liver cancer cell lines were 276 to 592 nmol/L, while that for isolated normal rat hepatocyte was 8.4 micromol/L. The cPrG-HCl treatment of Huh-7 cells induced apoptosis as confirmed by the appearance of a subG(1) population, intranucleosomal DNA fragmentation, and chromatin condensation. cPrG-HCl raised the pH of acidic organelles and lowered pHi (below pH 6.8). In addition, the apoptosis in Huh-7 cells induced by cPrG-HCl was strongly suppressed when the cells were cultured with imidazole, a cell-permeable base. In the in vivo assay, nude mice bearing subcutaneous xenografted Huh-7 cells received 2 weeks of treatment with cPrG-HCl (1 or 10 mg/kg/d) subcutaneously. This treatment significantly inhibited tumor growth compared with the control after 8 days. The control mice were treated with 1% dimethylsulfoxide (DMSO) in saline (vehicle). A histopathological examination using the terminal deoxynucleotidyl transferase mediated dUTP biotin nick end labeling (TUNEL) method showed apoptosis in the treated tumor cells. No pathological changes were observed in any organs, and the serum alanine transaminase levels remained within normal limits. These results suggest that cPrG-HCl may be useful for the treatment of hepatocellular carcinoma.
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PMID:Cycloprodigiosin hydrochloride, a new H(+)/Cl(-) symporter, induces apoptosis in human and rat hepatocellular cancer cell lines in vitro and inhibits the growth of hepatocellular carcinoma xenografts in nude mice. 1049 40

Inhibitory effects of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on the proliferation of a variety of cancer cell lines have been extensively reported. We have studied the effect of 1,25-(OH)2D3 (10(-11)-10(-6) M) on the proliferation of a number of human and rat liver cancer cell lines. Additionally, the effect of 1,25-(OH)2D3 (0.02-0.5 microg/kg per day) on the rate of growth of liver cancer cell line xenografts in nude mice was also investigated. In vitro, proliferation of Hep-3B, PLC/PRF/5, and SKHEP-1 cells was significantly inhibited by 1,25-(OH)2D3, while HTC and Novikoff cells were more resistant to the inhibitory effects of the drug. In vivo, treatment of SKHEP-1 tumor bearing nude mice with different doses of 1,25-(OH)2D3 significantly retarded tumor growth without the development of hypercalcemia.
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PMID:In vitro and in vivo inhibition of liver cancer cells by 1,25-dihydroxyvitamin D3. 1076 28

Dichloroacetate (DCA) is an important by-product of the chlorination of drinking water that produces liver cancer in rodents. Assessment of the risk that results from concentrations that occur in drinking water will be dependent upon the mode of action held responsible for these tumors. A study by Stauber and Bull [Stauber, A.J. and Bull, R. J (1997) Differences in phenotype and cell replicative behavior of hepatic tumors inducted by dichloroacetate (DCA) and trichloroacetate (TCA). Toxicol. Appl. Pharmacol. 144, 235-246] in mice treated with DCA demonstrated a lesion distribution that was skewed towards many small, altered foci of cells that are assumed to be precursor lesions [EPA, (1996). U.S. Environmental Protection Agency: Proposed Guidelines for carcinogen risk assessment; notice. Fed. Reg. 61, pp. 17960-10811]. The present study was designed to determine the extent to which the tumorigenic effects of DCA could be explained by its effect on tumor growth rates (i.e. tumor promoting activity). In vivo magnetic resonance imaging (MRI) allowed accurate determination of growth rates of individual lesions in mice that had been treated with DCA in drinking water at 2 g/l. Out of thirty treated mice, ten were found to have hepatic tumors detectable by MRI at 48 weeks of treatment. These tumor-bearing animals were assigned to two groups matched on the size of lesions observed by in vivo MR1. Treatment with DCA continued in one group of five mice and was stopped in the other. For both groups, tumor growth rates were determined by measuring changes in size of all lesions greater than 1 mm(3) in volume during a 14-day period. Removal of DCA treatment resulted in growth rates that could not be distinguished from zero across all lesion sizes represented in the sample. These data are in agreement with previous observations of DCAs effects on replication rates within tumors (Stauber and Bull, (1997)). Tumor growth rates observed in animals maintained on treatment decreased with lesion volume in a manner that is consistent with a stochastic Gompertz birth-death process proposed by Tan [Tan, W.Y. (1986) A stochastic Gompertz birth-death process. Stat. Prob. Lett. 4, 25-28]. Parameters of this model obtained by fitting measured growth rates were used to predict the lesion-size distribution expected after one year of DCA treatment. The shape of the predicted lesion-size distribution was similar to that observed by Stauber and Bull (Stauber and Bull, (1997)) in mice sacrificed after 40 weeks of DCA treatment. We conclude that the effects of DCA on the division and/or death rates of spontaneously initiated cells can account for the predominance of small lesions in DCA-treated animals.
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PMID:In vivo MRI measurements of tumor growth induced by dichloroacetate: implications for mode of action. 1077 Nov 36

