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)

Vinorelbine is a new 5' nor Vinca alkaloid, active by i.v. route, in various types of cancer disease such as non-small cell lung cancer and advanced breast cancer. In order to evaluate the possibility of using this drug for local treatment of cancer, Vinorelbine-loaded bioresorbable polymeric implants were prepared using a copolymer of D,L-lactic and glycolic acids (PLA 37.5 GA 25). According to the manufacturing process, the 1.2-mm-diameter cylindrical rods obtained had a drug content of 1, 5, or 20% (w/w) and released half of their content within about 6 days in vitro. In vivo release in rats was slower, half of the drug being released after about 14 days. A dose-dependent antitumoral effect was observed in mice (solid P388 leukemia model) when implants were administered into or in contact with the tumor. At highest drug loads and when administered soon after tumor implantation, Vinorelbine implants were more effective than i.v. administration (median survival time of treated animals related to untreated controls, greater than 360 versus 188). In dogs, results of toxicity experiments revealed that administration of implants in vital organs must be avoided. On the contrary, s.c. administration was well tolerated. A transient local necrosis was observed in the days following implantation, but normal skin was recovered after about 10 weeks. Thus, a clinical trial was conducted on patients with head and neck cancer; implantation of 20% loaded polymeric implants into the tumor sites succeeded in 8 of 9 patients. The sole failure was attributed to the unusual hardness of the tumor tissue. Except for a local transient inflammatory reaction (easily treated with nonsteroidal antiinflammatory agents), no other sign of toxicity was detected, and patients tolerated the device well. Fourteen days after implantation, patients underwent their planned surgery, and the implants were recovered. Residual drug content varied from 24 to 55%. In all cases, there was a clearly delimited necrotic area around the implant, ranging from 0.5 to 3.5 cm in diameter. In the smallest tumors, necrosis was also observed in the normal tissue inside this area. These results invite further studies to evaluate such drug-loaded polymeric implants.
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PMID:Experimental studies and preliminary clinical trial of vinorelbine-loaded polymeric bioresorbable implants for the local treatment of solid tumors. 191 58

In a series of 46 cases of primary mammary ductal carcinoma, immunohistochemical markers of differentiation (casein, human placental lactogen, alphalactalbumin, pregnancy specific beta-1 glycoprotein, secretory component, CEA, and peanut lectin agglutinins [PLA]), were quantitated via point-counting. An immunoperoxidase bridge (PAP) was used to identify all except the PLA, in which an avidin-biotin complex with alkaline phosphatase development was employed. For none of the markers was there any difference in the quantity present in tumors of patients who had recurred versus the tumors of patients who had enjoyed a minimum of five years disease-free survival. Nonneoplastic epithelium was only rarely positive for these markers. Although eventually surmounted, technical problems significantly hampered application of morphometry to this histochemical material. The authors conclude that these markers have little relationship to differentiation toward mammary duct epithelium and that they do not provide significant prognostic information in patients with breast cancer.
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PMID:Correlation of immunohistochemical markers with patient prognosis in breast carcinoma: a quantitative study. 609 96

Mechanisms by which vitamin D analogues promote apoptosis in tumour cells are unclear. In this study we have examined possible interactions between the synthetic vitamin D analogue CB1093 and two other known mediators of apoptosis, TNFalpha and ceramide, in MCF-7, T47D and Hs578T breast cancer cells. These studies indicated that cytosolic phospholipase A(2) (cPLA(2)) is involved in CB1093 as well as TNFalpha-mediated cell death. CB1093 promoted both TNFalpha and ceramide-induced c-PLA(2) activation, which was inversely related to loss of cell viability in MCF-7 and Hs578T cells. TNFalpha alone (5-20 ng/ml) failed to induce cytotoxicity and activation of cPLA(2) in T47D cells. However, pretreatment of these cells with CB1093 potentiated C(2)-ceramide-induced cPLA(2) activation and cell death. Treatment with CB1093 alone induced loss of cell viability and DNA fragmentation in all three cell lines by 5 days and these effects were accompanied by activation of cPLA(2). Furthermore, co-treatment with the cPLA(2) inhibitor AACOCF(3) led to partial protection against loss of cell viability induced by CB1093 in Hs578T and T47D cells as well as MCF-7 cells. The broad-spectrum caspase inhibitor z-VAD-fmk prevented TNFalpha but not C(2)-ceramide and CB1093-mediated release of arachidonic acid and cell death in MCF-7 cells. These results indicate that CB1093 potentiates responsiveness of breast cancer cells to TNFalpha and suggest that ceramide and/or cPLA(2) might be involved as downstream effectors in vitamin D-mediated caspase-independent cell death.
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PMID:Interactions of vitamin D analogue CB1093, TNFalpha and ceramide on breast cancer cell apoptosis. 1116 41

