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)

Tamoxifen (TXF), a triphenylethylene antiestrogen, is the major therapeutic agent for breast cancer. In rare cases, TXF treatment appears to increase incidence of endometrial cancer. Also in rats, TXF was found to induce hepatocellular carcinoma. Previous studies suggested that metabolism of TXF may contribute to its antiestrogenic and anticancer activity. The current study demonstrates a novel route of TXF metabolism. TXF is metabolized by rat and human liver microsomes into a reactive intermediate (txf*) which binds irreversibly to microsomal proteins. The binding requires NADPH and O2 and is inhibited by CO, inhibitors of P-450, and antibodies to rat NADPH-P450 reductase, indicating catalysis by P450. Phenobarbital treatment of rats markedly increases binding, suggesting the involvement of induced P450s. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of proteins from incubation of [14C] TXF with phenobarbital-treated microsomes exhibits a major radiolabeled zone which corresponds to a molecular weight of approximately 54,000, suggesting binding to a P-450. Cysteine and glutathione inhibited the binding of TXF without significantly affecting P-450-mediated metabolism of TXF, possibly by reacting with txf* or by competing for the same binding sites. Exposure of phenobarbital-treated microsomes and control-microsomes to 50 degrees C for 90 s, which inactivates the flavin-containing monooxygenase (FMO), diminished binding and pH 8.6 enhanced binding. Also, alternate FMO substrates inhibited binding. These findings indicate that P-450 and possibly FMO catalyze the reactions leading to the formation of txf*. However, incubations with single-labeled and dual-radiolabeled tamoxifen or with [14C]TXF-N-oxide demonstrated that monodesmethyl-TXF and TXF-N-oxide, the principal P-450 and FMO-mediated metabolites, respectively, are not on the major route of txf* formation, indicating that txf* could not be an aldehyde derived from tamoxifen nitrone. Thus, though the structure of txf* was not characterized, certain possibilities were excluded. Speculations on the structure of txf* and on its possible pharmacological and toxicological activity are presented.
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PMID:Cytochrome P-450-mediated activation and irreversible binding of the antiestrogen tamoxifen to proteins in rat and human liver: possible involvement of flavin-containing monooxygenases in tamoxifen activation. 193 68

Because prolonged estrogen therapy can initiate hepatic adenomas, and estrogen receptors (ER) are found in 33% of hepatocellular carcinomas, a Phase II study of antiestrogen therapy was initiated in patients with hepatocellular carcinoma. Tamoxifen (20 mg twice a day) was administered to 33 patients who had biopsy proven and measurable hepatocellular carcinoma and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. No patient had a complete or partial antitumor response; eight patients had stable disease ranging from 5 to 13 months. The median survival time for all patients was 6 months from the initiation of tamoxifen therapy. Four patients have continuing long-term survival of 18+, 22+, and 39+ months.
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PMID:A phase II trial of tamoxifen in hepatocellular carcinoma. 216 Mar 13

Following reports that specific estrogen receptors could be detected in samples of hepatocellular carcinoma tissue, a prospective randomized controlled trial was undertaken in 59 patients, half of whom received doxorubicin (60 mg/m2 at 3-week intervals) and half doxorubicin and tamoxifen (10 mg twice per day). Response occurred in three (11%) of those patients receiving doxorubicin alone and in four (16%) of those given both drugs. This difference was not statistically significant nor was the difference in survival when compared by life-table analysis. One patient treated with both drugs achieved complete remission for 30 months which was maintained (on tamoxifen alone) for 18 months before death from a non-tumor-related condition. Tamoxifen may have a role in maintenance of doxorubicin-induced remissions.
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PMID:Controlled clinical trial of doxorubicin and tamoxifen versus doxorubicin alone in hepatocellular carcinoma. 244 52

A 52 years old female with hepatocellular carcinoma (HCC) was treated successfully with Tamoxifen. The tumor involved IV hepatic segment with hilar extension and biliary obstruction, was unresectable, and had been pretreated with hormone-chemotherapy. Tamoxifen treatment induced a PR of 6 months, with normalization of serum bilirubin, reduction of alfa-fetoprotein level and improvement of PS, and was free of toxicity. At disease progression intra-arterial chemotherapy with Cis platinum (CDDP) and 5-FU gave a further 4 months PR, until disease progression and exitus in hepatic coma. Tamoxifen therapy, even in the absence of E.R. assay is a useful tool in the management of HCC patients. Further randomized studies are necessary to ascertain the role of Tamoxifen in the treatment of HCC.
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PMID:[Hepatocellular carcinoma (HCC): the long-term response to tamoxifen. A clinical case report and review of the literature]. 256 Jan 53

