Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three topics are briefly reviewed relating to carcinogenesis of estrogen responsive tissues: (a) enzymology of benzo(a)pyrene activation by human tissues, (b) microsomal activation of estrogens to estrogen arene oxides and (c) estrogen and progesterone receptor studies in endometrial carcinoma. The following working hypothesis is stated on the etiology of gynecologic tumors: "Environmental chemicals, such as cigarette smoke, polycyclic and polyhalogenated hydrocarbons, etc., induce special forms of cytochrome P-450 monooxygenase and related enzyme systems which can activate endogenous or prescribed estrogens and non-steroid antiestrogens to act as initiators and/or promoters of neoplasia in estrogen-dependent organs." The role of estrogen receptors is perceived as a homing device or cellular "Trojan Horse" for these activated estrogens.
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PMID:Carcinogen activation by human uterine enzymes. 46 42

Inhibitors of aromatase, the cytochrome P-450 enzyme complex responsible for the biosynthesis of estrogens, may be useful as therapeutic agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer. Several 7 alpha-thio-substituted androstenediones have proven to be potent inhibitors of aromatase in vitro and in vivo. Recent research efforts have focused on designing aromatase inhibitors with both substitution at C-7 and extended linear conjugation in rings A and B of the steroid nucleus. The targeted compounds, 7-substituted 4,6-androstadiene-3,17-diones 4-10, were prepared by the addition of either Grignard or lithium reagents to 3,3:17,17-bis(ethylenedioxy)-5-androsten-7-one (3). Inhibitory activities of the compounds were evaluated in vitro by enzyme kinetic studies employing the microsomal fraction isolated from human term placenta. 7-Benzyl- and 7-phenethyl-4,6-androstadiene-3,17-dione analogues are effective inhibitors with apparent Ki's of 60.9-174 nM, while the 7-phenyl analogue exhibited an apparent Ki of 1.424 microM. Thus, several 7-substituted 4,6-androstadiene-3,17-diones were prepared and exhibited good competitive inhibition of aromatase in vitro in human placental microsomes.
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PMID:Synthesis and biochemical studies of 7-substituted 4,6-androstadiene-3,17-diones as aromatase inhibitors. 229 6

Inhibitors of aromatase, the cytochrome P-450 enzyme complex responsible for the biosynthesis of estrogens, may be useful therapeutic agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer. 7 alpha-Substitution of androstenedione results in inhibitors of enhanced affinity for aromatase, with 7 alpha-(4'-amino)phenylthio-4-androstene-3,17-dione (7 alpha-APTA) exhibiting an apparent Ki of 18 nM and being among the most potent competitive inhibitors produced. The effects of this potent competitive 7 alpha-substituted C19 aromatase inhibitor on reduction of the number and size of the 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats was investigated. Tumor-bearing rats receiving 25 or 50 mg 7 alpha-APTA/kg/day demonstrated reductions in tumor volumes during the first week. Tumor volumes continued to decrease during the studies, resulting in tumor volume reductions of approximately 40 and 80%, respectively. Tumors in rats of the control group receiving only vehicle steadily increased in size during the studies. The tumor reductions in a 50-mg/kg/day-treated group were reversed by coadministration of 7 alpha-APTA at 50 mg/kg/day and estradiol at 0.3 microgram/kg/day for the last 3 weeks, indicating that the tumors were still responsive to estrogen. Plasma levels of estradiol were lower in the animals treated with 7 alpha-APTA at the end of the treatments. Thus, 7 alpha-APTA is effective in reducing tumor volumes in the estrogen-dependent 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma rat model. These results encourage further development of these steroids as potential medicinal agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer.
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PMID:Effects of the aromatase inhibitor 7 alpha-(4'-amino)phenylthio-4-androstene-3,17-dione on 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats. 314 Oct 48

