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)

It has been hypothesized that hepatocellular carcinoma might be a long-term adverse effect of tamoxifen therapy. Data from nine population-based cancer registries in the United States were used to investigate time trends in the incidence of hepatocellular carcinoma in white women previously diagnosed with invasive breast cancer during 1974-1987 and followed until 1989. Of particular interest were the rates after 1977, the year tamoxifen was licensed by the FDA. Compared to rates in all white women, no increased risk of hepatocellular carcinoma was found in women most likely to have received tamoxifen--those 50 years of age or more at diagnosis of breast cancer and diagnosed after 1977. These results suggest that tamoxifen does not cause a large increase in the incidence of hepatocellular carcinoma within the first decade after use. However, smaller and/or later increases in the risk for hepatocellular carcinoma are possible and warrant continued monitoring of women treated with tamoxifen.
Breast Cancer Res Treat 1994
PMID:The incidence of hepatocellular carcinoma in US white women with breast cancer after the introduction of tamoxifen in 1977. 794 18

The final decade of the century confirms the importance of latest generation progestogens in terms of decreased risks associated with the use of doses of ethinyl estradiol of 50 gamma or more, equally effective in contraception of this type. These new combination very considerably limit the untoward effects seen in the past regarding carbohydrate and lipid metabolism, as well as cardiovascular disease. Concerning carcinogenesis, the long term protective effect against carcinomas of the endometrium and ovary is now accepted, while studies of breast cancer are not unanimous in their condemnation, the same applying to the risk of hepatocarcinoma. Regulation of cycles is satisfactory and the vaginal flora little affected. Moderate and stable fibroids seem to be well controlled, the same applying to mucosal hyperplasia. Pregnancy, particularly rare, is not influenced unfavourably and the effect on lactation appears to be nil. Provided that regular monitoring is ensured and contraindications are respected, age does not appear to be an absolute limiting factor to its use but the risk of concomitant smoking remains.
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PMID:[Current status of estrogen-progestational contraception]. 797 41

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

We have used human procathepsin D isolated from supernatant of human breast cancer cell line ZR-75-1 to test its mitogenic activity for a broad spectrum of human-derived cell lines. These cell lines included: breast cancer cell lines ZR-75-1, MDA-MB-436, MBA-MD-483 and MDA-MB-231, B lymphoblastoid cell line Raji, the monocytoid cell line U937, T lymphoblastoid cell line 8402, epitheloid carcinoma cell line HELA, hepatocellular carcinoma cell line Hep G2, breast milk epithelial cell line HBL-100 and angiosarcoma cell line HAEND-1. We have tested the level of proliferation of these cell lines depending on the presence of procathepsin D in the medium. In parallel we have also measured the effect of insulin-like growth factor II under the same experimental conditions. We have found a significant difference between the influence of IGF II and that of procathepsin D. While IGF II promoted in practically the same way the proliferation of all cell lines tested, procathepsin D had a very pronounced effect on breast cancer cell lines only. This finding might help to explain some contradictory results of prognostic significance of procathepsin D in human breast cancer.
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PMID:Effect of human procathepsin D on proliferation of human cell lines. 801 70

The antitumor efficacy of IL-2 is limited to renal cancer and melanoma. Several cytokines have been associated with IL-2 in an attempt to improve its activity, without, however, any clear benefit. Recent experimental and clinical studies have suggested the possibility to manipulate the host biological response by immunomodulating neurohormones, such as the pineal hormone melatonin (MLT). On the bases of these considerations, we have designed a neuroimmunotherapeutic protocol with low-dose IL-2 subcutaneous therapy (3 million IU/day for 6 days/week for 4 weeks) plus MLT (40 mg/day orally, starting 7 days before IL-2) in advanced solid neoplasms other than renal cancer and melanoma, which are generally resistant to IL-2 alone. The study included 82 patients, 72 of whom showed distant organ metastases. Tumor histotypes were, as follows: non-small cell lung cancer: 19; hepatocarcinoma: 16; colon cancer: 15; gastric cancer: 11; cancer of pancreas: 11; breast cancer: 6; miscellaneous: 4. Objective tumor regression were achieved in 17/82 (21%) patients, consisting of CR in 4 (liver: 2; pancreas: 1; stomach: 1) and PR in 13 (lung: 4; liver: 4; stomach: 2; pancreas: 1; breast: 1; colon: 1). The median duration of response was 8+ months. A stabilization of disease was obtained in 30 patients, while the other 35 patients progressed. The lack of progression was associated with a significantly higher increase in lymphocyte and eosinophil mean number and with a significantly lower increase in neopterin mean levels. The treatment was well tolerated in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cancer immunotherapy with low-dose interleukin-2 subcutaneous administration: potential efficacy in most solid tumor histotypes by a concomitant treatment with the pineal hormone melatonin. 802 99

