Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0025202 (melanoma)
69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cyclic peptide, cyclopentapeptide cyclo(lys-Arg-Gly-Asp-phe) (c(KRGDf)), which is known to target alpha(v)beta3 integrin, is dual-labeled with a radiotracer, (111)indium, for gamma scintigraphy as well as with a near-infrared dye, IRDye800, for continuous-wave (cw) imaging of alpha(v)beta3 positive human M21 melanoma in xenografts. Twenty-four hours after administration of the dual-labeled peptide at a dose equivalent to 90 microCi of (111)In and 5 nmol of near-infrared (NIR) dye, whole-body gamma scintigraphy and cw imaging was conducted. Image acquisition time was 15 min for the gamma scintigraphy images and 800 ms for the optical images acquired using an NIR sensitive intensified charge-coupled device. The results show that while the target-to-background ratio (TBR) of nuclear and optical imaging were similar for surface regions of interest and consistent with the origin of gamma and NIR radiation from a common targeted peptide, the signal-to-noise ratio (SNR) was significantly higher for optical than nuclear imaging. Furthermore, an analysis of SNR versus contrast showed greater sensitivity of optical over nuclear imaging for the subcutaneous tumor targets. While tomographic reconstructions are necessary to probe TBR, SNR, and contrast for interior tissues, this work demonstrates for the first time the direct comparison of molecular optical and planar nuclear imaging for surface and subsurface cancers.
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PMID:Quality analysis of in vivo near-infrared fluorescence and conventional gamma images acquired using a dual-labeled tumor-targeting probe. 1629 70

Ubiquitin-conjugating enzyme (Ubc9) was originally thought to be a conjugating enzyme for ubiquitylation, but was later shown to be responsible for the most recently identified type of post-translational modification, (i.e., SUMO [small ubiquitin-related modifier]) conjugation or sumoylation. Like ubiquitylation, sumoylation modulates protein function through post-translational covalent attachment to lysine residues within targeted proteins. However, although ubiquitylation can lead to protein degradation through the 26S proteasome, sumoylation does not cause protein degradation; instead, it has been implicated in other cellular processes, such as regulating the activity of transcription factors, mediating nuclear translocation of proteins or the formation of subnuclear structures. Interestingly, some proteins can be modified at the same lysine residue by both SUMO and ubiquitin, but with distinct functional consequences. Given that many proteins involved in cell-cycle regulation, proliferation, apoptosis and DNA repair are targets for sumoylation, alterations of sumoylation could ultimately have an impact on cell growth, cancer development and drug responsiveness. As Ubc9 is the sole E2-conjugating enzyme required for sumoylation, and, in particular, Ubc9 is upregulated in an increasing number of human malignancies, such as ovarian carcinoma, melanoma and lung adenocarcinoma, it is a potential target for cancer therapy.
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PMID:Targeting Ubc9 for cancer therapy. 1630 Apr 71

The antimetastatic ruthenium complex imidazolium trans-imidazoledimethylsulfoxide-tetrachlorouthenate (NAMI-A) is tested in the B16 melanoma model in vitro and in vivo. Treatment of B6D2F1 mice carrying intra-footpad B16 melanoma with 35 mg/kg/day NAMI-A for 6 days reduces metastasis weight independently of whether NAMI-A is given before or after surgical removal of the primary tumor. Metastasis reduction is unrelated to NAMI-A concentration, which is 10-fold lower than on primary site (1 versus 0.1 mM), and is correlated to the reduction of plasma gelatinolitic activity and to the decrease of cells expressing CD44, CD54, and integrin-beta(3) adhesion molecules. Metastatic cells also show the reduction of the S-phase cells with accumulation in the G(0)/G(1) phase. In vitro, on the highly metastatic B16F10 cell line, NAMI-A reduces cell Matrigel invasion and its ability to cross a layer of endothelial cells after short exposure (1 h) to 1 to 100 microM concentrations. In these conditions, NAMI-A reduces the gelatinase activity of tumor cells, and it also increases cell adhesion to poly-L-lysine and, in particular, to fibronectin, and this effect is associated to the increase of F-actin condensation. This work shows the selective effectiveness of NAMI-A on the metastatic melanoma and suggests that metastasis inhibition is due to the negative modulation of tumor cell invasion processes, a mechanism in which the reduction of the gelatinolitic activity of tumor cells plays a crucial role.
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PMID:Inhibition of B16 melanoma metastases with the ruthenium complex imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate and down-regulation of tumor cell invasion. 1636