Aromatase is the cytochrome P-450 complex responsible for oestrogen biosynthesis in vivo. Inhibitors of this enzyme complex might therefore serve to modulate oestrogen-dependent processes by interfering with the production of oestrogens. Thus, these agents may be useful in reproductive processes and in treating oestrogen-dependent disease states such as breast and endometrial cancer. We have demonstrated that inhibitors such as the naturally occurring flavonoids having 5,7-dihydroxy substituents can bind to human placental cytochrome P-450 with affinity comparable to their ability to inhibit aromatization of androstenedione and testosterone to oestradiol and oestrone, respectively. It appears that the mechanism of this inhibition requires the flavonoid to bind to the active site of the cytochrome P-450 without prior generation of metabolic intermediate products. Our data also suggest that the presently known differences in potency of inhibition of cytochrome P-450-mediated aromatization of steroids by different hydroxylated derivatives of 5,7-dihydroxyflavones may arise from their different binding affinity to the enzyme, particularly those compounds hydroxylated in the C3 position in ring C of the flavonoid nucleus.
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PMID:Spectral perturbation of human microsomal cytochrome P-450 by flavonoid binding. 324 Mar 23

A case-control study was designed to identify associations between polymorphisms at p53, cytochrome P-450 (CYP1A1) and glutathione-S-transferases and endometrial cancer susceptibility. Among all polymorphisms analysed, an insertional variant in p53 (P53PIN3) and two polymorphisms in the 3'-end and exon 7 of CYP1A1 showed significant association with enhanced endometrial cancer risk.
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PMID:Susceptibility to endometrial cancer: influence of allelism at p53, glutathione S-transferase (GSTM1 and GSTT1) and cytochrome P-450 (CYP1A1) loci. 915 64

We describe here a case-control study to identify associations between polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) and cytochrome P-450 1A1 (CYP1A1) genes and susceptibility to endometrial cancer. Accordingly, genotype frequencies in 80 endometrial carcinoma patients were compared with frequencies in 60 controls. DNA analysis suggest a significantly increased endometrial cancer risk with an alanine to valine substitution at nucleotide 677 of MTHFR gene with an odds ratio of 2.8 (95% confidence interval: 1.36-6.14, P = 0.002). Moreover, the tumors from patients with the valine allele were more undifferentiated (P = 0.03). On the other hand, a recently described mutation in exon 7 of CYP1A1 gene (threonine exchanged to asparagine in codon 461) showed a strong association with endometrial cancer risk with an odds ratio of 6.36 (95% confidence interval: 1.99-26.5, P = 0.0004). Thus, this study suggests that polymorphisms at MTHFR and a novel CYP1A1 variant could influence susceptibility to endometrial cancer, although larger sample sizes would be required to corroborate these findings.
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PMID:Germ line polymorphisms in cytochrome-P450 1A1 (C4887 CYP1A1) and methylenetetrahydrofolate reductase (MTHFR) genes and endometrial cancer susceptibility. 945 Apr 74

Endometrial polyps and endometrial neoplasms are a recognized complication of chronic tamoxifen treatment. This study describes an endometrial carcinoma that developed in a woman receiving low-dose tamoxifen treatment for breast cancer. Little is known about steroid receptor status, somatic alterations in oncogenes and tumor suppressor genes, and inherited susceptibility in endometrial carcinomas associated with tamoxifen use. In the present case, the endometrial carcinoma was negative for estrogen receptors and weakly positive for progesterone receptors. In addition, analysis of K-ras, c-erbB2/neu, cyclin D1, and p53 status revealed a codon 12 point mutation in the K-ras oncogene. The patient was determined not to be a carrier of germ-line mutations in cytochrome P-450 1A1 (CYP1A1), an estrogen-metabolizing gene previously associated with enhanced endometrial cancer risk, but she was a carrier of a methylenetetrahydrofolate reductase gene variant related with putative alterations in DNA methylation.
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PMID:Endometrial carcinoma in tamoxifen-treated breast cancer patient: clinicopathological, immunohistochemical, and genetic analysis. 1054 49

