Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A binary logistic model is used for predicting response to cytotoxic chemotherapy for a breast cancer patient on the basis of her tumor enzyme activity profile. The enzymes used in the model are lactate dehydrogenase, nicotinamide adenine dinucleotide phosphate-isocitrate dehydrogenase, and phosphoglucomutase, all of which were measured on primary tumor specimens from each patient. The statistical model provides an estimate of the probability that an individual will respond to treatment. Chemotherapeutic treatment consisting of combination cytotoxic drugs and subsequent evaluation of patient response followed cooperative group protocol guidelines, including outside review to confirm the patient evaluation. The model based on this study, which represents 5 years of patient follow-up, correctly predicts clinical outcome in 32 of the 37 cases available.
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PMID:A statistical model for predicting response of breast cancer patients to cytotoxic chemotherapy. 66 49

A novel ADP-ribosyltransferase (ADPRT) is reported from sera of both healthy human subjects (n = 25) and patients with colorectal tumors (n = 12) and breast cancer (n = 55). In sera of healthy controls (n = 25) the average ADPRT values were 250 +/- 56 picokatal/liter. ADPRT serum activities in metastatic cancer patients (n = 47) were three times higher (p less than 0.01) than in normal controls. A tumor origin of the serum ADPRT can be inferred from the statistical correlation (R = 0.74) between tumor and serum levels. The radiometric test procedure (CV 20-25%) is critically validated and kinetic properties of serum ADPRT have been studied, showing a competitive inhibition by nicotinamide, benzamide and 3-aminobenzamide. The kinetic parameters of serum ADPRT resemble those reported for nuclear ADPRT, thus indicating that serum ADPRT activity could be due to a nuclear enzyme released from the tumor cells.
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PMID:A new ADP-ribosyltransferase in human serum: significance in cancer. 313 17

Two distinct aromatase-active protein complexes are solubilized by use of deoxycholate and separated by diethylamino-ethyl-cellulose chromatography from lyophilized powder of 900 X g precipitate fraction of human term placenta. Aromatase activity to produce estriol, the major estrogen of human pregnancy, was designated to be aromatase I activity and measured by estriol formation from 16 alpha-hydroxytestosterone. Aromatases II activity was the designation for that which produces estrone plus estradiol and was measured by androstenedione aromatization. Aromatases II and I are eluted with 0.25 M and 0.5 M Tris buffer, respectively, from diethylaminoethyl-cellulose column in an Mr 2 million soluble complex. Each has a minimum active Mr 135,000 subunit, which is isolated by Bio-Gel filtration in the presence of detergents, and consists of a reduced nicotinamide adenine dinucleotide phosphate:cytochrome P-450 reductase (Mr 83,000) and a cytochrome P-450 (Mr 52,000). Aromatase II was found to be the major aromatase, containing approximately five times more aromatase activity, reduced nicotinamide adenine dinucleotide phosphate:cytochrome c reductase activity, cytochrome P-450, and protein than did aromatase I. Antibodies raised in rabbits against aromatase II and its reductase suppressed aromatase II activity of breast cancer tissues, as well as of adult male lung tissue, placental microsomes, and solubilized aromatase. The breast carcinoma specimens responded to the antibodies in different degrees, but there was no response to antibodies against rat liver cytochrome P-450. The results indicate similar antigenic structures for breast cancer and placental aromatase but not for rat liver cytochrome P-450.
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PMID:Multiple forms of aromatase and response of breast cancer aromatase to antiplacental aromatase II antibodies. 617 1

A fluorescein-linked estrogen was synthesized as a non-invasive, non-radiochemical means of detecting the levels and distribution of estrogen receptors in histological preparations of breast and endometrium. 17 alpha-Ethynylestradiol-21-carboxylic acid was coupled via octane-1,8-diamine to fluorescein-isothiocyanate yielding a promising ligand, N-fluoresceinyl-5,N"-[8-(3,17 beta-dihydroxy-19-nor-17 alpha-pregna-1,3,5 (10)-triene-20-yne-21-carboxylic acid amide)]octylthiourea (F8DE) for an estrogen receptor. High-performance liquid chromatography on preparative reversed-phase C18 columns was used to purify the final product. Using cytosolic receptor preparations from bovine uterus and human uterus and breast cancer, the binding of F8DE was determined by competition analyses to have a Kd value of 10(-8) M. High- and low-molecular-weight forms of estrogen receptors were separated on TSK 3000SW and 4000SW columns by high-performance size-exclusion chromatography. Specific binding of radio labeled estradiol-17 beta to these forms was inhibited in the presence of F8DE, indicating association with the fluorescein-linked steroid.
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PMID:Use of high-performance liquid chromatography in the evaluation of the synthesis and binding of fluorescein linked steroids to estrogen receptors. 663 Mar 43

