Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Local formation of oestrogens from androgens by aromatase cytochrome P-450 within brain cells is crucial for the sexual differentiation of the mammalian CNS. Aromatase activity has been detected in several brain regions of the developing rodent brain. In the present study, we used a mouse-specific, peptide-generated, polyclonal aromatase antibody to determine whether neurones and/or glial cells in the developing brain are involved in androgen aromatization and if aromatase-immunoreactive (Arom-IR) cells exhibit a sex-specific distribution and regional-specific morphological characteristics. For these experiments, gender-specific cell cultures were prepared from embryonic day 15 mouse hypothalamus and cortex. Specificity of the immunoreaction was confirmed by Western-blot analysis and by inhibition of aromatase activity using tissue homogenates from mouse ovaries and male newborn hypothalamus and from male hypothalamic cultures with known aromatase activity, respectively. Arom-IR cells were found in both hypothalamic and cortical cultures. Double-labeling experiments revealed that Arom-IR cells co-stained only for the neuronal marker MAP II, but never for glial markers. Therefore aromatase immunoreactivity is specifically neuronal. Regional differences in the morphology of Arom-IR neurones were observed between both brain regions. In hypothalamic cultures, IR-neurones represented a heterologous population of phenotypes (magnocellular, small bipolar and multipolar neurones with long processes showing varicose-like structures or without processes). Cortical Arom-IR neurones were always oval in shape with short or no IR-processes. Sexual dimorphisms in numbers of Arom-IR neurones were found in the hypothalamus with significantly higher cell numbers in male cultures.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aromatase-immunoreactivity is localised specifically in neurones in the developing mouse hypothalamus and cortex. 819 60

Aromatase (estrogen synthetase) inhibitors are superior to tamoxifen in terms of both efficacy and toxicity in the treatment of advanced breast cancer and also in the neoadjuvant setting. Recent results from the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial showed a marked reduction in contralateral primary breast cancer with anastrozole, an apparent prevention effect. A similar effect was seen in the MA.17 adjuvant trial comparing letrozole with placebo after 5 years of adjuvant tamoxifen. This has accelerated interest in aromatase inhibitors as primary preventive therapy. Two studies being conducted by the National Cancer Institute of Canada's Clinical Trials Group select women by virtue of mammographic breast density. The International Breast Cancer Intervention Study 2 trial randomizes women at elevated risk to anastrozole or placebo. Because of its steroidal structure, exemestane may be more effective than the nonsteroidal aromatase inhibitors and may protect bone and lipid metabolism from the effects of estrogen ablation. Elevated prostaglandin E2 levels from cyclooxygenase-2 induction by preinvasive and invasive breast lesions increase a number of tumor-promoting pathways, including aromatase, as well as angiogenetic, antiapoptotic, and others. Additive or synergistic effects between celecoxib, a cyclooxygenase-2 inhibitor, and exemestane have been demonstrated and have led to the National Cancer Institute of Canada's Clinical Trials Group MAP.3 trial, which will randomize women at elevated risk to placebo or to exemestane with or without celecoxib. The efficacy and long-term toxicity data from the aromatase inhibitor prevention trials, and the identification of risk profiles from trial results, are awaited with interest.
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PMID:Prevention strategies with aromatase inhibitors. 1473 94

The recent past has witnessed the appearance of substantial data relating to endocrine therapy of breast cancer. In the adjuvant therapy setting in early breast cancer, several large, well-conducted, randomized, double-blind clinical trials have provided evidence for the value of the third-generation aromatase inhibitors (AI) anastrozole, exemestane, and letrozole. The three major studies to date [i.e., Arimidex, tamoxifen alone, or in combination (ATAC), International Exemestane Study (IES), and letrozole after 5 years of tamoxifen (MA.17)] evaluated three different populations of women from the standpoints of duration of prior tamoxifen and thus time since the treatment of the primary breast cancer. A consistent pattern of improvement in disease-free survival was seen whether the control arm was tamoxifen (ATAC and IES) or placebo following tamoxifen (MA.17). From a toxicity standpoint, the major findings with the AIs were a decreased incidence of thromboembolic events and endometrial cancers but an increase in musculoskeletal complaints and potential for decreasing bone density. The last issue should be clarified with ongoing studies addressing the impact of the three AIs on bone density and fractures. In summary, based on ATAC, IES, and MA.17, respectively, the following conclusions can be drawn relating to postmenopausal women with hormone receptor positive early breast cancer: anastrozole is a reasonable choice for initial endocrine adjuvant therapy, exemestane should be considered for women who have received 2 to 3 years of tamoxifen, and letrozole should be considered for those who have completed about 5 years of tamoxifen. In the prevention setting, tamoxifen has been evaluated in multiple trials involving >28,000 women and, despite clear evidence of benefit, the level of acceptance of this agent by women seems to be low. Two recently developed prevention trials, IBIS 2 and MAP.3, involve the study of aromatase inhibitors against a placebo control rather than tamoxifen. Whereas the recent adjuvant trials have established the value of the third-generation aromatase inhibitors in early-stage breast cancer, the marked reductions in contralateral breast cancers seen in these trials suggest they will be of value in the prevention setting in women at increased risk of developing the disease.
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PMID:Endocrine therapy trials of aromatase inhibitors for breast cancer in the adjuvant and prevention settings. 1570 84