Estrogen has been shown to contribute greatly to growth and development in endometrial cancer. And recent research has suggested that intratumoral production of estrogen may play important roles in this cancer tissue. On the other hand, pregnane X receptor (PXR), a new member of nuclear receptors, has been shown to mediate the genomic effects of steroid hormones, including estrogen and xenobiotics. And this receptor is thought to regulate the expression of the cytochrome P-450 3A (CYP3A) gene family, which plays important roles in the metabolism of endogenous steroids and xenobiotics. Various levels of PXR expression were found in endometrial cancer tissues but not normal tissues. Tissues showing high PXR expression showed significantly high expression of CYP3A4/7 and low expression of estrogen receptor (ER) compared with levels in tissues showing low PXR expression. In endometrial cancer cell lines, HEC-1 cells, which express high PXR and low ER and progesterone receptor, show a stronger transcriptional response of the PXR-CYP3A pathway to the PXR ligands, especially endocrine-disrupting chemical, than do Ishikawa cells. These data suggest that the steroid/xenobiotics metabolism in the tumor tissue through PXR-CYP3A pathway might play an important role, especially in alternative pathway for gonadal hormone and endocrine-disrupting chemical effects on endometrial cancer expressing low ER alpha.
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PMID:Expression and potential roles of pregnane X receptor in endometrial cancer. 1297 Mar 23

This commentary article provides an overview of recent clinical research trials involving anastrozole and its evolving role in the management of breast cancer. Anti-aromatase agents inhibit the cytochrome P-450 component of the aromatase enzyme complex responsible for the final step of estrogen biosynthesis in peripheral tissues which are the main source of estrogen in postmenopausal women. Anastrozole is a third-generation non-steroidal aromatase inhibitor. It has been shown to be superior to megestrol acetate, in terms of survival and adverse effects, as a second-line therapy in postmenopausal women with estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive advanced breast cancer. Phase III clinical trials have also demonstrated that anastrozole significantly prolongs the time to tumour progression compared with tamoxifen as a first-line therapy for ER- and/or PgR-positive advanced breast cancer in postmenopausal women. Furthermore, the preliminary results of the Arimidex, Tamoxifen, Alone and in Combination (ATAC) study have shown that adjuvant anastrozole is superior to tamoxifen in terms of disease-free survival (DFS), non-musculoskeletal adverse effects and prevention of contralateral breast cancer in postmenopausal women with early, ER-positive breast cancer. Although longer follow-up is required to assess the long-term effects of anastrozole on bone mineral density, cognitive function and overall survival, the drug has been recently approved for adjuvant use in postmenopausal women with early, ER-positive breast cancer who are unable to tolerate tamoxifen or at an increased risk of developing thromboembolism or endometrial cancer. The potential role of anastrozole in the neoadjuvant setting, the management of DCIS, premenopausal breast cancer and breast cancer prevention is currently being investigated.
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PMID:Focus on anastrozole and breast cancer. 1468 37

Recent studies have revealed that pregnane X receptor (PXR) can function as a master regulator to control the expression of phase I and phase II drug-metabolizing enzymes, as well as members of the drug transporter family, including multiple drug resistance (MDR) 1, which has a major role in multidrug resistance. Previously, we have demonstrated that steroid/xenobiotics metabolism by tumor tissue through the PXR-cytochrome P-450 3A (CYP3A) pathway might play an important role in endometrial cancer. In this study, we examined which endocrine-disrupting chemicals (EDCs) and anticancer agents might be ligands for PXR and whether these chemicals enhanced PXR-mediated transcription through two different PXR-responsive elements (PXREs), CYP3A4 and MDR1, in endometrial cancer cell lines. Some steroids/EDCs strongly activated PXR-mediated transcription through the CYP3A4-responsive element compared with the MDR1-responsive element, whereas these steroids/EDCs also enhanced the CYP3A4 expression compared with the MDR1 expression. In contrast, the anticancer agents, cisplatin and paclitaxel, strongly activated PXR-mediated transcription through the MDR1-responsive element compared with the CYP3A4-responsive element, whereas these drugs also enhanced the MDR1 expression compared with the CYP3A4 expression. We also analyzed how these ligands regulated PXR-mediated transcription through two different PXREs. In the presence of PXR ligands, there was no difference in the DNA binding affinity of the PXR/retinoid X receptor heterodimer to each PXRE, but there were different interactions of the coactivator to each PXR/PXRE complex. These data suggested that PXR ligands enhanced PXR-mediated transcription in a ligand- and promoter-dependent fashion, which in turn differentially regulated the expression of individual PXR targets, especially CYP3A4 and MDR1.
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PMID:The pregnane X receptor regulates gene expression in a ligand- and promoter-selective fashion. 1565 19


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