Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aminopeptidase N (APN/CD13) is a transmembrane ectoenzyme occurring on a wide variety of cells. In contrast to monocytes and granulocytes, lymphocytes of peripheral blood do not express CD13 Ag. However, tumor-infiltrating T cells in renal cell cancer as well as synovial fluid T cells from patients suffering from various forms of arthritis can be CD13 positive. To learn more about expression of CD13 in these tissues, we cocultured lymphocytes with different adherent cell lines. CD13 expression was induced in T and B lymphocytes upon adhesion to fibroblast-like synoviocytes, HUVEC, renal tubular epithelial cells, and monocytes/macrophages but not always upon interaction with different tumor cell lines. Induction of APN was rapid, occurring as early as 1 h after coincubation. Expression persisted for >3 days and partially resisted inhibition by cycloheximide. Fixation of adherent cells with paraformaldehyde could not prevent induction of CD13 in lymphocytes. Soluble APN from human kidneys or placenta could not induce CD13 expression on lymphocytes. Induction of CD13 Ag on lymphocytes required direct cell-to-cell contact as shown in experiments using dual chambers. Lymphocytes exhibited an induction not only in CD13 protein but also in Ala-pNA-cleaving enzyme activity and in CD13 mRNA. Lymphocytic expression of CD13 represents a potentially increased cellular ability to inactivate inflammatory mediators. Furthermore, CD13 could be involved in adhesion, in lymphocytic migration, or in the Ag processing of peptides bound in the groove of MHC class II molecules.
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PMID:Induction of aminopeptidase N/CD13 on human lymphocytes after adhesion to fibroblast-like synoviocytes, endothelial cells, epithelial cells, and monocytes/macrophages. 912 Mar 3

CD13/Aminopeptidase N (APN) is a ubiquitous cell surface enzyme thought to be involved in downregulation of regulatory peptide signals, in binding viruses, and possibly in tumor invasion. Functional aspects of CD13/APN were probed using two monoclonal antibodies (F23 and MY7) to two distinct epitopes on the protein and using substrates and inhibitors of the enzyme. F23 was capable of completely blocking, and MY7 was capable of partially blocking, the binding of substrate to APN and the enzymatic activity of APN. The number of epitopes on APN was quantitated by flow cytometry and by radiobinding with Scatchard analysis. There were approximately 20,000 F23 epitopes per HL60 cell, whereas there were about 10,000 MY7 epitopes per cell. After binding of F23 or natural peptide substrates, the number of MY7 epitopes increased to become equimolar with F23 epitopes, showing a conformational change in CD13/APN structure that reveals MY7 epitopes. Mild proteinase treatment also revealed the hidden epitopes and equalized epitope numbers. The presence of cryptic epitopes may explain the different effects of these antibodies on substrate binding and enzymatic activity. Competition analysis identified the substrate binding site as involving the zinc binding domain of the enzyme. The substrates blocked F23 epitopes (zinc binding domain of the enzyme) and MY7 epitopes, whereas inhibitors blocked only the F23 epitopes, and downregulated MY7 epitopes. A dimeric structure for CD13/APN, in its native, membrane-bound state was directly demonstrated by cross-linking with Bis (sulfosuccinimidyl) suberate and gel electrophoresis. Despite the conformational changes that increased or decreased MY7 epitopes in CD13/APN after substrate or inhibitor binding, neither substrates nor inhibitors caused alterations in the ratio of homodimers to monomers. This suggests that APN undergoes intramolecular conformational changes rather than gross separation of protomers during its regulation. A model for the conformational regulation of APN is proposed.
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PMID:Cryptic and regulatory epitopes in CD13/aminopeptidase N. 919 31

