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)

This report describes biodistribution characteristics of three ternary ligand complexes [(99m)Tc(SQ168)(tricine)(L)] (SQ168 = [2-[[[5-[carboonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonic acid]-Glu(cyclo{Lys-Arg-Gly-Asp-d-Phe})-cyclo{Lys-Arg-Gly-Asp-d-Phe}; L = TPPTS (trisodium triphenylphosphine-3,3',3' '-trisulfonate), ISONIC (isonicotinic acid) and PDA (2,5-pyridinedicarboxylic acid)) in athymic nude mice bearing MDA-MB-435 human breast cancer xenografts. Ternary ligand complexes [(99m)Tc(SQ168)(tricine)(L)] (L = TPPTS, ISONIC and PDA) were prepared and were analyzed by a reversed HPLC method. Surprisingly, coligands have little impact on log P values of their ternary ligand (99m)Tc complexes even though HPLC retention times suggest that [(99m)Tc(SQ168)(tricine)(PDA)] and [(99m)Tc(SQ168)(tricine)(ISONIC)] are more hydrophilic than [(99m)Tc(SQ168)(tricine)(TPPTS)]. The results from biodistribution studies indicated that excretion kinetics of the (99m)Tc-labeled cyclic RGDfK dimer can be modified by the choice of coligand. The fact that all three radiotracers show high tumor uptake during the 2 h study period suggests that the coligand has minimal effect on the tumor targeting capability of the (99m)Tc-labeled cyclic RGDfK dimer. Results from the blocking experiment suggest that the tumor localization of the (99m)Tc-labeled cyclic RGDfK dimer is integrin alpha(v)beta(3)-mediated. On the basis of their liver uptake and tumor/liver ratios, we believe that PDA has the advantage over TPPTS and ISONIC for the (99m)Tc-labeling of HYNIC-biomolecule conjugates.
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PMID:Effect of coligands on biodistribution characteristics of ternary ligand 99mTc complexes of a HYNIC-conjugated cyclic RGDfK dimer. 1628 58

The Arg-Gly-Asp (RGD) sequence was selected by using phage-display peptides to target tumors, focusing on targeting alpha(v) integrins in tumor blood vessels. Recent studies suggest that peptides containing the RGD sequence can bind to tumor cells, as well as tumor endothelial cells. To investigate whether the RGD peptide has other effects on tumor cells expressing alpha(v) integrins, besides its tumor targeting capability, we designed and synthesized a 10-amino peptide that contained the RGD sequence in a cyclic conformation with a disulfide bond, which specifically bound to breast cancer cell lines MDA-MB-231 and MCF-7. We found that this RGD peptide, GCGGRGDGGC, inhibited tumor cell proliferation in a dose-dependent manner, and also induced apoptosis and G1-phase cell cycle arrest in both of the cell lines that bound and internalized the peptide. Normal ovarian epithelial cells, which did not bind the RGD peptide, were unaffected. RGD peptide treatment also reduced cell invasiveness in both cell lines in vitro. This study suggests that the RGD peptide not only possesses tumor targeting capacity, but also has direct tumor cytotoxic and invasiveness inhibition effects dependent on the blockage of alpha(v) integrin activity, which would make it more efficient in tumor targeting therapy.
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PMID:Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro. 1632 42