We have developed a parenteral delivery system for the administration of the highly promising pure antiestrogen RU 58668 (RU). Two types of nanoparticles (NP) made of biodegradable copolymers and coated with polyethylene-glycol (PEG) chains were prepared: nanospheres (NS) (diameter, approximately 110 nm) and nanocapsules (NC) with an oily core (diameter, approximately 250 nm). The amount of RU incorporated into NS and NC was approximately 33 vs. approximately 5 microg RU/mg of polymer, respectively. Coating with PEG chains prolonged the antiestrogenic potency of RU, as shown by a prolonged antiuterotrophic activity of encapsulated RU into PEG-poly(D,L lactic acid) (PLA) NS, as compared to that of conventional nonpegylated NS. In mice bearing MCF-7 estrogen-dependent tumors, free RU injected at 4.3 mg/kg/week by i.v. route slightly decreased the estradiol-promoted (0.5 mg/kg/week) tumor growth while RU-loaded PEG-PLA NS injected at the same dose strongly reduced it. Analysis of cell cycle parameters in tumors treated with RU indicated that RU-loaded PEG-PLA NS injected at 4.3 mg/kg/week in MCF-7 tumors decreased cyclin D(1) and cyclin E simultaneously, and increased p27. The antitumoral activity of RU encapsulated within pegylated NC was stronger than that of RU entrapped with pegylated NS loaded at an equivalent dose. Indeed, the former decreased the tumor size in nude mice transplanted with the estrogen receptor-positive but estrogen-independent MCF-7/Ras breast cancer cells at a concentration 2.5 times lower than that of the latter (0.4 mg/kg/week compared to 1 mg/kg/week). Empty PEG-PLA NS and NC were devoid of antiuterotrophic and antitumoral activities. Altogether, these results suggest that the incorporation of the pure antiestrogen RU into long-circulating NP could represent a novel antiestrogen drug delivery system for the parenteral route.
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PMID:In vitro and in vivo biologic evaluation of long-circulating biodegradable drug carriers loaded with the pure antiestrogen RU 58668. 1284 87

Nanospheres (NS) formulated using biodegradable and biocompatible polymers, poly(D,L-lactide-co-glycolide) (PLGA), poly(D,L-lactide) (PLA) and poly(epsilon-caprolactone) (PCL), loaded with the pure anti-estrogen RU 58668 (RU), a promising estrogen-dependent anticancer agent, have been prepared. They all possess a small size compatible with an intratumoral extravasation behavior and their pegylation reduce significantly their zeta potential. Characterization by freeze fracture electron microscopy have shown that NS are spheric particles with a size ranging between 30 and 50nm and a tendency to agglomerate which is reduced by polyethylene glycol (PEG) grafting. PEG-grafted NS are all non-toxic as revealed by cell viability assay. A specific cellular model has been used to evaluate not only the release extent of the drug but also its biological activity. All formulations tested showed that they release slowly RU as measured by the delayed ability of RU to inhibit estrogen-induced transcription in human breast cancer cells and that they possess only a small amount of surface adsorbed RU.
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PMID:Pure antiestrogen RU 58668-loaded nanospheres: morphology, cell activity and toxicity studies. 1475 10

The Arg-Gly-Asp (RGD) peptide sequence was conjugated to poly (lactid acid), (PLA), microcapsules. These hollow, biodegradable PLGA microcapsules were developed in our laboratory for use as ultrasound contrast agents. By modifying the surface of the agent with a targeting ligand, it can be targeted to a specific address within the body. This application is ideal for both targeted imaging and/or targeted drug delivery. Integrins are membrane-spanning proteins in cells that play a vital role in cell attachment and many other processes. The RGD peptide sequence targets integrins expressed during angiogenesis, alphavbeta3 and alphavbeta5. The integrins specific to angiogenesis are more active during cancer and can be used as receptors for the RGD-conjugated contrast agents. Although the generic RGD sequence is not specific to only alphavbeta3 and alphavbeta5 integrins, it is an excellent candidate for proof of concepts studies such as described here. Preliminary in vitro results indicate that the modified capsules remain highly echogenic (maximum enhancement of 20 dB in vitro) and adhere specifically to a breast cancer cell line MDA-MB-231 in static experiments. However, no adherence is seen with either unmodified capsules (negative control), or when cells that have been pre-saturated with RGD ligand are contacted with modified capsules (positive control). Specific targeting of ultrasound contrast agents could lead the way to imaging as a method for discrimination of malignant from benign.
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PMID:Polymeric contrast agent with targeting potential. 1504 80

The principal secreted estrogen, 17beta-estradiol rapidly activates signaling cascades that regulate important physiological processes including ion transport across membranes, cytosolic pH and cell proliferation. These effects have been extensively studied in the MCF-7 estrogen-responsive human breast carcinoma cell line. Here, we demonstrate that a physiological concentration of 17beta-estradiol caused a rapid, synchronous and transient increase in intracellular calcium concentration in a confluent monolayer of MCF-7 cells 2-3 min after treatment. This response was abolished when cells were pre-incubated with the phospholipase A(2) (PLA(2)) inhibitor quinacrine or with the cyclooxygenase inhibitor indomethacin. The translocation of GFP-cPLA(2)alpha to perinuclear membranes occurred 1-2 min after 17beta-estradiol treatment; this translocation was concurrent with the transient phosphorylation of cPLA(2)alpha at serine residue 505. The phosphorylation and translocation of cPLA(2) were sensitive to inhibition of the extracellular signal regulated kinase (ERK) signaling cascade and occurred simultaneously with a transient activation of ERK. The phosphorylation of cPLA(2) could be stimulated by membrane impermeable 17beta-estradiol conjugated to bovine serum albumen and was blocked by an antagonist of the classical estrogen receptor. Here we show, for the first time, that PLA(2) and the eicosanoid biosynthetic pathway are involved in the 17beta-estradiol induced rapid calcium responses of breast cancer cells.
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PMID:Estrogen induces phospholipase A2 activation through ERK1/2 to mobilize intracellular calcium in MCF-7 cells. 1637 35