One method of nonviral-based gene therapy is to implant microencapsulated nonautologous cells genetically engineered to secrete the desired gene products. Encapsulating the cells within a biocompatible permselective hydrogel, such as alginate-poly-L-lysine-alginate (APA), protects the foreign cells from the host immune system while allowing diffusion of nutrients and the therapeutic gene products. An important consideration is which kind of cells is the best candidate for long-term implantation. Our previous work has shown that proliferation and differentiation of encapsulated C2C12 myoblasts in vitro are significantly improved by inclusion of basic fibroblast growth factor (bFGF), insulin growth factor II (IGF-II), and collagen within the microcapsules ("enhanced" capsules). However, the effects of such inclusions on the functional status of the microcapsules in vivo are unknown. Here we found that comparing the standard with the enhanced APA microcapsules; there was no difference in the rates of diffusion of recombinant products of different sizes, that is, human factor IX (FIX, 65 kDa), murine IgG (150 kDa), and a lysosomal enzyme, beta-glucuronidase (300 kDa), thus providing a key requirement of such an immunoprotective device. Furthermore, the creatine phosphokinase activity and myosin heavy chain staining (markers for differentiation of the myoblasts) and the cell number per capsule in the enhanced microcapsules indicated a higher degree of differentiation and proliferation when compared to the standard microcapsules, thus demonstrating an improved microenvironment for the encapsulated cells. Efficacy was tested in a melanoma cancer tumor model by treating tumor induced by B16-F0/neu tumor cells in mice with myoblasts secreting angiostatin from either the standard or enhanced APA microcapsules. Mice treated with enhanced APA-microcapsules had an 80% reduction in tumor volume at day 21 compared to a 70% reduction in those treated with standard APA-microcapsules. In conclusion, enhancement of APA microcapsules with growth factors and collagen did not adversely affect their permeability property and therapeutic efficacy. However, the enhanced differentiation and viability of the encapsulated myoblasts in vivo should be advantageous for long-term delivery with this method of gene therapy.
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PMID:Enhancement of myoblast microencapsulation for gene therapy. 1647 Aug 9

Monoclonal antibody (mAb) 38C2 belongs to a group of catalytic antibodies that were generated by reactive immunization and contains a reactive lysine. 38C2 catalyzes aldol and retro-aldol reactions, using an enamine mechanism, and mechanistically mimics natural aldolase enzymes. In addition, mAb 38C2 can be redirected to target integrins alpha(v)beta(3) and alpha(v)beta(5) through the formation of a covalent bond between a beta-diketone derivative of an arginine-glycine-aspartic acid (RGD) peptidomimetic and the reactive lysine residue in the antibody combining site to provide the chemically programmed mAb cp38C2. In this study, we investigated the potential of enhancing the activity of receptor-binding small molecule drug (SCS-873) through antibody conjugation. Using a M21 human melanoma xenograft model in nude mice, cp38C2 inhibited the growth of the tumor by 81%. The chemically programmed antibody was shown to be highly active at a low concentration while SCS-873 alone was ineffective even at dosages 1,000-fold higher than those used for the chemically programmed antibody. In vitro programming of the catalytic antibody was shown to be as effective as in vivo programming. In an experimental metastasis assay, treatment with mAb cp38C2 significantly prolonged overall survival of tumor-bearing severe combined immuno-deficient (SCID) mice when compared to treatment with unprogrammed mAb 38C2, SCS-873 alone or the integrin-specific monoclonal antibody LM609. In vitro, cp38C2 inhibited human and mouse endothelial and human melanoma cell adhesion, migration and invasion. Additionally, cp38C2 inhibited human and mouse endothelial cell proliferation and was active in complement-dependent cytotoxicity assays. These studies establish the potential of chemically programmed monoclonal antibodies as a novel and effective class of immunotherapeutics that combine the merits of traditional small molecule drug design with immunotherapy.
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PMID:Small molecule drug activity in melanoma models may be dramatically enhanced with an antibody effector. 1657 Feb 83