Loss of Wnt-5a protein expression is associated with shorter recurrence-free survival in breast carcinoma patients and increased motility in mammary cell lines. Based on sequence analysis of Wnt-5a, we identified 14 peptide fragments and investigated their ability to mimic the effects of Wnt-5a on mammary cell adhesion and migration. Two of these peptides significantly increased adhesion and impaired migration in the non-tumorigenic HB2 breast epithelial cell line and in the MDA-MB-468 breast cancer cell line, both of which show little endogenous expression of the Wnt-5a protein. We removed two amino acids at a time from the N terminus of the shorter of these two peptides to identify the shortest peptide that still inhibited migration. The influence on tumor cell adhesion was gradually lost and was no longer detectable when only six amino acids remained. However, formylation of the N-terminal methionine of this hexapeptide restored its effect on adhesion and reduced tumor cell motility via a Frizzled-5 receptor-dependent mechanism, even at a low pH such as encountered in breast tumor tissue. This formylated hexapeptide ligand induced a rapid cytosolic calcium signal, whereas it did not affect the cellular levels of unphosphorylated beta-catenin or active JNK. The novel formyl-Met-Asp-Gly-Cys-Glu-Leu peptide ligand is not only a valuable experimental tool but has also a potential role in antimetastatic treatment of the 50% of human breast cancer patients that have reduced endogenous Wnt-5a protein expression.
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PMID:A formylated hexapeptide ligand mimics the ability of Wnt-5a to impair migration of human breast epithelial cells. 1633 May 45

In studies of cell adhesion, migration, growth, differentiation, and apoptosis, synthetic peptides containing the RGD (Arg-Gly-Asp) motif have been extensively used as the inhibitors of integrin-ligand interactions. The RGD motif is an integrin-recognition motif found in many ligands, so that the RGD-containing peptides can be used to probe integrin functions in various biological systems. A linear RGD is a tripeptide consisting of a flexible structure that makes the motif bind to its receptor with inefficient chelating affinity. Therefore, we designed a cyclic-RGD peptide (Tpa-RGDWPC, cRGD) with rigid skeleton to closely bind with its receptor. The cRGD was obtained by solid-phase peptide synthesis method using Rink amide resin. We showed that the cRGD exerts more potency than linear RGD on inhibiting cell growth of MCF-7 breast carcinoma cells. This stimulated us to question how cRGD inhibits cell growth of MCF-7 cells. Moreover, understanding what molecular mechanism underlies the effect that RGD motif exerts on MCF-7 cells is also of considerable importance. We used proteomics and bioinformatics to survey the global changes in proteins after cRGD treatment in MCF-7 cells. The classification of these proteins is shown according to the different biological processes in which they are involved. Most of the proteins that appear to be strongly influenced by cRGD treatment are involved in metabolism, cell growth, responsive to external stimulus, cell communication, reproduction and cell death. This is the first report which monitors the protein expression profile of MCF-7 cells in response to treatment with RGD-containing peptides in a time-course analysis. The clustering data indicated temporal patterns of altered protein expression that can be categorized into early, intermediate and late response proteins. These patterns of protein expression may be important for predicting its response to cRGD. In summary, these results provide a molecular explanation for the properties of cRGD in breast cancer cells and present a valuable in-depth description of their possible impact on breast cancer therapy.
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PMID:Proteomics analysis of a novel compound: cyclic RGD in breast carcinoma cell line MCF-7. 1661 96

The Cytochrome P450 1B1 (CYP1B1) is one of the major CYP450 enzymes catalyzing 4-hydroxylation, an important elimination step for estrogens. Relatively little is known, however, about the impact of this gene on the onset and cessation of menstruation, which are significant milestones in a woman's life and predictors of many hormone related diseases. In this report, we described the association of four SNPs in the CYP1B1 gene, Arg48Gly, Ala119Ser, Leu432Val, and Asp449Asp, with the ages of menarche and menopause, years of menstruation and total number of menstrual cycles. Included in the study were 1958 community controls from two recently completed population-based case-control studies of breast cancer and endometrial cancer. No association was observed between the CYP1B1 polymorphisms and the age of menarche among either pre- or post-menopausal women. Among the women who experienced natural menopause, the three non-synonymous SNPs were significantly associated with menopausal age, years of menstruation, and total number of menstrual cycles. The Gly and Ser alleles of Arg48Gly and Ala119Ser were associated with later menopause, more years of menstruation and more menstrual cycles, while women with allele Val at Leu432Val had a 0.9 year earlier menopause, 1.0 year shorter reproductive span, and 12.6 fewer menstrual cycles than those women without this allele. In conclusion, the results from this study suggested that CYP1B1 genetic polymorphisms may be associated with the natural onset of menopause.
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PMID:Polymorphisms of the CYP1B1 gene may be associated with the onset of natural menopause in Chinese women. 1676 47

