Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Androgen receptor (AnR) and estrogen receptor (ER) are known to exist in human hepatocellular carcinoma (HCC), but the low binding capacity casts doubts on the efficacy of endocrinotherapy. However, we focussed on the favorable dissociation constant and displacement of AnR and ER. Efficacy of endocrinotherapy for HCC was investigated using rat HCC cell line (AH66F) resembling the properties of human HCC and sex hormone receptors. In rat HCC AH66F, we confirmed that the AnR and ER were both positive and were mentioned binding capacity, dissociation constant and displacement resembled those of human HCC. In rat HCC AH66F, administrations of Tamoxifen converted AnR and ER responses to negative. Rat HCC AH66F was transplanted intraperitoneally to Donryu rats, various endocrinotherapies administered and the number of survival days compared with a control group. In male and female rats, the number of survival days was both in the orchidectomied (p < 0.01) and the Tamoxifen treated (p < 0.001) group significantly prolonged. However, in the group treated with medroxyprogesterone acetate no significant differences were observed. Also, in experiments with AnR (-) and ER (-) rat HCC cell line AH60C all endocrinotherapies were ineffective. Above results confirmed the efficacy of endocrinotherapy for rat HCC with positive sex hormone receptors.
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PMID:[Experimental studies on endocrine therapy for rat hepatocellular carcinoma]. 856 76

1. Mechanisms of drug toxicity operating in human HepG2 hepatoma cells have been assessed using cyclosporin A (CsA) and tamoxifen as examples. 2. Either 150 microM CsA or 50 microM tamoxifen caused approximately 50% loss of HepG2 cell viability. alpha-Tocopherol (32 microM) almost completely prevented cell death due to either CsA or tamoxifen. Tamoxifen stimulated malondialdehyde formation. The toxicity of CsA but not tamoxifen was increased by the glutathione synthesis inhibitor, buthionine-S,R-sulphoximine, and decreased by the glutathione precursor, L-cysteine. Thus, while both CsA and tamoxifen toxicities involved lipid peroxidation, reduced glutathione (or sulphydryl groups) protected against CsA but not tamoxifen. 3. CsA was metabolized to M1 and/or M17 in HepG2 cells. The effects of the cytochrome P450 inhibitors, ketoconazole and metyrapone, indicated that P450 played a role in the toxicity of CsA but not tamoxifen. The effects of superoxide dismutase and cytochrome c indicated that tamoxifen toxicity involved superoxide formation. 4. These results show that several oxidative mechanisms of drug toxicity operate in HepG2 cells.
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PMID:Drug toxicity mechanisms in human hepatoma HepG2 cells: cyclosporin A and tamoxifen. 857 71

The main adverse effects of tamoxifen, aspirin, oral contraceptives (OCs) and retinoids used as chemopreventive agents in humans are reviewed and quantified here. With regard to tamoxifen, there are suggestions of some excess risk of liver, and perhaps gastrointestinal, cancers. The public health impact of such associations, if any, is still unclear. Tamoxifen use is associated with endometrial and myometrial hyperplasia. Data from five studies based on 174 cases indicate that the overall relative risk (RR) of endometrial cancer in ever tamoxifen users is 1.73 (95% confidence interval = 1.1-2.6). However, there is a significant difference between the results of American and European studies, so the relationship between tamoxifen and endometrial cancer remains open to debate. The major side-effect of aspirin is gastrointestinal lesions; the risk of these is increased two- to tenfold, depending on the dose. Aspirin is also associated with an increased risk of haemorrhagic stroke, although its protection against other types of stroke and against myocardial infarction leads to a favourable pattern of risk for all cardiovascular conditions. Short-term side-effects of OCs include vascular diseases and a moderately increased risk of breast cancer. The RR of cervical cancer and hepatocellular carcinoma are also increased in OC users, although the public health impact of such associations is small. Toxicity associated with retinoid treatment is rarely serious as most effects observed are reversible on stopping use. Side-effects include changes in the skin and mucous membranes (dry skin, hair loss, dry nose, conjunctivitis), musculoskeletal symptoms, ophthalmological effects, changes in transaminase activity, changes in clinical chemistry markers (increase in serum triglycerides and decrease in high-density lipoproteins) and, rarely, central nervous system effects. A serious toxicological aspect of retinoid treatment is teratogenesis; its use should therefore be avoided in women with childbearing potential, and, in cases of use, conception should be delayed for a long time after stopping treatment. Thus, when considering side-effects of chemoprevention, the major issues of concern are the rare long-term effects (chiefly neoplasms), and the need for more precise overall risk-and cost-benefit assessment, particularly for healthy people.
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PMID:Adverse effects of preventive therapy in humans. 892 25

