UMLS:C0006142 - FACTA Search

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To develop inhibitors of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) without residual estrogenic activity, the synthesis of 16 alpha-(bromoalkylamide) derivatives of estradiol was performed starting from a key intermediate aldehyde obtained from commercially available estrone. In addition, series of 16 alpha-(bromoalkyl) and 16 alpha-(bromoalkynyl) derivatives of estradiol were also prepared as model compounds. All new compounds inhibited human placental cytosolic 17 beta-HSD (type 1) with IC50 values ranging from 1.7 to 10.6 microM. From these results, we observed that a primary bromide produces a greater inhibition of 17 beta-HSD activity than secondary bromide, and that a shorter 16 alpha-side chain increases the inhibiting activity. In the estrogen-sensitive ZR-75-1 human breast cancer cell line, the 16 alpha-(bromoalkylamide)-estradiol series had no estrogenic activity at 30 nM, and only the compound with a shorter side chain length showed an estrogenic activity at 1000 nM. Interestingly, at this concentration, the compound with an intermediate side chain length showed an antiestrogenic activity of 74%, whereas the compound with the longer side chain length showed 34% of antiestrogenic activity. In this test, other 17 beta-HSD inhibitors (without bromoalkylamide side chain) were fully estrogenic. Among synthesized compounds, the estradiol derivative 4 (N-butyl, N-methyl, 9-[3',17' beta-(dihydroxy)-1',3',5'(10')-estratrien-16' alpha-yl]-7-bromononamide) was the best compromise for a dual-action inhibitor. This compound inhibited moderately and reversibly the 17 beta-HSD type 1 activity, but possessed no estrogenic activity and exhibited antiestrogenic activity in the ZR-75-1 cell line.
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PMID:Synthesis and evaluation of estradiol derivatives with 16 alpha-(bromoalkylamide), 16 alpha-(bromoalkyl) or 16 alpha-(bromoalkynyl) side chain as inhibitors of 17 beta-hydroxysteroid dehydrogenase type 1 without estrogenic activity. 893 31

We examined in vitro cytotoxic activity of imidazolyl-1,3,5-triazine derivatives using human breast cancer cell lines (MCF-7, R-27, T-47D and ZR-75-1) and murine leukemia cell line (P388). The percentage of viable cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazorium bromide (MTT) assay. Hexamethylmelamine (HMM), a 1,3,5-triazine derivative has previously been recognized as an antitumor agent effective against lung, ovarian and breast cancer, but failed to show a significant cytotoxic activity in the present study. In contrast, four imidazolyl-1,3,5-triazine derivatives, 2-(1-imidazolyl)-4,6-bis(morpholino)-1,3,5-triazine, 2-(1-imidazolyl)-4-morpholino-6-(3-thiazolidinyl)-1,3,5-triazine, 2-(4-cyano-4-phenylpiperidino)-4-(1-imidazolyl)-6-morpholino-1,3,5-triaz ine and 2-(1-imidazolyl)-4-(N-methyl-N-phenylamino)-6-morpholino-1,3,5-triazine showed cytotoxic activity for most cell lines, which was significantly greater than the activity of hydroxymethylpentamethylmelamine (HMPMM), a major metabolite of HMM.
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PMID:In vitro cytotoxicity of imidazolyl-1,3,5-triazine derivatives. 921 94

Insulin-like growth factor (IGF) -independent growth inhibition of human breast cancer cells, Hs578T, by IGF-binding protein-3 (IGFBP-3) has previously been demonstrated. Cell growth is a balance between proliferation and programmed cell death (apoptosis). We have investigated whether IGFBP-3 can affect apoptosis of Hs578T cells. As no induction of apoptosis was found, we also investigated its effect on the response to ceramide, an intracellular second messenger that mediates the signal for apoptosis. Using the cell permeable ceramide analogue, C2, induction of apoptosis was established by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay, trypan blue uptake, morphological criteria, and flow cytometry. Incubation of cells with non-glycosylated IGFBP-3 (ngIGFBP-3; 0.5-100 ng/ml) resulted in no growth inhibition or increase in apoptosis; whereas, C2 (1-30 microM) resulted in a dose-dependent induction of apoptosis. Addition of IGFs to the cells, alone or with C2, elicited no response in terms of proliferation or survival, respectively. When the cells were preincubated with ngIGFBP-3 before addition of C2 (2-5 microM), apoptosis was accentuated in a dose-dependent manner (at 100 ng/ml IGFBP-3, apoptosis increased from 11 to 88%). In conclusion, we found that IGFBP-3 had no direct inhibitory effect on Hs578T cells but could accentuate apoptosis induced by the physiological trigger ceramide in an IGF-independent manner.
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PMID:Insulin-like growth factor-binding protein (IGFBP-3) predisposes breast cancer cells to programmed cell death in a non-IGF-dependent manner. 932 80

