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  • 1
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Human breast tumours are diverse in their natural history and in their responsiveness to treatments. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems transduce ...
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pyridylglutarimide 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione (PyG) is a novel inhibitor of aromatase that was shown to cause effective suppression of plasma oestradiol levels in postmenopausal patients. In four patients receiving oral doses of PyG (500 mg) twice daily for 3–4 days, oestradiol levels fell to 31.1%±6.3% of baseline values within 48 h and remained suppressed during treatment. Of a further six patients who received oral PyG (1 g) as a single dose, five had quantifiable oestradiol levels. Oestradiol suppression was sustained for 36 h and recovery correlated with a fall of PyG concentrations below a threshold value of ca. 2 μg/ml. The pharmacokinetics of PyG were non-linear and, when fitted to the integrated Michaelis-Menten equation, yielded good parameter estimates forC o (21.7±1.82 μg/ml),K m (2.66±0.68 μg/ml) and Vmax (0.86±0.06 μg ml−1 h−1). On subsequent repeated dosing with PyG, both theK m (4.31±0.48 μg/ml) and the Vmax (1.83±0.13 μg ml−1 h−1) values increased and recovery from oestradiol suppression was more rapid, indicating that PyG induces its own metabolism.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] The mechanisms causing resistance to chemotherapeutic drugs in cancer patients are poorly understood. Recent evidence suggests that different forms of chemotherapy may exert their cytotoxic effects by inducing apoptosis1. The tumor suppressor gene P53 has a pivotal role inducing apoptosis in ...
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  • 4
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Gene amplifications and deletions frequently have pathogenetic roles in cancer. 30,000 radiation-hybrid mapped cDNAs provide a genomic resource to map these lesions with high resolution. We developed a cDNA microarray-based comparative genomic hybridisation method for analysing DNA copy number ...
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1573-7217
    Keywords: aromatase inhibitor ; breast cancer ; endocrine therapy ; NMR spectroscopy ; plasma lipids ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Side-effects following long-term endocrine therapy might have clinical implications. The aim of this study was to study potential methods to detect effects on plasma induced by hormonal therapies. The composite methylene (chemical shift between 1.2-1.4 ppm) and methyl (0.8-0.9 ppm) aliphatic peaks of the1H magnetic resonance spectrum (500 MHz) were analyzed in consecutive plasma samples of 23 cancer patients drawn before and during treatment with hormonally acting drugs. The aliphatic peaks were analyzed for line width at half-height and then averaged. In addition,13C magnetic resonance spectroscopy (125 MHz) analyses were done in selected patients. The blood samples were analyzed for triglyceride, cholesterol, apolipoprotein A1 (apo A1), and apolipoprotein B (apo B) levels. The methylene line width increased significantly after 9 weeks of tamoxifen (41.4 vs. 37.6 Hz). A trend of differences was observed in the saturated part of the13C magnetic resonance spectrum. A significant decrease in total cholesterol (mean decrease, 13%), increases in apo A1 (9%) and in the ratio of apo A1 to apo B (28%), but unchanged total triglycerides were found, indicating a decrease in LDL and increase in HDL lipoproteins in these patients following tamoxifen therapy. During dose escalation with the aromatase inhibitor exemestane, the methylene line width seemed to decrease (31.9 vs. 38.8 Hz, at 12 weeks and baseline, respectively). Significant decreases in total (13%) and HDL (32%) cholesterol, apo A1 (25%), and total triglyceride (16%) levels were found during the same interval. The apo A1/apo B ratio decreased by 25%. For patients on dexamethasone, the proton aliphatic line widths increased one day after the initiation of therapy. The changes in line shape observed during dexamethasone therapy indicated lower levels of triglyceride-rich relative to triglyceride-poor lipoproteins, consistent with results from the lipid analyses. In conclusion, nuclear magnetic resonance spectroscopy might have potential to detect effects on plasma induced by endocrine therapy. The lipid analyses in these patients were in support of the changes in lipid profile as evaluated by nuclear magnetic resonance spectroscopy.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Breast cancer research and treatment 49 (1998), S. S45 
    ISSN: 1573-7217
    Keywords: aromatase ; estrogens ; hormones ; exemestane ; breast cancer ; therapy ; pharmacology ; formestane