Recent studies on HCC treatment reveal a tendency to use combined immuno-chemo-therapy. Additionally, new agents have been suggested in this field. We therefore studied 7 patients with proven inoperable HCC who were treated in accordance with the following protocol, and 5 untreated patients used as controls. Therapeutic trial: 1) 1FNa (Roferon): 6 MU x 7 days consecutively every 3 weeks, 2) Adriamycin (doxorubicin): 60 mg/m2 i. v. once every 3 weeks (500 mg total dose), 3) Tamoxifen: 10 mg p.o. twice daily continuously 4) Desferrioxamine (DFO): 500 mg i.m. daily x 7 days consecutively every 3 weeks, 5) ascorbic acid: 300 mg p.o. daily 1 hour after DFO administration x 7 days consecutively every 3 weeks. Follow-up studies were performed monthly and comprised clinical, biochemical, radiological and immunological (T-cell subsets, NK cells, monocyte-macrophage function, IL-2r expression, HLA-DR expression) parameters. Compared with the control group, the treated group had a longer survival rate (p < 0.001), increased tumor regression and less progressive disease. Immunologically, the treated patients with the maintenance of a sufficient immune status were associated with a prolonged survival rate. No serious side effects of the regimen were observed. In conclusion, IFNa combined with chemohormonal therapy appears to be beneficial in HCC patients. In addition, a prolonged survival rate might correlate with the maintenance of an adequate immune status in the patients.
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PMID:Recombinant a2 interferon (a-IFN) with chemo-hormonal therapy in patients with hepatocellular carcinoma (HCC). 778 31

Thirty-six consecutive patients with advanced hepatocellular carcinoma and chronic liver disease were randomly allocated to two groups: group I included 20 patients who were treated with 10 mg bid. tamoxifen and group II with 16 non-treated patients. The two groups were homogeneous according to clinical and analytical data. Survival curves in the tamoxifen-treated patients improved significantly when compared with the non-treated group (p = 0.01). Cumulative survival at the end of the first year was 48.5% in the treated patients and 9.1% in controls. Median survival was 261 days in the treated group vs. 172 in the non-treated group (p < 0.05). Complications of cirrhosis and worsening of the performance status test occurred less in the treated patients than in the controls, but not significantly so. Tamoxifen was well tolerated and no marked side effects were observed. In this series, tamoxifen improved survival in patients with advanced hepatocellular carcinoma.
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PMID:Controlled trial of tamoxifen in patients with advanced hepatocellular carcinoma. 793 Apr 68

Tamoxifen is the major therapeutic agent for the treatment of hormone-dependent breast cancer. Tamoxifen treatment appears to be associated with an increased incidence of endometrial carcinoma in humans and hepatocellular carcinoma in rats. These carcinogenic effects of tamoxifen might be induced by the formation of a tamoxifen reactive intermediate that binds covalently to macromolecules. Liver microsomal cytochrome P450s (CYPs) catalyze the metabolism of tamoxifen, forming a reactive intermediate that binds irreversibly to microsomal proteins, primarily to a 54 kDa protein (Mani, C. and Kupfer, D., Cancer Res., 51, 6052-6058, 1991). The current study identifies the P450 enzymes that catalyze the activation of tamoxifen to a reactive intermediate in rats and humans. Among the species examined, rats, chickens and humans demonstrate low tamoxifen binding activity, ranging from 0.1 to 0.4 nmol bound/mg protein/h. In contrast, hamsters and mice exhibit high binding, 1.2 and 1.6 nmol/mg protein/h respectively. Treatment of male rats with phenobarbital or pregnenolone-16 alpha-carbonitrile (PCN) markedly elevated the binding of tamoxifen to liver microsomal proteins. Methylcholanthrene treatment had no effect on binding. These findings suggested the involvement of CYP3A in catalysis of the covalent binding. Alternate substrates of CYP3A, cortisol and erythromycin, inhibited tamoxifen binding in liver microsomes from PCN- and phenobarbital-treated rats. Treatment of rats with troleandomycin (TAO), an inducer of CYP3A, followed by the dissociation of the TAO-CYP3A complex, elevated the covalent binding to liver microsomes approximately 3-fold. Antibodies against rat CYP3A1 strongly inhibited tamoxifen binding to liver microsomes from PCN- and phenobarbital-treated rats, whereas the antibodies anti-CYP2B1/2B2 did not inhibit binding. In humans, tamoxifen binding was inhibited by the anti-rat CYP3A1 IgG and also by alternate substrates of CYP3A. These results indicate that the activation of tamoxifen to a reactive intermediate by rat and human liver microsomes is principally catalyzed by CYP3A enzymes.
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PMID:Involvement of cytochrome P4503A in catalysis of tamoxifen activation and covalent binding to rat and human liver microsomes. 800 Dec 26

