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)

The hepatoproliferative and cytochrome P450 enzyme inducing effects of two antiestrogens, tamoxifen and toremifene, were compared in female Sprague-Dawley rats using immunohistochemical staining methods. Equimolar doses of the antiestrogens (tamoxifen 45 mg/kg and toremifene 48 mg/kg) were given by oral administration to 6-week-old rats for 12 months including a 3-month recovery period. Controls received the vehicle carboxymethylcellulose. Altogether 90 rats were used in the study. Five rats per dose group were killed after 14 days, 5 weeks, 3, 6 and 12 months of treatment as well as after the 3-month recovery period. Hepatocellular carcinoma was found in four out of five rats after 12 months of tamoxifen treatment. After the 3-month recovery period all tamoxifen-treated rats had large liver tumors (diameter up to 3 cm). No tumors were observed in toremifene-treated rats. Liver cell proliferation was measured by the index of proliferating cell nuclear antigen (PCNA) expression. Immunohistochemical staining with the placental form of glutathione S-transferase (GST-P) was used as a marker for preneoplastic foci. Cytochrome P450 induction was measured using specific antibodies to isoenzymes. Tamoxifen increased the incidence of GST-P-positive foci significantly by 3 months of treatment but toremifene did not as compared with the controls. Liver cell proliferation increased significantly only in the liver tumors of tamoxifen-treated rats after 12 months of treatment and during the recovery period. Both antiestrogens induced the isoenzymes CYP2B1/2 and CYP3A1 within 14 days although tamoxifen was a more powerful inducer. Immunohistochemistry of rat liver sections showed a centrilobular localization of these induced enzyme proteins. The expression of CYP2B1/2 and 3A1 could also be observed in foci after 3 and 6 months of administration and in liver adenomas and in some carcinomas after 12 months of administration with tamoxifen. The results show that tamoxifen, but not toremifene, has the potential to induce and promote the development of rat hepatocarcinogenesis in this experimental model.
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PMID:Comparison of the effects of tamoxifen and toremifene on rat hepatocarcinogenesis. 1095

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with increasing incidence in Western countries. Many pharmacologic treatments have been tested against HCC; most of them belong to three categories: chemotherapy, hormone therapy, and immunotherapy. Neither single agent nor combination chemotherapy have demonstrated a clear reproducible advantage in terms of overall survival; therefore, systemic or intraarterial chemotherapy should not be considered as standard strategies for patients with HCC. Tamoxifen and antiandrogen therapy were not effective in prolonging survival when tested in randomized, controlled trials. Promising results have been obtained with octreotide in a small randomized trial, but confirmation studies are needed. Although adoptive immunotherapy was effective in the adjuvant setting, interferon should be further investigated in this setting or investigated as a preventive strategy in cirrhotic patients. On the contrary, interferon does not seem to have a role in advanced disease, where it is tolerated poorly. In the future, innovative and promising therapeutic strategies will be tested in HCC, including new biologic target-based drugs, cyclooxygenase inhibitors, and gene therapy.
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PMID:Hepatocellular carcinoma: systemic treatments. 1239 14

In the Asia-Pacific region and elsewhere, almost 85% of patients with hepatocellular carcinoma (HCC) are inoperable at diagnosis and have a dismal prognosis. Tamoxifen (TMX) is believed to inhibit HCC positive for estrogen receptor (ER), but most HCCs are ER negative. Results of previous phase 3 trials in inoperable HCC have been conflicting and inconclusive. At higher doses, however, TMX inhibits HCC through ER-independent mechanisms. A multicenter randomized controlled trial was performed to assess the role of high-dose TMX versus placebo (P) in the treatment of patients with inoperable HCC with respect to survival and quality of life (QoL). A total of 329 patients from 10 centers in 9 countries in the Asia-Pacific region enrolled in a double-blind randomized controlled trial of TMX 120 mg/d (TMX120) against P as a control arm with an intermediate dosage of TMX 60 mg/d (TMX60) to assess possible dose response. An independent data monitoring committee reviewed all aspects of the trial. QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. Three-month survival rates for the P, TMX60, and TMX120 groups were 44%, 41%, and 35%, respectively, with a statistically significant trend difference in survival across the 3 treatment regimens (P =.011). There was a significantly higher risk of death in the TMX120 group compared with the P group (hazard ratio, 1.39; 95% confidence interval, 1.07-1.81). Adverse drug reactions were reported in 3% (9 patients), and 8 patients were lost to follow-up. In conclusion, TMX does not prolong survival in patients with inoperable HCC and has an increasingly negative impact with increasing dose. No appreciable advantage to QoL with TMX was observed.
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PMID:High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial. 1239 33