New data show that perioperative cytostatic therapy is beneficial in the case of liver transplantation for hepatic cancer. However, it has not been established clearly whether chemotherapy interferes with graft rejection. We therefore studied the interactions between tumor growth and graft rejection, especially with regard to chemotherapy, using a combined tumor/transplantation model. As a tumor model, we used the Novikoff hepatoma, a malignant hepatoma that was injected subcutaneously into the backs of rats. Heterotopic heart grafting served as the transplantation model. In a first step (a), we studied the effect of cytostatic therapy on tumor growth: tumor cells were injected, and in four groups epirubicin, cyclosporine, epirubicin + cyclosporine, and placebo were applied, in corresponding groups, transplantation was additionally performed. Tumor growth was measured and the resected tumors were examined by histology and immunohistology. In a second step (b), we studied the effect of chemotherapy on graft rejection: transplantation was performed and the above-mentioned drugs were applied; in corresponding groups, a solid tumor was additionally induced and resected immediately before transplantation. The results of these procedures were as follows: (a) Epirubicin decreased tumor growth and diminished the volume-increasing effect of cyclosporine significantly. After transplantation, tumor growth was similar. (b) Epirubicin prolonged graft survival significantly, and the combination with cyclosporine had an augmenting effect. In the corresponding groups, graft survival was similar. In conclusions. chemotherapy diminishes the tumor-increasing effect of cyclosporine and does not interfere negatively with graft survival. It might therefore be beneficial after transplantation for malignancy.
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PMID:The efficacy of adjuvant cytostatic therapy after organ transplantation for malignancy: an experimental study with a combined transplantation/tumor model. 1083 50

Endostatin inhibits angiogenesis and tumor growth in mice. The role of its endogenous precursor collagen XVIII in human cancer is unknown. In normal tissues, two variants of collagen XVIII, namely, the short and long forms regulate tissue specificity, the long form being almost exclusively expressed by hepatocytes in the liver. We analyzed RNA arrays from 57 hepatocellular carcinomas (HCCs) with common and variant-specific probes and investigated the relationships between collagen XVIII expression and angiogenesis by measuring the CD34-positive microvessel density. Low collagen XVIII expression by tumor hepatocytes was associated with large tumor size (r, -0.63; P < 0.001) and replacement of trabeculae with pseudoglandular-solid architecture (chi2, 28; P < 0.001), which indicate tumor progression. Tumors expressing the highest collagen XVIII levels were smaller and had lower microvessel density (P = 0.01) than those expressing moderate levels; and HCCs with the lowest collagen XVIII levels approached a plateau of microvessel density, which indicated that a decrease in collagen XVIII expression is associated with angiogenesis in primary liver cancer. HCCs recurring within 2 years of resection showed 2.2-fold lower collagen XVIII mRNA than nonrecurring ones (P = 0.02). The findings relied on the hepatocyte-specific long form. Thus, the endogenous expression of the endostatin precursor decreases along with tumor progression in HCCs.
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PMID:Tumor progression is associated with a significant decrease in the expression of the endostatin precursor collagen XVIII in human hepatocellular carcinomas. 1119 95

