Carcinoma hepatocellular

A comprehensive study of the tolerance of laboratory animals to vapors of 2-nitropropane was reported in 1952 (100). In a study pubHshed in 1979, rabbits and rats survived exposure to nitromethane for six months at 750 and 100 ppm, respectively, with no unexpected findings (101). Similarly, no compound-related effects were found for rabbits exposed to 2-nitropropane at 200 ppm or for rabbits or rats exposed at 27 ppm. Liver damage was extensive in male rats exposed at 207 ppm for six months, and hepatocellular carcinomas were observed. Subsequendy, the International Agency for Research on Cancer (lARC) found that there is "sufficient evidence" to conclude that 2-nitropropane causes cancer in rats but that epidemiologic data are inadequate to reinforce the conclusion in humans (102). The National Toxicology Program also concluded that it "may reasonably be anticipated to be a carcinogen" (103). 

Hepatitis B virus (HBV) Hepatocellular carcinoma Progenomic RNA Inhibition of viral gene expression... 

Kim Y, Yoon JW, Xiao X et al (2007) Selective down-regulation of glioma-associated oncogene 2 inhibits the proliferation of hepatocellular carcinoma cells. Cancer Res 67(8) 35 83-3593... 

HBV infection remains a major worldwide public health problem. The World Health Organization estimates that there are still 350 million chronic carriers of the vims, who are at risk of developing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The success of IFN-a treatment - mainly performed as combined treatment with adenine-arabinoside - has been measured by the normalization of liver enzymes, loss of HBe antigen and of detectable viral DNA in the serum of patients. It has been estimated from several clinical trials that as many as 40% of treated HBV patients would respond to therapy with IFN-a or combined treatment with nucleoside analogues and IFN-a. 

Similar to HBV, infections with hepatitis C virus (HCV) have a high rate of progression from an acute to a chronic state that frequently leads to cirrhosis or hepatocellular carcinoma [2]. Monotherapy for HCV infection with IFN-a or combined therapy with ribavirin and IFN-a is associated with initial rates of response as high as 40%. The rates of sustained responses are, however, lower and also depend on the viral genotype. In patients infected with HCV genotype 2 or 3, the response was maximal after 24 weeks of treatment, whereas patients infected with genotype 1 -the most frequent in the USA and Europe - required a minimum treatment course of 48 weeks for an optimal outcome. 

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

Hepatocellular carcinoma (HCC) develops in patients with chronic liver diseases associated with hepatitis B and hepatitis C vims infections with high incidences. Here, an acyclic retinoid has been shown to suppress the posttherapeutic recurrence after interferon-y or glycerrhicin treatment in cirrhotic patients who underwent curative treatment of preceding tumors. The retinoid induced the disappearance of serum lectin-reactive a-fetoprotein (AFP-L3), a tumor marker indicating the presence of unrecognizable tumors in the remnant liver, suggesting a deletion of such minute (pre)malignant clones (clonal deletion). As a molecular mechanism of the clonal deletion, a novel mechanism of... 

Okuno M, Kojima S, Moriwaki H (2001) Chemopreven-tion of hepatocellular carcinoma concepts, progress and perspectives. J Gastroenterol Hepatol 16 1329-35... 

Worldwide, 15 million HBsAg carriers are also infected with hepatitis D/delta virus (HDV) (Gaeta et al. 2000). This situation represents a major therapentic challenge, as most of these patients have advanced liver disease, inclnding cirrhosis in 60-70% of cases, and hepatocellular carcinoma (Fattovich et al. 2000 Saracco et al. 1987). No specific HDV inhibitors have been developed, and IFN-a-based treatment is more difficnlt in HBV-HDV infection than in HBV monoinfection. HDV RNA levels in sernm can be nsed to monitor treatment efficacy. The endpoint of therapy is HDV RNA clearance and ALT normalization, and this is sometimes achieved after the end of treatment. A snstained response can lead to HBsAg clearance from serum. 

Lin SM, Yu ML, Lee CM, Chien RN, Sheen IS, Chu CM, Liaw YE (2007) Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma. J Hepatol 46 45-52... 

Individuals with chronic hepatitis B have a high risk to develop cirrhosis and, once cirrhosis is present, the 5-year cumulative risk to develop hepatocellular carcinoma is about 10-15% (Fattovich et al. 2004). 

Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH (2006) Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295(l) 65-73... 

The list of vimses involved in other human cancers includes hepatitis B, which is associated with hepatocellular carcinoma human papilloma viruses with cervical, penile and some anal carcinomas human T-cell lymphotropic virus type 1 associated with adult T-cell leukaemia/lymphoma syndrome and HIV with Kaposi s sarcoma. 