There has been increasing interest in peptides containing the Arg-Gly-Asp (RGD) sequence for targeting of alpha(v)beta(3) integrins to image angiogenesis. [(18)F]Galacto-RGD has been successfully used for positron emission tomography applications in patients. Here we report on the preclinical characterization of a (99m)Tc-labeled derivative for single-photon emission computed tomography. c(RGDyK) was derivatized with HYNIC at the amino group of the lysine [c(RGDyK(HYNIC)) or HYNIC-RGD]. (99m)Tc labeling was performed using coligands (tricine and EDDA), as well as (99m)Tc(CO)(3)(H(2)O)(3). Radiolabeled peptides were characterized with regard to lipophilicity, protein binding and stability in buffer, serum and tissue homogenates. Integrin receptor activity was determined in internalization assays using alpha(v)beta(3)-receptor-positive M21 and alpha(v)beta(3)-receptor-negative M21L melanoma cells. Biodistribution was evaluated in normal and nude mice bearing M21, M21L and small cell lung tumors. HYNIC-RGD could be labeled at high specific activities using tricine, tricine-trisodium triphenylphosphine 3,3',3''-trisulfonate (TPPTS), tricine-nicotinic acid (NA) or EDDA as coligands. [(99m)Tc]EDDA/HYNIC-RGD, [(99m)Tc]tricine-TPPTS/HYNIC-RGD and [(99m)Tc]tricine-NA/HYNIC-RGD showed protein binding (<5%) considerably lower than [(99m)Tc](CO)(3)/HYNIC-RGD and [(99m)Tc]tricine/HYNIC-RGD. [(99m)Tc]EDDA/HYNIC-RGD revealed high in vitro stability accompanied by low lipophilicity with a log P value of -3.56, comparable to that of [(18)F]Galacto-RGD. In M21 cells for this compound, the highest level of specific and rapid cell uptake (1.25% mg protein(-1)) was determined. In vivo, rapid renal excretion, low blood retention, low liver and muscle uptakes and low intestinal excretion 4 h postinjection were observed. Tumor uptake values were 2.73% ID/g in M21 alpha(v)beta(3)-receptor-positive tumors versus 0.85% ID/g in receptor-negative tumors 1 h postinjection. Small cell lung tumors could be visualized using gamma camera imaging. [(99m)Tc]EDDA/HYNIC-RGD shows encouraging properties to target alpha(v)beta(3) receptors in vivo with high stability and favorable pharmacokinetics. Tumor uptake studies showed specific targeting of alpha(v)beta(3)-receptor-positive tumors with tumor-to-organ ratios comparable to those of [(18)F]Galacto-RGD.
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PMID:[99mTc]HYNIC-RGD for imaging integrin alphavbeta3 expression. 1712 66

Members of the nuclear factor-kappa beta (NF-kappaB) family maintain cellular homeostasis by enhancing the transcription of genes involved in inflammation, immune response, cell proliferation, and apoptosis. Melanoma tumor cells often express inflammatory mediators through enhanced activation of NF-kappaB. The NF-kappaB activation appears to result from the enhancer formation including NF-kappaB and lysine acetyl transferases such as p300, CREB (cyclic AMP-responsive element binding protein)-binding protein (CBP), and/or p300/CBP associating factor (PCAF). We observed that proteins expressed by Hs294T metastatic melanoma cells are highly acetylated compared with normal melanocytes, and dominant-negative PCAF reduced the basal and tumor necrosis factor-alpha-stimulated transcriptional activity of NF-kappaB. The promoter activity of NF-kappaB-regulated chemokines was also reduced by the expression of dominant-negative PCAF. The promoters of these chemokines contain a CCAAT displacement protein (CDP)-binding site near the NF-kappaB element. compared with vector-transduced cells, in CDP-transduced Hs294T cells: (i) over-expressed CDP bound efficiently to PCAF, (ii) tumor necrosis factor-alpha-stimulated chemokine expression and NF-kappaB-mediated transcription were reduced, and (iii) the binding of CBP to Rel A was reduced. These data suggest that CDP inhibits cytokine-induced NF-kappaB-regulated chemokine transcription. This study contributes to our understanding of the role of CDP in an enhanceosome of NF-kappaB-mediated chemokine transcription in human melanoma cells.
Melanoma Res 2007 Apr
PMID:CCAAT displacement protein regulates nuclear factor-kappa beta-mediated chemokine transcription in melanoma cells. 1749 84