There is no standard treatment for patients with unresectable hepatocellular carcinoma (HCC). Survival benefits derived from medical interventions are controversial. The aim of this systematic review was to assess the evidence of the impact of medical treatments on survival. Randomized controlled trials (RCTs) that were published as full papers assessing survival for primary treatments of HCC were included. MEDLINE, the Cochrane Library, CANCERLIT, and a manual search from 1978 to May 2002 were used. The primary end point was survival, and the secondary end point was response to treatment. Estimates of effect were calculated according to the random effects model. Sensitivity analysis included methodological quality. We identified 61 randomized trials, but only 14 met the criteria to perform a meta-analysis assessing arterial embolization (7 trials, 545 patients) or tamoxifen (7 trials, 898 patients). Arterial embolization improved 2-year survival compared with control (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.32-0.89; P =.017). Sensitivity analysis showed a significant benefit of chemoembolization with cisplatin or doxorubicin (OR, 0.42; 95% CI, 0.20-0.88) but none with embolization alone (OR, 0.59; 95% CI, 0.29-1.20). Overall, treatment induced objective responses in 35% of patients (range, 16%-61%). Tamoxifen showed no antitumoral effect and no survival benefits (OR, 0.64; 95% CI, 0.36-1.13; P =.13), and only low-quality scale trials suggested 1-year improvement in survival. In conclusion, chemoembolization improves survival of patients with unresectable HCC and may become the standard treatment. Treatment with tamoxifen does not modify the survival of patients with advanced disease.
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PMID:Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. 1254 Jul 94

Hepatocellular carcinoma (HCC) ranks fifth in frequency worldwide among all malignancies and causes 1 million deaths annually. The management of HCC begins with diagnostic confirmation by radiologic imaging or histology. Staging is essential, as the choice of therapy depends on the functional state of the liver and the extent of tumor growth. Surgery, in the form of either hepatic resection or orthotopic liver transplantation, is the only potentially curative treatment. Transarterial chemoembolization is commonly used as either palliative treatment or adjunctive therapy to surgery, and a survival benefit with this therapy has just recently been demonstrated in a randomized, controlled trial. Patients with inoperable HCC may benefit from local ablative therapy that may still have curative potential in those with sufficiently small lesions and adequate liver function. For patients with advanced HCC, systemic chemotherapy has been widely employed, despite low efficacy and significant complication rate. Tamoxifen did not improve survival in large clinical trials. Gene therapy is an exciting approach to treating HCC but is still largely confined to preclinical and experimental settings.
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PMID:Management of hepatocellular carcinoma. 1268 89

Effective therapy for advanced hepatocellular carcinoma (HCC) is lacking. Conventional chemotherapy was judged to be ineffective. We previously demonstrated that the histone deacetylase inhibitor Trichostatin A (TSA) blocks growth of HCC cells in vitro. The anti-tumoral effect of a combination of more than 2 classes of drugs remains unexplored. Four hepatoma cell lines were incubated with increasing concentrations of Tamoxifen (TAM), 9-cis retinoic acid (CRA), the methioninaminopeptidase inhibitor TNP-470 and TSA as single agents and in combination. Anti-proliferative and pro-apoptotic effects were assessed using BrdU-incorporation, FACS analysis and immunocytochemistry. Central pro- and anti-apoptotic proteins were measured by semi-quantitative Western blotting and substrate assays. All single substances inhibited proliferation and induced apoptosis in HCC cells only at high concentrations. The combination of TAM/CRA/TNP/TSA multiplied the anti-tumoral effects, reaching up to 93% inhibition of proliferation and 63% induction of apoptosis after 24 h in Hep1B cells. Pro-apoptotic factors bax and caspase 3 were highly increased with quadruple therapy, while anti-apoptotic bcl-2 decreased to undetectable levels. Fibroblasts remained largely unaffected. While the single substances were not effective on hepatoma cells in tolerable doses, their combination significantly increases anti-tumoral efficacy. Combination therapy with biomodulators is a promising treatment option for HCC.
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PMID:A quadruple therapy synergistically blocks proliferation and promotes apoptosis of hepatoma cells. 1506 30