The liver is an organ that shows variable effects from trichloroethylene among species, and this can probably be attributed to interspecies differences in metabolism (see Section 2.4.2.1). Specifically, the apparent difference in susceptibility to trichloroethylene-induced hepatocellular carcinoma between humans and rodents may be due to metabolic differences (see Section 2.4.2.3). Kidney effects are also variable among species. Humans and mice are less sensitive than rats. In rats exposed chronically to trichloroethylene, toxic nephrosis characterized as cytomegaly has been reported (NTP 1988). The kidney effects in rats do not seem to be related to an increase in alpha-2 -globulin (Goldsworthy et al. 1988). Effects on the nervous system appear to be widespread among species, presumably due to interactions between trichloroethylene and neuronal membranes. 

The amino acid sequence of the human erythrocyte glucose transporter was deduced from the nucleotide sequence of a cDNA clone in 1985 [106]. Polyclonal antibodies raised against the protein were used to screen a Xgtl I cDNA library prepared from the human hepatocellular carcinoma cell line HepG2. (Like many other transformed... 

Iron overload is known to be toxic and potentially fatal. The major pathological effects of hepatic iron overload are fibrosis and cirrhosis, and hepatocellular carcinoma (Bonkovsky, 1991). The role of free radicals in the pathology of hepatic iron overload has been the subject of a detailed review recently (Bacon and Britton, 1990). 

Hereditary hemochromatosis is an autosomal recessive disease of increased intestinal iron absorption and deposition in hepatic, cardiac, and pancreatic tissue. Hepatic iron overload results in the development of fibrosis, hepatic scarring, cirrhosis, and hepatocellular carcinoma. Hemochromatosis can also be caused by repeated blood transfusions, but this mechanism rarely leads to cirrhosis. 

Only 10% to 15% of patients have acute hepatitis C that resolves without any further sequelae.10 In more than 85% of cases, hepatitis C develops into a chronic disease. Approximately 70% of chronic HCV cases progress to mild, moderate, or severe hepatitis. While the natural history of the progression to cirrhosis is not clear, it is estimated that 10% to 20% of cases may take up to 20 to 40 years from the time of exposure to advance from fibrosis to cirrhosis.10 Fifteen to twenty percent of patients infected with HCV develop complications associated with cirrhosis. Once cirrhosis is confirmed, the rate of developing hepatocellular carcinoma increases to 1% to 4% per year.10 The estimated death rate from HCV infection is 1.8 deaths per 100,000 persons per year.12,15... 

General outcomes for treating hepatitis are to (1) prevent the spread of the disease (2) prevent and treat symptoms (3) suppress viral replication (4) normalize hepatic aminotransferases (5) improve histology on liver biopsy and (6) decrease morbidity and mortality by preventing cirrhosis, hepatocellular carcinoma, and ESLD. 

Hepatitis B virus is a blood-borne or sexually transmitted virus. Most acute infections occur in adults, while chronic infections usually occur in individuals infected as infants or children. However, about 10% of adults who contract hepatitis B virus will fail to clear their infection and develop chronic hepatitis B infection. Individuals with chronic hepatitis B infection are at risk for cirrhosis or hepatocellular carcinoma. Vaccination with hepatitis B vaccine is the most effective way to prevent hepatitis B infection.6... 

Yang X, Lu P, Fujii C, et al. Essential contribution of a chemokine, CCL3, and its receptor, CCR1, to hepatocellular carcinoma progression. Int J Cancer 2006 118 1869-1876. 

T. Konno and H. Maeda, Targeting chemotherapy of hepatocellular carcinoma Arterial administration of SMANCS/Lipiodol, in Neoplasm in the Liver (K. Okada and K. G. Ishak, eds.), Springer-Verlag, New York, 1987, p. 343. 

The following example is based on a risk assessment of di(2-ethylhexyl) phthalate (DEHP) performed by Arthur D. Little. The experimental dose-response data upon which the extrapolation is based are presented in Table II. DEHP was shown to produce a statistically significant increase in hepatocellular carcinoma when added to the diet of laboratory mice (14). Equivalent human doses were calculated using the methods described earlier, and the response was then extrapolated downward using each of the three models selected. The results of this extrapolation are shown in Table III for a range of human exposure levels from ten micrograms to one hundred milligrams per day. The risk is expressed as the number of excess lifetime cancers expected per million exposed population. 

Seco-3,4-taraxerone and seco-3,4-friedelin 2 abrogated the survival of human hepatocellular carcinoma (Hep-G2) and human epidermoid carcinoma (A-431) cell lines cultured in vitro with IC50 values of 11.7 and 38.2 mM, and inhibited the enzymatic activity of topoisomerase at dose of 7 pM (35). 

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