Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human colorectal and pulmonary carcinomas have been shown to contain high levels of opioid peptides and their corresponding membrane-bound receptors. Therefore possible targeted drugs, consisting of modified enkephalins linked to cytotoxic drugs, were designed. Such conjugates were expected to be specifically internalized within opioid receptor-bearing cells. As a model to this approach, we have synthesized enkephalin-ellipticinium conjugates in which the D-Ala2-D-Leu5-enkephalin (DADLE) was coupled to the 2-nitrogen of either ellipticine or 9-hydroxyellipticine, two drugs acting through different mechanisms of cytotoxicity. These conjugates, DADLE-ellipticinium (NME) and DA-DLE-9-hydroxyellipticinium (NMHE), respectively, were previously shown to retain in vitro both opioid receptors and DNA affinities close to those of the parent compounds. In this paper, we first show that each individual moiety in the complexes remains capable of recognizing its cellular targets. Thus, pretreatment of NG108-15 cells containing delta-opioid receptors by the DADLE-ellipticinium conjugates induced a loss of opioid receptor (down-regulation), while the smaller peptide conjugates, tyrosinyl-D-alanylglycine-ellipticinium, prepared as control, do not. On the other hand, peptide-NMHE conjugates were able to induce DNA topoisomerase II-associated DNA strand breaks suggesting that they have a mode of action similar to that of their parent molecule, NMHE. We then examined whether or not these molecules could exert a specific toxicity on opioid receptor-bearing cells. However, when tested on NG108-15 tumor cells and L-fibroblasts as control, the enkephalin-ellipticinium conjugates (DADLE-NME and DADLE-NMHE) proved to be similarly more cytotoxic on both cell lines than their ellipticinium (NME and NMHE) precursors. In order to understand this apparent lack of specificity we examined the cellular accumulation and distribution of DADLE-NME by fluorescence techniques. These experiments revealed that an important intracellular overconcentration caused by a nonspecific process is probably masking the specific targeted effect of the conjugates. Hence, the project of linking DADLE to highly cytotoxic molecules which cannot cross the plasma membrane without site-directed targeting is discussed.
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PMID:Attempts to target antitumor drugs toward opioid receptor-rich mouse tumor cells with enkephalin-ellipticinium conjugates. 253 35

Six patients with systemic sclerosis (SS) and discoid lupus erythematosus (DLE) were studied to determine whether such cases have some common clinical and laboratory findings. DLE preceded SS in all cases. Three patients had diffuse scleroderma with lung and esophagus involvements and the others limited scleroderma. Three patients had anti-topoisomerase-I and antiribonucleoprotein antibodies, 2 had either of them and the remaining anticentromere antibodies. Four had DLE located on the scalp, leading to alopecia. The other 2 had DLE on the face and extremities. No case fulfilled criteria for systemic lupus erythematosus (SLE). The present cases with SS and DLE, but without SLE, indicate that this type of systemic-cutaneous collagen disease overlap does exist and may be not so rare.
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PMID:Systemic sclerosis (scleroderma) associated with discoid lupus erythematosus. 821 19

The performance of immunoassays for the detection of autoantibodies is of critical importance to the diagnosis and assessment of patients with systemic lupus erythematosus (SLE). Our objective was to compare 3 multiplexed assays for measurement of multiple autoantibodies and their association with global disease activity, active nephritis and cumulative organ damage in systemic lupus erythematosus (SLE). Stored sera, clinical and laboratory data from the enrollment visit of a long-term lupus registry were used. Autoantibodies were measured using the BioPlex 2200 ANA screen (Bio-Rad), QuantaPlex ENA8 (INOVA Diagnostics) and recomLine ANA/ENA (Mikrogen). The analytes included dsDNA, chromatin, ribosomal P protein, SS-A/Ro60, Ro52, SS-B/La, Sm, U1-RNP, centromere B, topoisomerase 1 and Jo-1 (histidyl tRNA synthetase). Global SLE disease activity was measured by the SLE disease activity index (SLEDAI) and cumulative organ damage by the SLICC/ACR damage index (SDI). One hundred ninety two patients (87% female; 91% Caucasian; mean disease duration 8.8years) were studied. Agreement between the 3 assays varied from 70% to 99% (Cohen's kappa: 0.04-0.88). There were significant associations between SLEDAI scores (excluding anti-dsDNA) and ANA (INOVA, Mikrogen), anti-dsDNA (Bio-Rad, Mikrogen), anti-chromatin (Bio-Rad, INOVA), anti-Ro (Mikrogen), anti-Sm and anti-U1-RNP (all 3 immunoassays) (p=0.002-0.05). Concurrent lupus nephritis was associated with anti-dsDNA (Bio-Rad (p=0.017) or Bio-Rad and Mikrogen together (p=0.015)). There was no significant association between autoantibodies and SDI scores. The overall agreement between assays for the detection of autoantibodies was reasonable. The greatest discordance (70-83%) occurred with those autoantibodies most strongly associated with global SLE disease activity (ANA, anti-dsDNA, anti-chromatin and anti-Sm). Furthermore, there were differences between assays in their associations with global SLE disease activity and lupus nephritis.
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PMID:Comparison between multiplex assays for autoantibody detection in systemic lupus erythematosus. 2043 30