26 cases of lymphoproliferative diseases were studied: 8 cases of reactive follicular hyperplasia (RFH), 11 cases of non-Hodgkin's malignant lymphomas (NML), 7 cases of lymphogranulomatosis (LGM). Only gamma-glutamyl transpeptidase (GGT) was found in lymphoid cells of B- and T-dependent areas of lymph nodes with reactive changes as well as in tumor cells of NML and LGM. GGT activity was more pronounced in NML of high-grade malignancy (centroblast and immunoblast) as compared to lymphomas of lower grade of malignancy (lymphocytic, centroblast-centrocytic and in Lennert lymphoma). GGT activity in cells of Hodgkin and Berezovsky-Sterberg in some cases of LGM was high, in others low. Significant differences in GGT activity between RFH and follicular centroblast-centrocytic lymphoma were not found. Activity of aminopeptidase M was observed in histiocytes, fibroblasts, vessels and areas of connective tissue growth. Aminopeptidase A activity was observed in vessels only. Activity of dipeptidyl(amino)peptidase IV was observed in some lymphoid cells in RFH, NML and LGM. Thus, GGT activity may be considered as a differential-diagnostic marker in separating NML of high and low degree of malignancy and this may presume a different sensitivity to the therapy.
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PMID:[Aminopeptidases in cells of non-Hodgkin's lymphoma of varying degrees of malignancy and in lymphogranulomatosis]. 933 54

In vitro effects of docetaxel on the human colon carcinoma cell line HT-29 were studied with respect to the expression of different adhesion and surface marker molecules, the adhesion and immunocytotoxicity of peripheral blood lymphocytes and the secretion of IFN-gamma and TNF-alpha. Docetaxel, in a low concentration range (1-3x10-9 M), increased the expression of the adhesion molecules LFA-3, ICAM-1, CD44s, CD44v6, CD15, CD13 and VLA-4/5/6 on the tumor cells. Unstimulated and interleukin-2 (IL-2) activated killer (LAK) cells showed a better adherence to docetaxel treated HT-29 cells than to untreated cells. In neutralization experiments, anti-LFA-3, -CD44v6, -CD15, -VLA -4 and anti-CD13 mAb reduced the lymphocyte adhesion to untreated and docetaxel treated cells at different degrees, while CEA mAb increased the adhesion. Unstimulated and IL-2 activated lymphocytes exhibited significantly higher cytotoxicities against docetaxel treated cells than against untreated HT-29 cells. Unstimulated and IL-2 stimulated lymphocytes secreted more TNF-alpha and IFN-gamma when cocultured with docetaxel treated HT-29 cells than with untreated cells. These results suggest, that the increased lymphocyte mediated cytotoxicity against docetaxel treated HT-29 colon carcinoma cells may reflect an immunological process coupled with induction of differentiation, that may contribute to the clinically known cytostatic effects of the drug.
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PMID:Docetaxel treatment of HT-29 colon carcinoma cells reinforces the adhesion and immunocytotoxicity of peripheral blood lymphocytes in vitro. 949 61

Actinonin, an antibiotic and CD13/aminopeptidase N (APN) inhibitor, has been shown to be cytotoxic to tumor cell lines in vitro. We investigated the antiproliferative effects of actinonin on human and murine leukemia and lymphoma cells. Actinonin inhibited growth of NB4 and HL60 human cell lines and AKR mouse leukemia cells in vitro with an IC50 of about 2-5 micrograms/ml. The inhibitory effect on CD13-positive cells was not blocked by pretreatment with the anti-CD13/APN monoclonal antibody F23, which binds with high affinity to the active site of CD13/APN and blocks its enzymatic activity. Moreover, F23 alone was not inhibitory to CD13-positive cells. Furthermore, a similar inhibitory IC50 of actinonin was seen in the CD13-negative cell lines RAJI and DAUDI human lymphoma. These data suggest that the inhibitory effect of actinonin is not mediated by inhibition of CD13/APN. Cell cycle analysis showed that actinonin induces a G1 arrest in HL60 and NB4 cells; apoptosis was observed in 20-35% of the cells as measured by intracellular flow cytometry. To assess whether these effects could be seen in vivo, the effect of actinonin on the syngeneic AKR mouse leukemia model was evaluated. Actinonin showed dose-dependent antitumor effects on AKR leukemia in vivo, resulting in a survival advantage. In conclusion, apoptosis, growth inhibition, and therapeutic effects in vivo are induced by actinonin and are not likely to be mediated by CD13/APN.
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PMID:Antitumor activity of actinonin in vitro and in vivo. 951 67