Tamoxifen inhibits the binding of [3H]nitrobenzylthioinosine ([3H]NBMPR) to human MCF-7 breast cancer cells with an IC50 of 8 microM. Tamoxifen at 30 microM changed the apparent Kd for [3H]NBMPR binding from 0.63 +/- 0.12 to 4.75 +/- 0.58 nM, with little effect on the Bmax (311000 +/- 76000 and 263000 +/- 46000 sites per cell for untreated and tamoxifen-treated cells respectively). Corresponding to this decrease in binding of [3H]NBMPR in the presence of tamoxifen was an inhibition of NBMPR-sensitive equilibrative transport of 50 microM [3H]uridine (IC50 7-10 microM). In the presence of 15 microM tamoxifen, the apparent K(m) for [3H]uridine transport was increased from 390 +/- 30 to 1500 +/- 250 microM, with no change in Vmax (12.0 +/- 0.1 and 11.3 +/- 4.3 microM/s for untreated and tamoxifen-treated cells respectively). The inhibitory effect of tamoxifen on NBMPR-sensitive equilibrative uridine transport was specific, as similar results were also observed in HL-60 leukaemia and EL4 lymphoma cells. Furthermore a similar concentration of tamoxifen had no effect on the NBMPR-insensitive equilibrative transport of uridine in MCF-7, HL-60 and Morris 7777 hepatoma cells, and on the Na(+)-dependent transport of uridine in murine splenocytes. In this paper we demonstrate that tamoxifen by itself might have some antiproliferative effects through inhibition of DNA synthesis by blocking the nucleoside salvage pathway.
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PMID:Tamoxifen inhibits nitrobenzylthioinosine-sensitive equilibrative uridine transport in human MCF-7 breast cancer cells. 900 90

Tamoxifen has been used most commonly to treat breast and endometrial cancer, two malignancies in which the antiestrogenic properties of tamoxifen have substantial therapeutic benefit. However, tamoxifen has been used in the treatment of other cancers as well, some in which an antiestrogen may be effective, but others in which estrogen receptor is not expressed. In estrogen receptor-negative cancers, tamoxifen has been shown to have therapeutic activity at doses approximately fourfold to eightfold above those used for estrogen receptor inhibition. It is thought that the primary mechanism of tamoxifen in estrogen-negative tumors is inhibition of protein kinase C. Clinical trials of tamoxifen in ovarian cancer, hepatocellular carcinoma, desmoid tumors, malignant glioma, pancreatic carcinoma, melanoma, and renal cell carcinoma are reviewed.
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PMID:Tamoxifen for the treatment of malignancies other than breast and endometrial carcinoma. 904 18

Human intestinal trefoil factor (hITF) is a small cysteine-rich protein expressed in the gastrointestinal (GI) tract. Its sequence is related to that of other trefoil peptides including the pNR-2/pS2 protein, which is regulated by oestrogen in breast cancer. This study was designed to investigate whether hITF is expressed in human carcinoma cells. cDNA was obtained by reverse transcription-polymerase chain reaction (RT-PCR) of gastric mucosal RNA and sequenced, establishing that this mRNA is expressed in the stomach. Expression of hITF was detected in a proportion of cell lines derived from malignancies of the GI tract, in hepatocellular carcinoma cells, and at highest levels in a small cell lung carcinoma cell line. Amongst breast cancer cell lines, it was expressed in all the oestrogen-responsive but in none of the oestrogen-nonresponsive breast cancer cell lines. The possibility that hITF expression in breast cells is controlled by oestradiol was then tested. Oestradiol treatment increased hITF expression between three- and ten-fold in the oestrogen-responsive breast cancer cell lines, demonstrating that, like pNR-2/pS2, hITF is regulated by oestrogen in breast cancer cells. Tamoxifen inhibited the induction of hITF expression by oestradiol but tamoxifen alone was a partial oestrogen agonist for hITF expression. These results show that hITF is expressed, sometimes ectopically, in several human malignancies, which suggests that trefoil peptides may have a more general role in tumourigenesis than hitherto appreciated. That the expression of hITF is regulated by oestrogen in breast cancer cells suggests that hITF expression may provide a novel marker for oestrogen responsiveness in breast cancer.
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PMID:Expression of human intestinal trefoil factor in malignant cells and its regulation by oestrogen in breast cancer cells. 930 61