The mechanism of mammalian polyamine transport is poorly understood. We have investigated the role of plasma-membrane potential (DeltaPsipm) in putrescine and spermidine uptake in ZR-75-1 human breast cancer cells. The rate of [3H]putrescine and [3H]spermidine uptake was inversely correlated to extracellular [K+] ([K+]o) and to DeltaPsipm, as determined by the accumulation of [3H]tetraphenylphosphonium bromide (TPP). Inward transport was unaffected by a selective decrease in mitochondrial potential (DeltaPsimit) induced by valinomycin at low [K+]o, but was reduced by approximately 60% by the rheogenic protonophore carbonylcyanide m-chlorophenylhydrazone (CCCP), which rapidly (<=15 min) collapsed both DeltaPsipm and DeltaPsimit. Plasma-membrane depolarization by high [K+]o or CCCP did not enhance putrescine efflux in cells pre-loaded with [3H]putrescine, suggesting that decreased uptake caused by these agents did not result from a higher excretion rate. On the other hand, the electroneutral K+/H+ exchanger nigericin (10 microM) co-operatively depressed -3H-TPP, [3H]putrescine and [3H]spermidine uptake in the presence of ouabain. Suppression of putrescine uptake by nigericin+ouabain was Na+-dependent, suggesting that plasma-membrane repolarization by the electrogenic Na+ pump was required upon acidification induced by nigericin, due to the activation of the Na+/H+ antiporter. The sole addition of 5-N, N-hexamethylene amiloride, a potent inhibitor of the Na+/H+ antiporter, strongly inhibited putrescine uptake in a competitive fashion -Ki 4.0+/-0.9 (S.D.) microM-, while being a weaker antagonist of spermidine uptake. The potency of a series of amiloride analogues to inhibit putrescine uptake was clearly different from that of the Na+/H+ antiporter, and resembled that noted for Na+ co-transport proteins. These data demonstrate that putrescine and spermidine influx is mainly unidirectional and strictly depends on DeltaPsipm, but not DeltaPsimit. This report also provides first evidence for a high-affinity amiloride-binding site on the putrescine carrier, which provides new insight into the biochemical properties of this transporter.
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PMID:Dependence of mammalian putrescine and spermidine transport on plasma-membrane potential: identification of an amiloride binding site on the putrescine carrier. 949 98

We have investigated the morphology and transfection activity of cationic liposome-DNA complexes (CLDC) under conditions relevant to both in vivo and in vitro studies. Moreover we have attempted to establish structure-function relationships relevant for high transfection activities under both conditions. CLDC were composed of dimethyldioctadecylammonium bromide with either 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or cholesterol (Chol) interacting either with pre-condensed DNA or with uncondensed plasmid DNA. Furthermore for steric stabilization 1% poly(ethylene glycol)-phospholipid conjugate was added to CLDC containing Chol and plasmid DNA. The in vivo studies were carried out in mice following i.v. injection, and the in vitro studies were performed on SK-BR-3 human breast cancer cells in the presence of media with serum. The morphology of the CLDC, monitored by freeze-fracture electron microscopy, was investigated after mixing with mouse serum or the medium where the cells were kept. The substitution of DOPE with Chol, and the addition of N-[omega-methoxypoly(oxyethylene)-alpha-oxycarbonyl-DSPE+ ++ are producing CLDC which are stabilized with respect to time and serum, and are relatively small (100-300 nm). These stabilized complexes show high expression of a marker gene in mouse lungs reaching expression values up to 10 ng luciferase per mg tissue protein, but relatively low expression in SK-BR-3 cells in vitro. Additionally, some of the complexes containing pre-condensed DNA look like 'map-pin' structures showing heads of the size of liposomes and short, stiff and tapering tails. The in vivo transfection activity of these preparations is highest. Similar complexes containing DOPE rather than Chol as helper lipid precipitate in the presence of serum and especially of cell medium and convert into hexagonal lipid (HII) phase. Such complexes, despite their high transfection activity in vitro, show very little transfection activity in vivo. These comparisons may help us to understand the fundamental difference between in vitro and in vivo activity of CLDC: high in vitro transfection activity seems to be associated with hexagonal lipid precipitates whereas high in vivo activity seems to be related with small, stabilized complexes, which in our case also exhibit some protrusions (map-pin structures).
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PMID:Ultrastructural characterization of cationic liposome-DNA complexes showing enhanced stability in serum and high transfection activity in vivo. 976 90