Trials with tamoxifen have clearly shown that the risk of developing oestrogen receptor positive breast cancer can be reduced at a late stage in the natural history with prophylactic agents. About half of the oestrogen receptor positive cases were prevented, but there was no beneficial effect on ER-negative cancers. The current challenge is to find new agents which achieve this or better efficacy but with fewer side effects. Recent results indicate that the SERM raloxifene has similar efficacy to tamoxifen, but leads to fewer endometrial cancers, gynaecologic symptoms, and thromboembolic events. Results for contralateral tumours in adjuvant trials suggest that aromatase inhibitors may be able to prevent up to 70-80% of ER-positive breast cancers, and this is currently being investigated in two large prevention trials, one using anastrozole (IBIS-II) and the other exemestane (MAP.3). New agents are needed, for receptor negative breast cancer and several possibilities are currently under investigation.
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PMID:Chemoprevention of breast cancer. 1822 88

Breast cancer incidence is increasing in all parts of the world. Although in Western countries death rates are declining, there is a need to make attempts to prevent the disease in order to reduce the trauma of diagnosis and treatment. Endocrine approaches to breast cancer prevention have been the most successful approach to cancer prevention to date. Studies with tamoxifen were initiated when it was noted that, during adjuvant treatment after surgery to prevent relapse, the incidence of new contralateral cancers was reduced by half. Four trials of >or=5 years of tamoxifen compared with placebo in women at increased risk of breast cancer were initiated in the 1980s and showed a similar reduction in breast cancer, but only in oestrogen-receptor-positive disease. Recent follow-up indicated that there is a carry-over effect of tamoxifen after the completion of treatment at 5 years so that the preventive effect at 10 years is significantly great than at 5. The selective oestrogen receptor modulator (SERM) raloxifene has also been assessed as a preventive agent in two major international randomized trials compared with placebo and shows a protective effect similar to that of tamoxifen. An American study subsequently compared tamoxifen and raloxifene in a trial of nearly 20,000 women at increased risk (the STAR trial) and demonstrated that the two agents were equally effective but that the toxicity of raloxifene was less. Adjuvant trials comparing tamoxifen and the modern potent aromatase inhibitors (anastrozole, letrozole and exemestane) indicate that they are superior to tamoxifen and reduce contralateral breast cancer by approximately 70%. This observation has led to the initiation of two trials in postmenopausal women comparing anastrozole (the IBISII trial) or exemestane (the MAP-3 trial) with placebo. Currently it is recommended that tamoxifen is used to prevent breast cancer in premenopausal women and raloxifene for postmenopausal women (it is not effective in the premenopausal group),and we await the results of the aromatase inhibitor trials.
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PMID:The endocrine prevention of breast cancer. 1897 Nov 22

The third-generation aromatase inhibitors (AIs), anastrozole, exemestane, and letrozole are potential agents for preventing estrogen receptor (ER)-positive breast cancer (BC) in high-risk postmenopausal women. No AI has yet been fully evaluated for prevention. Each AI is incorporated into the design of a phase 3 randomized BC prevention trial based on hypothesis-generating contralateral breast cancer (CLBC) data from a corresponding adjuvant trial. Arimidex, tamoxifen alone or in combination (ATAC) pitted anastrozole against tamoxifen for 5 years as "initial adjuvant" therapy, showing at 33.3 months fewer CLBCs with anastrozole versus tamoxifen (odds ratio [OR] 0.42 overall; OR 0.29 ER-positive BCs), offering the hypothesis on which IBIS-II (International Breast Cancer Intervention Study) is based. "High-risk" IBIS-II compares anastrozole to placebo for the primary prevention of BC in 6000 postmenopausal women. IES (Intergroup Exemestane Study) compared exemestane to tamoxifen following 2-3 years of adjuvant tamoxifen in 4742 postmenopausal women with ER-positive BCs. The benefit from "switching" to exemestane in reducing CLBCs (HR 0.44 at 30.6 months) underlies MAP.3 (Mammary Prevention 3), which compares exemestane to placebo for primary BC risk reduction in 4560 postmenopausal women. MA.17 showed reduced CLBC incidence (HR 0.57) at 2.4 years in postmenopausal women with receptor-positive tumors receiving "extended adjuvant" letrozole compared to placebo following 5 years of tamoxifen. The Study of Letrozole and Raloxifene (STELLAR), using as the control raloxifene, the new U.S. standard drug for BC prevention, would complete the trio of AI prevention trials, but STELLAR is currently on hold.
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PMID:Phase 3 trials of aromatase inhibitors for breast cancer prevention: following in the path of the selective estrogen receptor modulators. 1925 Feb 1