We have synthesized a stable and clinically relevant nanodevice (cRGD-BT-ND; ND for short) that exhibits superior binding to the biologic target alphavbeta3 integrins, when either compared to the same free cRGD peptide or to the biotinylated nanodevice without covalently attached peptides (BT-ND). Selective targeting of alphavbeta3 integrins was achieved by coupling cyclic cRGD peptides to the nanodevice (ND) surface, while biotin groups (BT) were used for amplified detection of bound cRGD-BT-ND by anti-biotin antibody or avidin linked to horseradish peroxidase after binding. The synthesis involved the following steps: the amino-terminated ethylenediamine core generation 5 poly(amidoamine) (PAMAM_E5.NH2) dendrimer was first partially acetylated and then biotinylated, and residual primary amine termini were converted to succinamic acid groups (SAH), some of which finally were conjugated with cRGD peptide residues through the amino group of the lysine side chain. The starting material and all derivatives were extensively characterized by polyacrylamide gel electrophoresis (PAGE), size exclusion chromatography (SEC), potentiometric acid-base titration, MALDI-TOF, and NMR. Cytotoxicity of all dendrimer derivatives was examined in B16F10 melanoma cell cultures using the XTT colorimetric assay for cellular viability. Binding of nanodevices to the biological target was determined using plates coated with human alphavbeta3 integrin and alphavbeta3 receptor expressing human dermal microvascular endothelial cells (HDMECs). The PAMAM_E5.(NHAc)72(NHBT)8(NHSAH)35(NHSA-cR GD)4 nanodevice is nontoxic within physiologic concentration ranges and specifically binds to the alphavbeta3 integrins, apparently much stronger than the cyclic cRGD peptide itself.
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PMID:Synthesis and characterization of PAMAM dendrimer-based multifunctional nanodevices for targeting alphavbeta3 integrins. 1756 76

Ultra-low-dose opioid antagonists enhance opioid analgesia and reduce analgesic tolerance and dependence by preventing a G protein coupling switch (Gi/o to Gs) by the mu opioid receptor (MOR), although the binding site of such ultra-low-dose opioid antagonists was previously unknown. Here we show that with approximately 200-fold higher affinity than for the mu opioid receptor, naloxone binds a pentapeptide segment of the scaffolding protein filamin A, known to interact with the mu opioid receptor, to disrupt its chronic opioid-induced Gs coupling. Naloxone binding to filamin A is demonstrated by the absence of [(3)H]-and FITC-naloxone binding in the melanoma M2 cell line that does not contain filamin or MOR, contrasting with strong [(3)H]naloxone binding to its filamin A-transfected subclone A7 or to immunopurified filamin A. Naloxone binding to A7 cells was displaced by naltrexone but not by morphine, indicating a target distinct from opioid receptors and perhaps unique to naloxone and its analogs. The intracellular location of this binding site was confirmed by FITC-NLX binding in intact A7 cells. Overlapping peptide fragments from c-terminal filamin A revealed filamin A(2561-2565) as the binding site, and an alanine scan of this pentapeptide revealed an essential mid-point lysine. Finally, in organotypic striatal slice cultures, peptide fragments containing filamin A(2561-2565) abolished the prevention by 10 pM naloxone of both the chronic morphine-induced mu opioid receptor-Gs coupling and the downstream cAMP excitatory signal. These results establish filamin A as the target for ultra-low-dose opioid antagonists previously shown to enhance opioid analgesia and to prevent opioid tolerance and dependence.
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PMID:High-affinity naloxone binding to filamin a prevents mu opioid receptor-Gs coupling underlying opioid tolerance and dependence. 1825 1

Irreversible chemical programming of monoclonal aldolase antibody (mAb) 38C2 has been accomplished with beta-lactam-equipped targeting modules. A model study was first performed with beta-lactam conjugated to biotin. This conjugate efficiently and selectively modified the catalytic site lysine (LysH93) of mAb 38C2. We then conjugated a beta-lactam to a cyclic-RGD peptide to chemically program mAb 38C2 to target integrin receptors alpha(v)beta(3) and alpha(v)beta(5). The chemically programmed antibody bound specifically to the isolated integrin receptor proteins as well as the integrins expressed on human melanoma cells. This approach provides an efficient and versatile solution to irreversible chemical programming of aldolase antibodies.
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PMID:Beta-lactam-based approach for the chemical programming of aldolase antibody 38C2. 1918 22


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