Abnormal dermal scarring which affects a large number of people is aesthetically disfiguring and can be functionally disabling. Existing medical and surgical strategies to prevent or to treat scars are frequently disappointing and more effective therapies are needed. Tamoxifen, which has been used extensively in the treatment of breast cancer over the last 20 years has recently been shown to inhibit the proliferation of fibroblasts cultured from keloid biopsies. Successful treatment of retroperitoneal fibrosis and desmoid tumours with tamoxifen has also been reported. We have investigated the potential of tamoxifen as an inhibitor of wound contraction, using fibroblast-populated collagen lattices as an in vitro model. From these studies we postulate that tamoxifen may have potential clinical significance in the treatment of abnormal scarring. Normal adult human skin fibroblasts were embedded within type I collagen, then medium either with or without addition of tamoxifen was added to the collagen lattices. Lattice diameters were measured at intervals to assess the influence of tamoxifen on the lattice contraction. The reversibility of the inhibitory effect of tamoxifen on lattice contraction was investigated by 'washing out the tamoxifen' at different time-points. To visualise changes in the morphology of fibroblasts MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] was added to the lattices. Tamoxifen at 1 and 5 microM had no significant influence on lattice contraction but higher concentrations of 50 and 100 microM completely inhibited contraction. At intermediate concentrations from 10 to 20 microM the degree of lattice contraction was dose-dependent. The reversibility of the inhibition was both dose- and time-dependent. Both the inhibition of contraction and the reversibility of inhibition appeared to correlate with changes in fibroblast morphology. The dose- and time-dependent inhibition of contraction by fibroblasts suggests that tamoxifen could be investigated as a novel potential therapeutic agent in treating abnormal dermal scarring.
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PMID:Topical tamoxifen--a potential therapeutic regime in treating excessive dermal scarring? 984 67

The epidermal growth factor receptor (EGFR) has been reported to be expressed in high levels in primary breast cancer by immunohistochemistry. In the present study, a reverse transcription (RT)-PCR assay using EGFR primers was developed and evaluated for the detection of circulating micrometastases in the blood of breast cancer patients. Total RNA was extracted from breast cancer cell lines and from the blood of 23 control individuals and 37 breast cancer patients. After reverse transcription, outer and nested primers for EGFR were used for cDNA amplification. RNA integrity was confirmed with parallel RT-PCR amplification using beta2-microglobulin primers. PCR products were electrophoresed on agarose gels containing ethidium bromide and visualized by UV photography. Southern blotting was used to confirm EGFR specificity. The nested EGFR RT-PCR assay was capable of detecting a lower limit of 100 fg of total RNA from the A431 cell line. EGFR RNA was identified from the blood of 4 of 18 (22%) metastatic breast cancer patients, 0 of 6 locally recurrent breast cancer patients, 0 of 13 adjuvant breast cancer patients, and 0 of 23 controls (P = 0.03, metastatic versus control). The 18 metastatic breast cancer patients all had progressive disease at the time of blood sampling. The identity of the four EGFR-positive bands was confirmed by Southern blotting. The presence of RT-PCR positivity for EGFR was not a treatment-related phenomenon, because three of the four EGFR-positive patients were not receiving treatment at the time of blood collection. RT-PCR for EGFR is a sensitive and specific method for the detection of circulating micrometastases in a proportion of patients with metastatic breast cancer.
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PMID:Detection of cancer cells in peripheral blood of breast cancer patients using reverse transcription-polymerase chain reaction for epidermal growth factor receptor. 986 18