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

The aim of this study was to analyze the incidence of malignancies in a large series of PBC patients from Italy. The overall sample included 178 patients (10 M, 168 F). The mean age at presentation was 52 yrs (range 29-74); 17 patients had histological stage I, 52 stage II, 66 stage III, 44 stage IV. The follow-up period ranged from 1 to 16 years (mean 5 years). During the follow-up, extra-hepatic malignancies developed in 6 cases (3.3%), and hepatocellular carcinoma (HCC) in a further 4 patients, all associated with cirrhosis (2.2%). Breast cancer developed only in one patient, resulting in a crude incidence rate of 130/100.000 person years among females. The calculated crude incidence of HCC was 492.4/100.000 person years. Three of the four patients with HCC had a superinfection with HCV. In conclusion, the incidence of breast cancer is not significantly increased. HCC has a relatively high prevalence in PBC and HCV superinfection may play an important role in favouring HCC.
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PMID:Incidence of hepatic and extra-hepatic malignancies in primary biliary cirrhosis (PBC). 812 93

alpha 1-Antichymotrypsin (alpha 1-ACHY) and alpha 1-antitrypsin (alpha 1-AT) are closely related glycoprotein protease inhibitors, present in plasma and other extracellular fluids, that neutralize proteases released by leukocytes in response to trauma and inflammatory stimuli. Both inhibitors are synthesized primarily by hepatocytes, although lower levels of synthesis by monocytes and breast and intestinal epithelial cells have been demonstrated. Recently, the immunohistochemical localization of alpha 1-AT and alpha 1-ACHY in intrauterine and extrauterine human trophoblastic tissue has been reported. In the present study, we have sought to determine whether human trophoblast is also able to synthesize alpha 1-AT and alpha 1-ACHY. Messenger RNA for both inhibitors was found by Northern blotting in chorionic villi obtained from first trimester and term placenta. Substantial differences in messenger levels for both inhibitors among individual placentas were noted. alpha 1-ACHY and alpha 1-AT messenger was also present in trophoblast cells in primary culture. Synthesis of alpha 1-AT and alpha 1-ACHY protein was demonstrated by SDS-PAGE after immunoprecipitation of [35S]-labeled alpha 1-AT and alpha 1-ACHY from conditioned media of trophoblast cells in culture metabolically labeled with [35S]-methionine. It is of some interest that the M(r) of the alpha 1-AT and alpha 1-ACHY secreted by trophoblast were 50,000 and 49,000, respectively, compared with 54,000 and 68,000 for these proteins in plasma (or secreted by HepG2 human hepatoma and MCF-7 human breast cancer cells).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synthesis of alpha 1-antichymotrypsin and alpha 1-antitrypsin by human trophoblast. 813 73

The objective of this report is to review the current and potential therapeutic uses of the progesterone antagonist drug RU 486 (mifepristone). Publications cited in peer-reviewed journals were identified through a search of the Index Medicus from 1987 through 1992. A wide range of research reports was reviewed, including human, animal, and tissue culture experiments. Data from published reports were included in this report if they addressed the mechanism of action, clinical indications, and potential uses for RU 486. The review disclosed that as a progesterone antagonist, RU 486 is clinically effective for inducing first-trimester abortions, for ripening and dilating the cervix to facilitate intrauterine surgical procedures, and as a postcoital contragestational agent. As a glucocorticoid antagonist, RU 486 is useful for treating inoperable cases of nonpituitary Cushing's syndrome. RU 486 is under investigation for use as an antineoplastic agent; it has shown promise as a treatment of meningioma, breast cancer, prostate cancer, and hepatoma. RU 486 may also have a role in the treatment of endocrinologic conditions such as endometriosis and premenstrual syndrome. I conclude that RU 486 is effective and in current clinical use for a number of reproductive indications and for treatment of Cushing's syndrome. The drug also has potential as therapy for certain neoplasms and endocrinologic conditions.
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PMID:RU 486. The progesterone antagonist. 825 38

The purification and identification of human prolactin (hPRL) had been delayed, compared with other pituitary hormones, until the determination of total amino acid sequence of hPRL in 1977. A full-length cDNA for the hPRL receptor was identified from hepatoma and breast cancer cell lines in 1989. Subsequent identification of cDNAs for PRL receptor of several species revealed that molecular size of PRL receptors could be classified into three forms, i.e., long, short and intermediate, according to the length of intracellular domain. The mechanism of post-receptor signal transduction has not been clarified yet. However, protein kinase C may be involved in this process. Further studies are necessary to investigate the relationship between molecular size of PRL receptor and postreceptor events.
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PMID:[Action mechanism of pituitary hormones--receptor and signal transduction--prolactin]. 825 31


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