Tumour cell hypoxia is a recognized cause of resistance to radiotherapy. Using clinically relevant dose-fractionation schedules in a mouse tumour model, the addition of carbogen and nicotinamide to overcome chronic and acute hypoxia results in a marked increase in radioresponsiveness with a lower degree of sensitization in normal tissue. Carbogen and nicotinamide were added to the palliative radiation treatment given to six patients with locally advanced breast cancer. The aim of the pilot study was to determine if patients tolerated the addition of carbogen and nicotinamide and to assess if there was any increase in radiosensitivity of the skin. Patients received 30 Gy prescribed to the intersection dose in six fractions over 17/18 days with full skin bolus to the tumour. All patients were given 6 g of nicotinamide orally 90 min before radiation treatment. Carbogen breathing was started 5 min prior to treatment and continued during it. Patients tolerated the treatment well, with vomiting in one patient being the only side effect that could be related to the nicotinamide, and this settled with an anti-emetic. No increase in skin reaction was noted with the addition of carbogen and nicotinamide, and good tumour regression was achieved.
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PMID:Short communication: the addition of carbogen and nicotinamide to a palliative fractionation schedule for locally advanced breast cancer. 753 98

Electron spin resonance (ESR) spectroscopy and oxygen consumption measurements using a Clark-type oxygen electrode have been used to study the metabolism of the estrogen 17 beta-estradiol by lactoperoxidase. Evidence for a one-electron oxidation of estradiol to its reactive phenoxyl radical intermediate is presented. The phenoxyl radical metabolite abstracts hydrogen from reduced glutathione generating the glutathione thiyl radical, which is spin trapped by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and subsequently detected by ESR spectroscopy. In the absence of DMPO, molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical. Similarly, the estradiol phenoxyl radical abstracts hydrogen from reduced beta-nicotinamide-adenine dinucleotide (NADH) to generate the NAD. radical. The NAD. radical is not spin trapped by DMPO, but instead reduces molecular oxygen to the superoxide radical, which is then spin-trapped by DMPO. The superoxide generated may either spontaneously dismutate to form hydrogen peroxide or react with another NADH to form NAD., thus propagating a chain reaction leading to oxygen consumption and hydrogen peroxide accumulation. Ascorbate inhibits oxygen consumption when estradiol is metabolized in the presence of either glutathione or NADH by reducing radical intermediates back to their parent molecules and forming the relatively stable ascorbate radical. These results demonstrate that the futile metabolism of micromolar quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence. The accumulation of intracellular hydrogen peroxide could explain the hydroxyl radical-induced DNA base lesions recently reported for female breast cancer tissue.
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PMID:The metabolism of 17 beta-estradiol by lactoperoxidase: a possible source of oxidative stress in breast cancer. 795 18

A rare complication occurring in a female patient who underwent conservative surgery and radiation therapy for breast cancer is described. Three weeks after the completion of radiotherapy, a diffuse bullous pemphigoid eruption developed in the irradiated area, spreading thereafter to the whole body. Although systemic cutaneous side effects have been reported after radiation therapy, this is the first occurrence of bullous pemphigoid ever reported in a female patient following treatment for breast cancer. Having made the diagnosis, an effective therapeutic regimen including nicotinamide and tetracycline was started. As the conservative management of breast cancer is now widely adopted, oncologists and physicians should be aware of such rare side effects due to radiation therapy.
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PMID:Bullous pemphigoid induced by radiation therapy. 884 29