To discover whether tamoxifen is able to extend the survival of patients with advanced hepatocellular carcinoma, we included 80 patients with cirrhosis and advanced hepatocellular carcinoma in a multicenter, double-blind, placebo-controlled trial in order to analyze the influence of treatment with tamoxifen on survival. The patients were randomized to receive tamoxifen, 40 mg/day (group 1), or placebo (group 2). Both groups were similar in age, sex, etiology of cirrhosis, biochemical, hematologic and hormonal parameters, morphology of the tumor (nodular vs multinodular or massive), Child-Pugh's score, and Okuda's stage. The 1-year survival rate was similar in both groups (30% in group 1 vs 37.8% in group 2; p = 0.31). Tamoxifen treatment was well tolerated by the patients. We conclude that tamoxifen does not extend the survival of patients with cirrhosis and advanced hepatocellular carcinoma.
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PMID:Tamoxifen does not improve survival of patients with advanced hepatocellular carcinoma. 960 Mar 69

Tamoxifen has become one of the most widely used drugs in the treatment of breast cancer, and concerns about its long-term safety and efficacy are being raised. Investigations in rats have suggested an association between the administration of tamoxifen and the development of hepatocellular carcinoma. However, no studies to date have demonstrated an increased incidence of hepatocellular carcinoma in women treated with tamoxifen. In the case reported, a 56-year-old woman presented with hepatocellular tumours after 6 years of tamoxifen therapy for breast cancer. The patient had no other risk factors for the development of hepatocellular carcinoma. She underwent successful resection of the lesions, and subsequent pathological studies confirmed hepatocellular carcinoma with a trabecular growth pattern similar to the histologic pattern seen in tamoxifen-induced hepatocellular carcinoma occurring in rat models.
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PMID:The association between tamoxifen and the development of hepatocellular carcinoma: case report and literature review. 1037 18

Hepatocellular carcinoma (HCC) is a common, potentially lethal tumor in human patients. Because the serum levels of transforming growth factor-beta1 (TGF-beta1) correlate with outcome in patients with HCC and because TGFbeta1 mRNA expression is increased in HCC tissues, it raises the possibility that TGF-beta1 may be of importance in the development, growth, and metastases of HCC. Tamoxifen has been used for the treatment of human HCC. However, clinical trials have produced conflicting results. To further delineate whether tamoxifen may be of benefit in altering the course of HCC, we documented the effects of 4-hydroxytamoxifen and 17beta-estradiol on TGF-beta1 mRNA and protein levels and cell proliferation in a human HCC cell line. PLC/PRF/5 cells were treated with carrier (controls), 4-hydroxytamoxifen, 17beta-estradiol, or TGF-beta1. 4-Hydroxytamoxifen and 17beta-estradiol decreased TGF-beta1 mRNA and protein levels in a time- and dose-dependent manner. TGF-beta1 significantly inhibited PLC/PRF/5 cell proliferation, whereas both 4-hydroxytamoxifen and 17beta-estradiol stimulated PLC/PRF/5 cell proliferation. The stimulatory effects of 4-hydroxytamoxifen on PLC/PRF/5 cell proliferation raise concerns regarding its use in the treatment of HCC in human patients and suggest that 4-hydroxytamoxifen may have no beneficial effects in some patients with HCC.
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PMID:Regulation of transforming growth factor-beta1 gene expression and cell proliferation in human hepatocellular carcinoma cells (PLC/PRF/5) by tamoxifen. 1040 64

Meta-analysis is increasingly used in hepatogastroenterology. Meta-analysis is of value to provide a systematic review of related trials and to display their results in an objective, easily understandable manner. When the trials are sufficiently homogeneous, meta-analysis can document the superiority, (a), or the lack of superiority (b) of a treatment with respect to another (e.g., (a) Interferon plus ribavirin vs Interferon for chronic hepatitis; (b) 5-ASA vs sulfasalazine for maintaining remission in ulcerative colitis). However the interpretation of meta-analysis requires caution. Meta-analysis can be unreliable or unstable if based on a few, small trials (e.g., Tamoxifen vs non-active treatment for hepatocellular carcinoma), or if distorted by confounding variables and publication bias (e.g., glucocorticoids vs standard treatment in alcoholic hepatitis). Eventually, qualitative heterogeneity makes the pooled results of meta-analysis meaningless or questionable (e.g., endoscopic sclerotherapy for prevention of first variceal bleeding in cirrhosis) and should prompt the search for its sources to plan future studies. Finally, meta-analysis of trials measuring the treatment effect of a drug vs a placebo when an active drug is available for comparison provides the limited informative content for the physician of the individual trials (e.g. 5-ASA vs placebo for maintaining remission in ulcerative colitis).
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PMID:Meta-analysis as a source of evidence in gastroenterology: a critical approach. 1073 May 66


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