Paclitaxel and methotrexate are active against a variety of solid tumors. Because of differences in their mechanisms of action and toxicity profiles, the combination of these two agents has clinical potential. Clinical studies of this combination are in progress. We studied the optimal schedule of paclitaxel and methotrexate in combination at various schedules in vitro using human lung cancer A549, breast cancer MCF7, ovarian cancer PA1, and colon cancer WiDr cells. Cells were simultaneously exposed to paclitaxel and methotrexate for 24 h and sequentially exposed to paclitaxel for 24 h followed by methotrexate for 24 h or vice versa. Cell growth inhibition after 5 days was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of drug combinations at the concentration of drug that produced 80% cell growth inhibition (the IC80 level) were analyzed by the isobologram method. The simultaneous exposure to paclitaxel and methotrexate produced additive to antagonistic effects in the A549 and PA1 cells, and antagonistic effects in the MCF7 and WiDr cells. The sequential exposure to paclitaxel followed by methotrexate produced additive effects in all four cell lines. The reverse sequence produced synergistic effects in the A549, MCF7, and WiDr cells, and additive effects in the PA1 cells. These findings suggest that a sequential administration of methotrexate followed by paclitaxel may be the appropriate schedule for this combination. On the basis of the observed in vitro synergism, further in vivo and clinical studies are necessary to clarify the toxicity and proposed antitumor effects of this schedule.
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PMID:Schedule-dependent synergism and antagonism between paclitaxel and methotrexate in human carcinoma cell lines. 1006 68

Hyaluronic acid (HA) is a component of the extracellular matrix (ECM) that exists as a high molecular weight polymer composed of alternating disaccharides, D-glucuronic acid and N-acetyl D-glucosamine. The interaction of hyaluronidase with HA results in the disruption of basement membrane integrity and produces an angiogenic response that has been implicated in tumor invasiveness and metastasis. Although hyaluronidase is present in several neoplasms, levels of hyaluronidase expression in breast cancer are not known. This investigation defines the correlation of elevated levels of hyaluronidase with breast adenocarcinoma invasiveness. Utilizing RT-PCR, RNA was extracted from paraffin embedded tissues (n=6) of patients diagnosed with fibrocystic breast changes, ductal carcinoma in situ (DCIS), and invasive adenocarcinoma. After constructing cDNA primers for base pairs 504 and 759 of the PH-20 gene (which is homologous to the hyaluronidase gene), PCR was performed and the products were visualized with ethidium bromide using gel electrophoresis. Invasive breast adenocarcinoma had a significantly higher level of hyaluronidase expression compared to other breast tissue samples; (32+/-15 vs. 8+/-3; p<0.03). Elevated levels of hyaluronidase correlated with invasive breast adenocarcinoma. Our data suggests that elevated levels of hyaluronidase are associated with breast adenocarcinoma invasive potential. Hyaluronidase may play an integral role in breast cancer invasion and metastasis.
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PMID:Association of hyaluronidase and breast adenocarcinoma invasiveness. 1020

The molecular mechanism of carboplatin [cis-1,1-cyclobutanedicarboxylatodiammineplatinum(II)] activation is still unresolved. We studied the binding of carboplatin to calf thymus DNA in the presence of thiourea, glutathione, and human breast cancer MCF-7 cell cytoplasmic extracts by measurement of DNA-dependent ethidium bromide fluorescence and atomic absorption spectroscopy. After a 96-hr period of reaction, the decrease in the DNA-dependent fluorescence yield of ethidium bromide due to the formation of platinum (Pt)-DNA adducts increased significantly in the presence of thiourea (6-fold) and glutathione (3- to 4-fold) as compared to the controls in the absence of the nucleophiles. There was also a marked elevation in the levels of platinum incorporated into DNA, measured by atomic absorption spectroscopy (2- to 3-fold and 5- to 7-fold for thiourea and glutathione, respectively). More remarkably, the Pt-DNA adducts formed in the presence of cytoplasmic extracts of MCF-7 human breast cancer cells also showed similar results in a dose-related fashion. Carboplatin, therefore, displayed a characteristic increase in DNA binding/damaging in the presence of the very same S-containing nucleophiles that showed the expected quenching effects in the case of cisplatin [cis-diamminedichloroplatinum (II)]. We propose a nucleophile-facilitated release of the active species of carboplatin prior to binding with DNA.
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PMID:Increased DNA-binding activity of cis-1,1-cyclobutanedicarboxylatodiammineplatinum(II) (carboplatin) in the presence of nucleophiles and human breast cancer MCF-7 cell cytoplasmic extracts: activation theory revisited. 1053 54

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