Hepatocellular carcinoma (HCC) is not only common, but often presents at a stage when potentially curative therapies are not feasible. Although hepatic artery chemoembolization likely confers survival benefit in unresectable HCC, the associated toxicities are substantial and warrant investigation of more efficacious and safe therapies. Many patients who present with unresectable HCC are not chemoembolization candidates, either because of extensive disease or severely impaired hepatic function. We reviewed 44 randomized trials investigating non-embolization-based therapies in unresectable HCC. Hepatic artery infusion of [I]lipiodol appears safe; initial studies suggest a survival benefit and efficacy comparable to more toxic embolization-based therapies. Some cytotoxic chemotherapy may confer a modest survival benefit in advanced HCC (including oral fluoropyrimidines, and hepatic arterial or i.v. cisplatin and doxorubicin). Tamoxifen does not confer survival benefit, either in advanced or limited HCC. Other therapies warranting further study include interferon (in optimally cytoreduced HCC), megestrol in patients with variant estrogen receptors, octreotide and pravastatin. More adequately powered, rigorously conducted studies will hopefully identify useful chemo-, radio-, immuno-, embolization-based and biologically targeted therapies during the next decade.
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PMID:Therapy for unresectable hepatocellular carcinoma: review of the randomized clinical trials-II: systemic and local non-embolization-based therapies in unresectable and advanced hepatocellular carcinoma. 1516 17

Hepatocellular carcinoma is the fifth most common malignant disorder and causes nearly 1 million deaths a year worldwide. A background of cirrhosis is the major risk factor, and in Asia and subSaharan Africa, cirrhosis is attributable mainly to endemic hepatitis B infection. In Europe and the USA the incidence of hepatocellular carcinoma is increasing as a result of the high prevalence of hepatitis C. The only curative treatments are surgical resection or liver transplantation, but only a few patients are eligible for these procedures. Local ablative treatments such as ethanol injection can lengthen survival in selected patients, and radiofrequency ablation also shows promise. Unfortunately, most patients are suitable only for palliative treatment because of the extent of their tumour or background liver disease or both. For these patients, a wide range of therapeutic interventions have been assessed, including transarterial embolisation (with or without chemotherapy), hormone therapy with antioestrogens and androgens, octreotide, interferon, and both arterial and systemic chemotherapy, of which only chemoembolisation improves survival over symptomatic care. Tamoxifen is ineffective, and there are insufficient randomised data to show the benefit of any other intervention. In this review, we focus on two ends of the therapeutic spectrum--transplantation, which is highly effective but applicable to only a few patients, and systemic chemotherapy, which is of uncertain benefit but widely applicable.
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PMID:Systemic treatment and liver transplantation for hepatocellular carcinoma: two ends of the therapeutic spectrum. 1523 Dec 47

Hepatocellular carcinoma (HCC) is one of the most common malignancies world wide. Several experimental treatments have been tested against HCC. Those are chemotherapy, high dose proton beam radiotherapy, external beam radiotherapy, cyberknife, antibody-directed therapy and immunotherapy. Neither single nor combination therapy have demonstrated any clear reproducible benefit in terms of overall survival. Tamoxifen and antiandrogen therapy were not effective in prolonging survival when tested in randomized controlled trial. The modern radiation therapy concept such as intensity-modulated, image-guided, and stereotactic body radiation therapy may show promising effects on HCC. The increasing promise of targeted drug therapy in cancer needs to be particularly pursued in the treatment of HCC, in which cytotoxic agents are not usually effective. Other approaches include hormonal manipulation, immunotherapy, and specific inhibition of angiogenesis or growth factors. These issues stress the need for basic research in carcinogenesis in general and HCC in particular.
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PMID:[Experimental treatment of hepatocellular carcinoma]. 1584 52

Hepatocellular carcinoma (HCC) is common worldwide and growing in importance in the West. HCC often occurs against a background of liver disease, tends to present at an advanced stage, and has a poor prognosis, suggesting that it is an ideal target for chemoprevention. We sought to identify in an animal model chemopreventive agents for HCC that might be tested in human subjects. To this end, we induced liver tumors by injecting ethyl-nitrosourea in 6-week-old male B6C3F1 mice. Two chemopreventive agents were administered over a period of 60 weeks: tamoxifen (420 mg/kg feed) and a retinoid, 13-cis-retinoic acid (200 mg/kg feed). Animals were killed at 60 weeks and their livers examined for HCC and premalignant lesions. All liver lesions (altered foci, adenomata, HCC) occurred significantly less frequently in the tamoxifen-treated group than the group given only ethylnitrosourea (HCC developed in 2 of 47 (4%) vs 11 of 44 (25%); P < .001). On the other hand, retinoic acid appeared to increase the number of liver tumors, and in 2 animals angiosarcoma developed. Tamoxifen significantly decreased the incidence of chemical hepatocarcinogenesis in this model, suggesting an important role for estrogens in the pathogenesis of HCC and suggesting that it should be tested in human beings as a chemopreventive agent against HCC.
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PMID:Chemoprevention of hepatocellular carcinoma: use of tamoxifen in an animal model of hepatocarcinogenesis. 1587 4


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