In vitro maturation of oocytes is a crucial step in assisted reproductive technologies in cattle; however, the molecular mechanisms of cumulus contribution to oocyte developmental potential require more investigation. Based on transcriptomic data, we studied by using real-time RT-PCR and western blot in bovine cumulus cells, the kinetics of expression of several candidate genes involved in oxidative stress response, apoptosis, steroid metabolism and signal transmission throughout IVM. Phosphorylations of the components of the main signaling pathways were also analyzed. In addition, IVM was performed in different maturation mediums which influenced the cumulus apoptosis, progesterone secretion and oocyte developmental competence. Glutathione-S-transferase A1 (GSTA1) transcript and protein abundance significantly decreased throughout IVM progression. Similarly, transcript levels of FSH receptor and aromatase (CYP19A1) and protein levels of three steroidogenic enzymes (steroidogenic acute regulatory protein, cytochrome P450scc and 3-beta-hydroxysteroid dehydrogenase) decreased along with progression of maturation and especially since 10 hours of IVM. Expression of progesterone receptor (PGR) and clusterin (CLU) mRNA and phosphorylations of protein kinases AKT, MAPK P38 and SMAD2 were particularly increased at 10 hours of IVM. This expression pattern supposed the role of these factors during oocyte metaphase-I check point of meiosis. Levels of CLU, GSTA1 and FSHR transcripts were higher in 199 basic hormone-free medium as compared to the medium 199EM, enriched in gonadotropins and growth factors, in which we recorded the higher developmental rate and progesterone secretion. Higher phosphorylation levels of SMAD2, AKT and MAP kinase JNK1, but not of MAP kinases ERK1/ERK2 or P38, was positively correlated with oocyte developmental competence and progesterone secretion and negatively correlated with cumulus apoptosis rate. These factors and signaling pathways in cumulus cells are potentially involved in controlling different stages of oocyte nuclear maturation and acquirement of its developmental potential.
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PMID:Kinetics of gene expression and signaling in bovine cumulus cells throughout IVM in different mediums in relation to oocyte developmental competence, cumulus apoptosis and progesterone secretion. 2096 3

For postmenopausal women with ductal carcinoma in situ (DCIS) where optimal local control or patient preference results in mastectomy, despite substantial risk of contralateral invasive breast cancer, tamoxifen is uncommonly prescribed based on unfavorable risk-benefit consideration. In the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) MAP.3 primary prevention trial, in postmenopausal women exemestane reduced invasive breast cancer incidence by 65% without increasing life-threatening side effects. In adjuvant breast cancer trials, the aromatase inhibitor exemestane as well as anastrozole and letrozole have all reduced new contralateral breast cancer incidence. Thus, aromatase inhibitors, and perhaps particularly exemestane, provide an option to address the risk of contralateral breast cancer in postmenopausal women with DCIS managed with mastectomy.
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PMID:Postmenopausal women with DCIS post-mastectomy: a potential role for aromatase inhibitors. 2275 92

Development of drugs to prevent breast cancer has focused largely on anti-estrogenic agents, leading to approval by the US FDA of two such agents for this purpose: tamoxifen and raloxifene. However, the uptake of these drugs by high-risk women and their primary care physicians has been limited, due in large part to a perceived unfavorable risk:benefit balance. The current focus is on aromatase inhibitors, which appear to have more acceptable side effects in addition to being more efficacious in reducing breast cancer risk in high-risk women. The placebo-controlled phase III MAP.3 trial tested the AI exemestane in high-risk women and documented a 65% relative reduction in total and a 73% reduction in ER-positive breast cancers in the intervention compared to the placebo group. Toxicities centered around musculoskeletal side effects, but in the relatively short 35-month median follow-up period, these did not impair quality-of-life. A bone study nested within MAP.3 demonstrated significant decreases in bone mineral density (BMD) and in structural parameters of bone quality. The strengths and weaknesses of preventive exemestane as evaluated in the MAP.3 trial are discussed as are relevant areas for future consideration: influence of obesity, alternative dosing, and biomarker use in phase III prevention trials of aromatase inhibitors.
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PMID:Exemestane: one part of the chemopreventive spectrum for ER-positive breast cancer. 2353 9

1,2,4-triazole is an important nucleus present in a large number of compounds. More than thirty-five compounds containing this nucleus are introduced into the market. 1,2,4-triazole nucleus is stable to metabolism and acts as an important pharmacophore by interacting at the active site of a receptor as hydrogen bond acceptor and as a donor. Due to its polar nature, the triazole nucleus can increase the solubility of the ligand and it can significantly improve the pharmacological profile of the drug. A large number of 1,2,4-triazole derivatives are reported to possess a wide range of bioactivities including anti-cancer activity. This review article describes the role of 1,2,4-triazole nucleus in different types of anti-cancer agents such as nucleoside based anti-cancer agents, kinase inhibitors, tubulin modulators, aromatase and steroid sulfatase inhibitors, methionine aminopeptidase inhibitors, tankyrase inhibitors and metal complex based anti-cancer agents. It is expected that the current review article will provide insight into various ligand-receptor interactions and help in the rational design and development of novel 1,2,4-triazole based anti-cancer drugs with improved selectivity for cancer cells.
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PMID:Recent Developments on 1,2,4-Triazole Nucleus in Anticancer Compounds: A Review. 2628 63


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