Early diagnosis of HCC is possible because certain risk factors for this tumor are known and because sensitive and relatively inexpensive diagnostic tools are available. Early diagnosis of HCC is also possible because of the long phase of asymptomatic tumor growth and the tumor's tendency to grow as a solitary mass in many patients. In two consensus development conferences held in Anchorage, Alaska and in Milan, Italy, chronic carriers of HBsAg, patients with cirrhosis, patients with rare metabolic liver diseases, and individuals with family histories of HCC were identified as patients at high risk for HCC and therefore as candidates for periodic screening. At the Anchorage conference, it was recommended that healthy carriers have at least yearly determinations of serum AFP and that carriers with additional risk factors (e.g., cirrhosis) be screened every 6 months by abdominal US scans and determination of serum AFP levels. No specific recommendations were released for HBsAg-negative patients with chronic liver disease. At the Milan conference, it was recommend that patients with cirrhosis or with certain congenital metabolic conditions known to be at risk for HCC should be screened by AFP determination and US scan twice a year. It was also recommended that HBsAg carriers older than 35 years or with family histories of HCC should be screened for HCC by determinations of serum AFP levels and aminotransferase levels once a year.
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PMID:Screening for cancer in viral hepatitis. 1121 10

Endostatin is an endogenous inhibitor of angiogenesis and tumor growth in mice, which may be generated by proteolytic cleavage of collagen XVIII. In normal tissues, 2 variants of the endostatin precursor, namely the SHORT and LONG forms, regulate tissue specificity. We analyzed 53 human liver biopsies (18 hepatocellular carcinomas, 16 metastases of colorectal cancer, 3 cholangiocarcinomas, and 16 controls) by RNA dot blots, double-labeling immunohistochemistry, and in situ hybridization, using common and variant-specific probes. Tumor hepatocytes expressed the LONG form, whereas cholangiocarcinoma cells expressed the SHORT form, which was deposited in tumor basement membranes. Metastatic colorectal carcinoma cells did not express collagen XVIII. In the stromal compartment of primary and metastatic cancers, myofibroblasts and vascular endothelial cells expressed the SHORT form. Both basement membrane components, collagen IV and the SHORT collagen XVIII form, were codistributed and their mRNA levels strongly correlated (R =.75, P <.001). In addition, freshly isolated human hepatocytes expressed the LONG form and culture-activated stellate cells the SHORT form. Moreover, the full-length LONG form is a plasma protein. Thus, the LONG form is a hepatocyte-specific variant, and the SHORT form is a major component of the tumor extracellular matrix in primary and metastatic liver cancers. In the clinical context, the global expression of the endogenous endostatin precursor, collagen XVIII, in liver cancer results from the combined expression profiles of tumor cells, stromal cells, and nontumor hepatocytes at the advancing edge of the tumor, particular to each type of cancer.
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PMID:Tumor hepatocytes and basement membrane-Producing cells specifically express two different forms of the endostatin precursor, collagen XVIII, in human liver cancers. 1128 51

Previous studies have shown that there is a high frequency of loss of heterozygosity (LOH) on chromosome 17p13.3 in hepatocellular carcinoma [HCC (M. Fujimori et al., Cancer Res., 51: 89-93, 1991; H. Nagai et al., Oncogene, 14: 2927-2933, 1997; V. Boige et al., Cancer Res., 57: 1986-1990, 1997; Z. Piao et al., Int. J. Cancer, 75: 29-33, 1998; and B. Charroux et al., J. Cell Biol., 148: 1177-1186, 2000)]. The minimum region of LOH on chromosome 17p13.3 in HCC has been defined within the region between D17S643 and D17S1574. Moreover, D17S926 in the minimum region of LOH has the highest frequency of LOH, and its sequencing analysis has been accomplished. In this region, 6 of 13 novel genes have been characterized (X. Zhao, D. Wan, M. He, Yu. Ye, Yi. He, L. Han, M. Guo, Y. Huang, W. Qin, M-W. Wang, W. Chong, J. Chen, L. Zhang, N. Yang, B. Xu, M. Wu, L. Zuo, and J. Gu. A high frequency LOH region on chromosome 17p13.3 in human HCC with densely clustered genes identified, submitted for publication). Here we describe the cloning and characterization of one of these novel genes, designated HCC suppressor 1 (HCCS1), located at this region. HCCS1 had 18 exons, and its full-length cDNA was 2.0 kb. The protein expression product of HCCS1 was located in mitochondria. HCCS1 had a high frequency of mutations in HCC samples, whereas no alteration has been found in matched noncancerous liver tissues. Immunohistochemistry revealed a significantly higher expression of HCCS1 in the noncancerous liver tissues (33 of 35 samples) than in the HCC samples (2 of 35 samples). Transfection of HCCS1 cDNA into the HCC cell line remarkably reduced the efficiency of its colony formation and inhibited tumor growth in nude mice. Taken together, these findings strongly suggest a potential role of HCCS1 as a HCC putative suppressor gene.
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PMID:A novel growth suppressor gene on chromosome 17p13.3 with a high frequency of mutation in human hepatocellular carcinoma. 1160 66