Excess 17beta-estradiol (E2), the most potent of human estrogens, is known to act as a stimulus for the growth of breast tumors. Human estrogenic 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), which catalyzes the reduction of inactive estrone (E1) to the active 17beta-estradiol in breast tissues, is a key enzyme responsible for elevated levels of E2 in breast tumor tissues. We present here the structure of the ternary complex of 17beta-HSD1 with the cofactor NADP+ and 3-hydroxyestra-1,3,5,7-tetraen-17-one (equilin), an equine estrogen used in estrogen replacement therapy. The ternary complex has been crystallized with a homodimer, the active form of the enzyme, in the asymmetric unit. Structural and kinetic data presented here show that the 17beta-HSD1-catalyzed reduction of E1 to E2 in vitro is specifically inhibited by equilin. The crystal structure determined at 3.0-A resolution reveals that the equilin molecule is bound at the active site in a mode similar to the binding of substrate. The orientation of the 17-keto group with respect to the nicotinamide ring of NADP+ and catalytic residues Tyr-155 and Ser-142 is different from that of E2 in the 17beta-HSD1-E2 complex. The ligand and substrate-entry loop densities are well defined in one subunit. The substrate-entry loop adopts a closed conformation in this subunit. The result demonstrates that binding of equilin at the active site of 17beta-HSD1 is the basis for inhibition of E1-to-E2 reduction by this equine estrogen in vitro. One possible outcome of estrogen replacement therapy in vivo could be reduction of E2 levels in breast tissues and hence the reduced risk of estrogen-dependent breast cancer.
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PMID:Structure of the ternary complex of human 17beta-hydroxysteroid dehydrogenase type 1 with 3-hydroxyestra-1,3,5,7-tetraen-17-one (equilin) and NADP+. 992 55

Palmitoylethanolamide (PEA) is a bioactive fatty acid amide belonging to the class of N-acyl-ethanolamines (NAEs). This compound has been known since the 1950s for its anti-inflammatory effects, but was re-discovered only after the finding that another NAE, arachidonoyl-ethanolamide (anandamide, AEA), could act as an endogenous ligand of cannabinoid receptors. Although a similar function for PEA has also been proposed, this compound does not activate the two cannabinoid receptor subtypes described to date. PEA and AEA are co-synthesized by cells, and PEA might act as an 'entourage' compound for AEA, i.e. as an endogenous enhancer of AEA biological actions. Indeed, long-term treatment of human breast cancer cells (HBCCs) with PEA downregulates the expression of the enzyme responsible for AEA degradation, the fatty acid amide hydrolase, thereby leading to an enhancement of AEA-induced, and cannabinoid CB1 receptor-mediated, cytostatic effect on HBCCs. AEA is also a full agonist for the receptors of another class of bioactive fatty acid amides, the N-acyl-vanillyl-amines (e.g. capsaicin and olvanil). These sites of action are known as vanilloid receptors of type 1 (VR1). PEA enhances the VR1-mediated effects of AEA and capsaicin on calcium influx into cells. These 'entourage' effects of PEA might be attributable to modulation of VR1 activity, and could underlie the enhancement by PEA, described here for the first time, of the antiproliferative effects of VR1 receptor agonists.
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PMID:Effect on cancer cell proliferation of palmitoylethanolamide, a fatty acid amide interacting with both the cannabinoid and vanilloid signalling systems. 1257 18

17-beta-Hydroxysteroid dehydrogenase type 1 (17betaHSD1), also called estradiol dehydrogenase, catalyzes the NADPH-dependent reduction of the weak estrogen, estrone, into the more potent estrogen, 17-beta-estradiol. 17betaHSD1 is an attractive drug target in hormone-sensitive breast cancer. Past efforts to develop selective inhibitors of 17betaHSD1 have focused on design of substrate analogs. It is challenging to develop steroid analogs that are devoid of any undesired biological activity. 17betaHSD1 is a member of the short-chain dehydrogenase/reductase (SDR) superfamily that includes many hydroxysteroid dehydrogenases. Members of the SDR family bind NAD(P)(H) in a motif that is a modified Rossmann fold. We demonstrated previously that the Rossmann folds of classical dehydrogenases can be selectively inhibited by derivatives and analogs of the natural product gossypol. In this study, we have addressed the question whether the modified Rossmann fold in 17betaHSD1 is a target for identification of lead compounds for structure-based drug design. 17betaHSD1 was purified from human placenta. 17betaHSD1 is inhibited by derivatives of gossypol with dissociation constants as low as 2 microM. Inhibition is competitive with the binding of cofactor. Molecular modeling studies using the published coordinates of human 17betaHSD1 suggest that these inhibitors occupy the modified Rossmann fold at the nicotinamide end of the dinucleotide-binding site, extending towards the substrate site. A computational approach was used to design potential new inhibitors of 17betaHSD1. The results suggest not only that derivatives of gossypol represent attractive lead compounds for structure-based drug design but also suggest that appropriate incorporation of a substrate analog into the design of these Rossmann fold inhibitors may provide pan-active site inhibitors that span the cofactor and substrate site, potentially offering specificity and increased potency.
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PMID:17-beta-Hydroxysteroid dehydrogenase type 1: computational design of active site inhibitors targeted to the Rossmann fold. 1260 34


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