Tamoxifen (TAM) is a triphenylethylene antiestrogen used for the treatment, and in clinical trials for the prevention, of breast cancer in women. In rats, TAM is a strong liver carcinogen which induces the formation of liver DNA adducts. The DNA of 24 hepatocarcinomas (HCCs) collected at necropsy from individual female Sprague-Dawley rats that were given 22.6 mg/kg TAM daily for 12 months was studied for the presence of mutations in exons 5-9 of the p53 gene by single-strand conformation polymorphism and DNA sequencing analysis. The sequences of introns 5-8 of the rat p53 gene were determined in order to design primers homologous to regions located in these introns. p53 mutations were found in 50% (12 of 24) of the HCCs. These mutations were all specifically clustered in two sites, codons 231 (exon 6-7) and 294 (exon 8). Nine HCCs contained a transition from adenine to guanine in the second base of codon 231 (CAC to CGC), which resulted in a histidine to arginine amino acid substitution; 4 HCCs contained a nonmiscoding transition from cytosine to thymidine in the third base of codon 294 (TGC to TGT; cysteine to cysteine). One HCC contained both mutations. The present report supports previous observations on the genotoxicity of TAM in rodents and raises concerns about its use as a chemopreventive agent against breast cancer in women.
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PMID:Frequent and specific mutations of the rat p53 gene in hepatocarcinomas induced by tamoxifen. 803 8

This article reports a prospective randomized controlled study to investigate the effect of sex hormone therapy combined with intra-arterial chemotherapy for hepatocellular carcinoma (HCC). Thirty patients with unresectable HCC were randomly divided into two groups. A catheter was inserted into the hepatic artery of all patients. The first group (group A) was administered 60 mg/m2 of cisplatin (CDDP) on day 15 and 13 mg/m2 of Adriamycin (ADM) on day 1 and 8 postoperatively via the hepatic artery cannula; in addition, a daily dose of 150 mg 5-fluorouracil (5-FU) was administered orally. Tamoxifen (TAM) 25 mg/m2 daily and medroxyprogesterone acetate (MPA) 400 mg/m2 daily were also administered orally. TAM and MPA administration were alternated every 4 weeks. For the second group (group B) the same protocol of anticancer drugs administration, without the hormonal agents, was given. At least three courses of the treatments were carried out. Twelve patients in group A and 14 in group B were evaluated. Partial response of the hepatic tumor to the treatments was observed in 33.3% of group A patients and 21.4% of group B patients, a difference that was not statistically significant. The 1-year survival rate was 44.5% in group A and 33.0% in group B. The performance status of 25% of the patients in group A was significantly improved compared with 14.3% in group B (p < 0.05). TAM- and MPA-combined chemotherapy may not prolong the survival of patients with HCC, although it improves their quality of life.
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PMID:Chemohormonal therapy of unresectable hepatocellular carcinoma. 839 72

Tamoxifen is the endocrine treatment of choice for all women with hormonally responsive breast cancer. 30 years of experience in both the laboratory and clinical setting have shown tamoxifen to be an effective adjuvant treatment with minor short term adverse effects. However, as therapeutic use has extended to 5 years and beyond, and as clinical trials begin which will assess the effectiveness of tamoxifen as a preventive treatment, concern about possible long term adverse effects is justified. Tamoxifen has an estrogen-like influence on the skeletal and cardiovascular systems, resulting in decreases in both postmenopausal bone loss and low density lipoprotein (LDL) levels. These effects will, it is hoped, result in decreases in the incidences of osteoporosis and coronary heart disease, which are major causes of morbidity and mortality in the postmenopausal age group. Tamoxifen therapy also results in decreased rates of contralateral breast cancer. Long term tamoxifen treatment may result in a small increase in the incidence of endometrial and/or hepatocellular carcinoma, but with millions of women taking tamoxifen for long periods, such small increases in incidence translate to a significant number of women at risk. Tamoxifen is clearly beneficial for short term treatment, but the clinical decision of tamoxifen use in the long term must be made on the individual benefits versus risks of tamoxifen treatment.
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PMID:A risk-benefit assessment of tamoxifen therapy. 850 18


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