Resveratrol is a naturally occurring polyphenol, which causes apoptosis in cultured cancer cells. We describe a cell surface resveratrol receptor on the extracellular domain of hetero-dimeric alphaVbeta3 integrin in MCF-7 human breast cancer cells. This receptor is linked to induction by resveratrol of extracellular-regulated kinases 1 and 2 (ERK1/2)- and serine-15-p53-dependent phosphorylation leading to apoptosis. The integrin receptor is near the Arg-Gly-Asp (RGD) recognition site on the integrin; an integrin-binding RGD peptide inhibits induction by resveratrol of ERK1/2- and p53-dependent apoptosis. Antibody (Ab) to integrin alphaVbeta3, but not to alphaVbeta5, inhibits activation by resveratrol of ERK1/2 and p53 and consequent apoptosis in estrogen receptor-alpha (ERalpha) positive MCF-7, and ERalpha-negative MDA-MB231 cells. Resveratrol is displaced from the purified integrin by an RGD, but not RGE, peptide, and by alphaVbeta3 integrin-specific Ab. Resveratrol action is blocked by siRNAbeta3, but not by siRNAalphaV. [14C]-Resveratrol binds to commercially purified integrin alphaVbeta3 and to alphaVbeta3 prepared from MCF-7 cells; binding of [14C]-resveratrol to the beta3, but not to the alphaV monomer, is displaced by unlabeled resveratrol. In conclusion, binding of resveratrol to integrin alphaVbeta3, principally to the beta3 monomer, is essential for transduction of the stilbene signal into p53-dependent apoptosis of breast cancer cells.
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PMID:Integrin alphaVbeta3 contains a receptor site for resveratrol. 1679 May 23

Although a primary route of breast cancer metastasis is believed to be via lymphatics, the molecular factors involved are poorly understood. We hypothesized that one such factor may be the integrin-binding protein osteopontin (OPN), and we investigated this clinically and experimentally. In breast cancer patients undergoing sentinel lymph node biopsy, OPN levels were significantly higher in lymph node metastases than in the primary tumor (P < 0.001). To test the functional contribution of OPN to lymphatic metastasis and to determine whether the RGD (Arg-Gly-Asp) integrin-binding sequence of OPN is important for this process, we transfected wild-type OPN or mutant OPN (lacking the RGD sequence) into MDA-MB-468 human breast cancer cells. In vitro, cells overexpressing OPN demonstrated increased anchorage-independent growth in soft agar (P = 0.001) and increased RGD-dependent adhesion (P = 0.045). Following mammary fat pad injection of nude mice, cells overexpressing OPN showed increased lymphovascular invasion, lymph node metastases, and lung micrometastases at earlier time points (P = 0.024). Loss of the RGD region partially abrogated this effect in the lymphatics (P = 0.038). These novel findings indicate that OPN is a key molecular player involved in lymphatic metastasis of breast cancer, potentially by affecting RGD-mediated adhesive interactions and by enhancing the establishment/persistence of tumor cells in the lymphatics.
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PMID:Role of the integrin-binding protein osteopontin in lymphatic metastasis of breast cancer. 1681 76

Novel amphiphilic conjugates consisting of an Arg-Gly-Asp (RGD) peptide binding motif and aliphatic fatty acids of varying chain length (C10-C18) were synthesized and evaluated for their ability to form micelles and bind specifically to alphaVbeta3 integrin over-expressing tumor cells. The aphilphiles were characterized by IR, proton NMR and mass spectrometry. The size and zeta potential of the resultant micelles were ranged from 178 to 450 nm and - 13.5 to 39.6 mV, respectively. The critical micellar concentration (CMC), drug loading efficiency and tumor cell binding of these amphiphiles were determined. The CMC values, determined by pyrene fluorescent probe method, ranged from 0.02 to 0.12 mM for C14-RGD, C16-RGD and C18-RGD. The C18-RGD micelles with lowest CMC were found to increase the solubility of taxol, a model anticancer drug, by 87%. C18-RGD amphiphiles also exhibited significantly higher (12.1 +/- 1.14%, P < 0.05) binding to alphaVbeta3 integrin over-expressing human breast cancer cells (HTB-129) when compared to normal human epidermal keratinocyte (NHEK) cells (6.68 +/- 0.34). The results from this study demonstrated the feasibility of designing RGD-fatty acid amphiphiles as micellar drug delivery carriers to target to cancer cells.
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PMID:Synthesis and characterization of RGD-fatty acid amphiphilic micelles as targeted delivery carriers for anticancer agents. 1736 73