Cyclooxygenases (COX) are rate-limiting enzymes involved in the conversion of PLA(2)-mobilized arachidonic acid into prostaglandins and thromboxanes. COX-2 is a key mediator of inflammation during both physiologic and pathologic responses to endogenous stimuli and infectious agents. Its overexpression has been detected in different cancers, including that of the breast. Using RNA interference, we have reduced the expression of COX-2 in the highly malignant breast cancer cell line MDA-MB-231 below detectable levels in response to interleukin-1 beta or 12-O-tetradecanoylphorbol-13-acetate treatment. Microarray analysis showed that COX-2 silencing resulted in the loss of mRNA expression of several oncogenic markers, such as matrix metalloproteinase-1, chemokine (C-X-C motif) receptor 4, and interleukin-11, which have been correlated with poor disease outcome, and in the up-regulation of antimetastatic transcripts, such as thrombospondin-1 and Epstein-Barr-Induced 3. Cells lacking COX-2 were less able to invade reconstituted extracellular matrix than parental cells in vitro. Consistent with these changes, loss of COX-2 resulted in the abolition or the significant delay of tumor onset when the cells were injected in the mammary fat pad of severe combined immunodeficient mice. Finally, silencing of COX-2 resulted in the inhibition of metastasis to the lungs of severe combined immunodeficient mice after intravenous injection. These data show that silencing of COX-2 abolishes the metastatic potential of MDA-MB-231 cells in vivo.
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PMID:Silencing of cyclooxygenase-2 inhibits metastasis and delays tumor onset of poorly differentiated metastatic breast cancer cells. 1751 Mar 10

Bee venom (BV) therapy (BVT), the therapeutic application of BV, has been used in traditional medicine to treat diseases, such as arthritis, rheumatism, pain, cancerous tumors, and skin diseases. BV contains a variety of peptides, including melittin, apamin, adolapin, the mast-cell-degranulating (MCD) peptide, enzymes (i.e., phospholipase [PL] A(2)), biologically active amines (i.e., histamine and epinephrine), and nonpeptide components which have a variety of pharmaceutical properties. BV has been reported to have anti-arthritis effects in several arthritis models. Melittin, a major peptide component of BV, has anti-inflammatory and anti-arthritis properties, and its inhibitory activity on nuclear factor kappaB (NF-kappaB) may be essential for the effects of BV. The anti-nociceptive effects of BV have also been demonstrated in thermal, visceral, and inflammatory pain models. Apcupoint stimulation (apipuncture) therapy into subcutaneous region may be important in the BV-induced anti-nociceptive effects. Multiple mechanisms, such as activation of the central and spinal opiod receptor, and alpha(2)-adrenergic activity, as well as activation of the descending serotonergic pathway have been suggested. The inhibition of c-Fos expression in the spinal cord by BV apipuncture in several nociceptive models is also reported to be a possible mechanism. BV also has anti-cancer activity. The cell cytotoxic effects through the activation of PLA(2) by melittin have been suggested to be the critical mechanism for the anti-cancer activity of BV. The conjugation of cell lytic peptide (melittin) with hormone receptors and gene therapy carrying melittin can be useful as a novel targeted therapy for some types of cancer, such as prostate and breast cancer.
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PMID:Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. 1755 25

Beta-lapachone (beta-lap) is a novel anticancer agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme overexpressed in a variety of tumors. Despite its therapeutic promise, the poor aqueous solubility of beta-lap hinders its preclinical evaluation and clinical translation. Our objective was to develop beta-lap-containing poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PLA) polymer micelles for the treatment of NQO1-overexpressing tumors. Several micelle fabrication strategies were examined to maximize drug loading. A film sonication method yielded beta-lap micelles with relatively high loading density (4.7+/-1.0% to 6.5+/-1.0%) and optimal size (29.6+/-1.5 nm). Release studies in phosphate-buffered saline (pH 7.4) showed the time (t(1/2)) for 50% of drug release at 18 h. In vitro cytotoxicity assays were performed in NQO1-overexpressing (NQO1+) and NQO1-null (NQO1-) H596 lung, DU-145 prostate, and MDA-MB-231 breast cancer cells. Cytotoxicity data showed that after a 2 h incubation with beta-lap micelles, a marked increase in toxicity was shown in NQO1+ cells over NQO1- cells, resembling free drug both in efficacy and mechanism of cell death. In summary, these data demonstrate the potential of beta-lap micelles as an effective therapeutic strategy against NQO1-overexpressing tumor cells.
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PMID:Beta-lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells. 1757 88


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