The matrix metalloprotease (MMP) family of enzymes and the urokinase plasminogen activator (uPA) pathway have both been implicated in tumor invasion and metastasis and in poor prognosis of cancer. We have previously shown that treatment with batimastat, a synthetic MMP inhibitor, leads to significant retardation but not regression of tumor growth in a human breast cancer xenograft model. In addition, batimastat treatment did not inhibit local tumor invasion, nor did it encourage stromal encapsulation of the tumor, suggesting the additional involvement of non-MMP proteolytic mechanisms. To investigate the presence of an alternative extracellular matrix protease whose activity is known to be important in breast cancer, but which is not inhibited by batimastat, expression of murine and human uPA were examined by in situ hybridization and ELISA. No differences were observed between untreated and batimastat-treated tumors regarding human uPA mRNA and protein. In contrast, murine uPA mRNA expression was increased at the tumor-stromal junction in batimastat-treated tumors in comparison with the control tumors. In agreement with these results, batimastat treatment was shown to significantly induce murine uPA protein content in the tumors. Inoculating MDA435/LCC-6 cells into immunodeficient, uPA-deficient mice resulted in tumor growth retardation as compared to tumor growth in littermate wild-type controls, while addition of batimastat treatment to uPA-/- mice did not result in further growth inhibition. The increased expression of stromal uPA may represent a cellular response to MMP inhibition and may demonstrate a new level of plasticity in the malignant progression of the disease. These results may have important implications for the clinical applications of MMP inhibitors, as well as for development of other anti-invasion drugs.
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PMID:Increased stromal expression of murine urokinase plasminogen activator in a human breast cancer xenograft model following treatment with the matrix metalloprotease inhibitor, batimastat. 1172 59

Although neovascularization is regarded as an essential factor for tumor growth, it is unclear whether pancreatic adenocarcinoma is also influenced by this process. Furthermore, the reported microvessel count (MVC) data can not be compared due to the diversity of evaluating methods, and the relation between MVC data and metastatic potentials remains controversial. A total of 24 pancreatic adenocarcinomas and 24 adjacent non-cancerous pancreatic parenchyma were analyzed for MVC using anti-CD31 antibody. In addition, the MVC of 15 hypervascular tumors (10 hepatocellular carcinomas: HCC and 5 islet cell pancreatic tumors: ICT), 30 other types of adenocarcinomas (10 gastric, 10 colon and 10 intraductal papillary mucinous tumors of the pancreas: IPMT), as well as that of non-cancerous areas, were also analyzed. The extent of hepatic and peritoneal spread in 24 pancreatic adenocarcinoma patients was classified and correlations with MVC were evaluated. The mean MVC of 24 pancreatic adenocarcinomas (31.6 +/- 11.1) was actually lower than that of HCCs (91.6) or ICTs (56.4). The diversity is temperate as compared with that of other adenocarcinomas, i.e., 42.9 in gastric carcinomas, 35.6 in colon carcinomas and 32.5 in IPMT. MVC in non-cancerous areas were significantly higher in the pancreas (112.8) than in the stomach (29.6) or colon (26.3). MVC ratios of the cancerous area to the non-cancerous area were significantly lower in the pancreas (0.2818 +/- 0.100) than in the stomach (1.569 +/- 0.526, p<0.001) or the colon (1.423 +/- 0.493, p<0.001). MVC were higher in diffuse hepatic metastasis patients (36.0) than in limited metastasis patients (25.7). In conclusion, MVC in pancreatic adenocarcinoma revealed vascular volume to actually be lower than that of hypervascular tumors. We believe, however, that this hypovascularity is due mainly to contrast with the hyper-vascular non-cancerous pancreas, since MVC in the cancerous area itself was at the same level as in other adenocarcinomas. In addition, we revealed MVC to be of value for predicting the extent of liver metastasis.
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PMID:Neovascularization in pancreatic ductal adenocarcinoma: Microvessel count analysis, comparison with non-cancerous regions and other types of carcinomas. 1183 87


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