In this study, a new poly(lactic acid)-poly (ethylene oxide)-Arg-Gly-Asp (PLA-PEO-RGD) derivative was synthesized, and paclitaxel-loaded PLA-PEO-RGD micelles were prepared by this derivative. The solubility assay showed that micelles mixed with Pluronic F-68 as surfactant could increase the solubility of this hydrophobic paclitaxel in aqueous solution. The cell-binding assay showed that PLA-PEO-RGD micelle (IC(50) = 11.13 +/- 1.38 nmol/L) had about 3.6-fold higher integrin avidity than PLA-PEO-RGD conjugates (IC(50) = 40.33 +/- 3.12 nmol/L). The avidity of micelle was also higher than RGD4C peptide (IC(50) = 24.44 +/- 1.21 nmol/L). The in vitro drug release profile of drug-loaded PLA-PEO-RGD micelles exhibited initial burst release to 37% +/- 2% (w/w) during the first 12 h, and then the release rate became steady in a controlled release manner. Furthermore, treatment of the MDA-MB-435 breast cancer cell line with paclitaxel-loaded PLA-PEO-RGD micelles yielded cytotoxicities, with EC(50) values of approximately 30 mumol/L. The paclitaxel-loaded PLA-PEO-RGD micelles treated group showed the most dramatic tumor reduction in MDA-MB-435 tumor-bearing nude mice, and the final mean tumor load was 31 +/- 16 mm(3) (mean +/- SD; n = 8). (125)I-labeled micelles administration resulted in significant (p < 0.001) higher tumor uptake (2.68% +/- 0.14%, ID/g) of PLA-PEO-RGD micelles compared to PLA-PEO micelles (0.84% +/- 0.09%, ID/g) after 2.5 h postinjection. Biodistribution study showed the best blood clearance of PLA-PEO-RGD micelles after 4.5 h postinjection. The results of this study suggest that paclitaxel-loaded PLA-PEO-RGD micelles based on the specific recognition of alpha(V)beta(3) integrin represent a potential and powerful target delivery technology.
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PMID:Arg-Gly-Asp (RGD) peptide conjugated poly(lactic acid)-poly(ethylene oxide) micelle for targeted drug delivery. 1789 65

Two new cyclic depsipeptides, 1962A (1) and 1962B (2), along with the three known cyclodipeptides cyclo-(Leu-Tyr) (3), cyclo-(Phe-Gly) (4), and cyclo-(Leu-Leu) (5) were isolated from the fermentation broth of the mangrove endophytic fungus (No. 1962) isolated from an old leaf of Kandelia candel collected in Hong Kong. Through spectroscopic experimentation, X-ray crystallographic analysis, and acid hydrolysis followed by chiral HPLC analysis, their structures were established to be 1962A, cyclo-(D-Leu-Gly-L-Tyr-L-Val-Gly-S-O-Leu) (1), and 1962B, cyclo-(D-Leu-Gly-L-Phe-L-Val-Gly-S-O-Leu) (2), respectively. Both of these new cyclo-depsipeptides were found to contain one d-amino acid. In the MTT bioassay, 1962A (1) showed weak activity against human breast cancer MCF-7 cells.
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PMID:Cyclic peptides from an endophytic fungus obtained from a mangrove leaf (Kandelia candel). 1794 38


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