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Steroidal aromatase inhibitors like formestane and exemestane are useful drugs for endocrine treatment of postmenopausal breast cancer. In addition, these drugs should be considered valuable probes to explore the biology of breast cancer with particular emphasis on possible relations between the degree of estrogen suppression and clinical efficacy and the possible role of intratumor estrogen synthesis. The fact that steroidal and non-steroidal aromatase inhibitors bind to different parts of the aromatase enzyme suggests these drugs may act in concert aggravating plasma estrogen suppression. Thus, use of a steroidal and a non-steroidal aromatase inhibitors in concert may be one way to improve breast cancer treatment and may also provide important information to a better understanding of the dose-response relationship between estrogen suppression and clinical effects. Further, the finding that patients progressing on non-steroidal aromatase inhibitors may respond to formestane as well as exemestane suggests these drugs may have differential effects, probably on the aromatization in the tumor tissue. Further studies are warranted to explore the influence of steroidal and non-steroidal aromatase inhibitors on intratumor aromatase activity and intratumor estrogen concentrations and to correlate these findings to intratumor drug concentrations. The findings that steroidal aromatase inhibitors may have clinical effects in patients progressing on treatment with the non-steroidal aromatase inhibitor aminoglutethimide is challenging, and suggest further studies to evaluate possible benefits of using different novel aromatase inhibitors in concert or sequence.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1573-7217
    Keywords: breast cancer ; disease-free interval ; estrogens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The influence of plasma estrogen levels on disease-free interval (time from primary treatment to first relapse, DFI) in breast cancer patients is not known. Any relation between plasma estrogens and the outcome in breast cancer patients may have implications considering use of hormone replacement therapy (HRT) in patients treated for breast cancer. We measured plasma estradiol (E2), estrone (E1), and estrone sulfate (E1S) in 92 postmenopausal women with breast cancer relapse and correlated plasma estrogen levels to the length of their disease-free interval (DFI1) and the length of the DFI in the subgroup of patients in whom this extended a time period of more than 2 years (DFI2). The length of DFI2 correlated negatively to plasma level of E1S (p 〈 0.025) and E2 (p 〈 0.05) and to the E2/E1 and E1S/E1 ratios (p 〈 0.05), while the length of DFI1 correlated negatively to plasma level of E1S (p 〈 0.025) and the E1S/E1 ratio (p 〈 0.005). We also analyzed for possible correlations between DFIs and plasma estrogen levels in subgroups based on tumor stage at diagnosis and previous therapy. In general, these subgroup analyses revealed negative correlations of statistical significance or borderline significance between the DFI1 and DFI2 and E2 and the E2/E1 ratio and non-significant negative correlations between plasma levels of E1S and DFI1 and DFI2. In particular, strong negative correlations between plasma estrogen levels and the length of DFI1 and DFI2 were found among patients responding to first line endocrine treatment for relapse and among patients with primar stage III tumors. Our findings suggest plasma E2 and E1S to stimulate the growth of micrometastases in patients treated for breast cancer.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Breast cancer research and treatment 49 (1998), S. S53 
    ISSN: 1573-7217
    Keywords: aromatase ; estrogens ; breast cancer ; hormones ; therapy ; pharmacology ; aromatase inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Anastrozole (Arimidex®, 2,-2[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3- phenylene]bis(2-methyl)propiononitrile) is a novel, potent aromatase inhibitor belonging to the triazole class. In vitro and in vivo animal studies have revealed the drug to be a potent inhibitor of the aromatase enzyme with no inhibitory activity versus other enzymes involved in steroid synthesis. The drug is a potent suppressor of plasma estrogens in healthy male and postmenopausal female volunteers as well as postmenopausal breast cancer patients, and anastrozole administered as 1 mg or 10 mg daily has been shown to inhibit in vivo aromatization by 96.7 and 98.1%, respectively. Two large, randomized studies revealed anastrozole to cause objective response rates and stable disease comparable to what was achieved with megestrol acetate but with a lower incidence of side effects. While follow-up results have not revealed any significant difference in time to relapse between the drug regimens, they have revealed an improved survival among patients treated with anastrozole 1 mg compared to megestrol acetate 160 mg daily. Further follow-up is required to finally decide whether there may be a survival benefit also among patients treated with anastrozole 10 mg daily and to evaluate whether the improvement in survival is associated with an improved disease-free survival as would be anticipated.
    Type of Medium: Electronic Resource
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