Immunoregulatory effects of thymic peptides on functions of polymorphonuclear leukocytes (PMNs) are poorly investigated. We studied the effects of prothymosin alpha 1 (Pro alpha 1) on PMNs from patients with colorectal tumors, breast tumors and melanoma (total n = 37) in comparison with healthy donors (n = 18), with respect to chemotaxis, cytotoxicity against HCT-116 colon tumor cells, oxidative response (chemiluminescence reaction) as well as expression of surface marker molecules. We found that Pro alpha 1 was equally effective in stimulating the chemotactic activity of PMNs from tumor patients and healthy donors (43% increase). PMNs from tumor patients, especially with breast tumor, showed a significant enhancement of cytotoxicity against the tumor target cells in comparison with healthy donors. With respect to the PMNs cytotoxicity, only about 50% of the colorectal tumor patients and healthy donors responded to Pro alpha 1 and FMLP. As to the oxidative response of PMNs, elevated levels were found only among colorectal tumor patients. Pro alpha 1 significantly increased the oxidative response in breast and colorectal tumor patients by 55% and 25%, respectively. Pro alpha 1 decreased the expression of CD16 on PMNs of healthy donors, but not that of CD11a, CD11b, CD11c, CD13, CD14, CD15 and CD32. Therefore, we suggest, that Pro alpha 1 may improve some PMN functions of tumor patients, associated with the proposed role in host-tumor interaction.
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PMID:Prothymosin alpha 1 effects in vitro on chemotaxis, cytotoxicity and oxidative response of neutrophils from melanoma, colorectal and breast tumor patients. 956 46

The application of ex vivo expansion to cell products pharmacologically purged in vitro may provide sufficient numbers of cells for rapid engraftment in a product with reduced tumor burden. To pursue this possibility we evaluated the effect of 4-hydroperoxycyclophosphamide (4-HC) treatment on granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (G-PBSC) and their subsequent expansion potential. A small number of G-PBSC CD34+ cells are resistant to 4-HC and are phenotypically and functionally immature. 4-HC-resistant G-PBSC cells are CD34+ bright, CD38+/-, DR(lo), CD13(lo), CD33-, CD71-, and rhodamine dull. In six experiments, treating G-PBSC with 60 microg/mL of 4-HC at 37 degrees C for 30 minutes reduced the number of colony-forming units (CFUs) per 5000 CD34+ cells by 96.3% (from 1333 +/- 137 to 46.5 +/- 11). This purging also reduced the frequency of 5-week long-term culture initiating cells (LTC-ICs) from 1/39 (range 1/27 to 1/62) to <1/1680 (range 1/1180 to 1/2420). Ex vivo expansion cultures were used to compare the proliferative potential of treated and untreated CD34+ cells. These cells were cultured with either the HS-5 stromal cell line serum-deprived conditioned media supplemented with 10 ng/mL kit ligand (HS-5CM/KL) or a recombinant growth factor mix (GFmix) containing 10 ng/mL each of interleukin (IL)-1, IL-3, IL-6, KL, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and 3 U/mL of erythropoietin. Culturing untreated CD34+ G-PBSC with 10% HS-5CM/KL increased total nucleated cells by 460-fold after 15 days. Progenitors, which were measured as CFUs, also increased by 47-fold over the same period. More significantly, culturing the 4-HC-treated CD34+ cells with HS-5/KL increased CFUs 98-fold and the nucleated cells increased 4573-fold. The absolute number of CFUs present after expansion of the 4-HC-resistant cells with HS-5CM/KL was threefold higher than that detected before purging and significantly higher than that obtained with GFmix. These data indicate that G-PBSC contain a very immature pool of cells not detectable using the 5-week LTC-IC assay, but have extremely high proliferative potential. Additionally, pharmacological purging of G-PBSC greatly reduces mature cells while retaining an immature population. Also significant is the finding that supernatant from the HS-5 bone marrow stromal cell line plus KL can fully regenerate progenitors from the 4-HC-resistant CD34+ G-PBSC.
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PMID:Ex vivo expansion of immature 4-hydroperoxycyclophosphamide-resistant progenitor cells from G-CSF-mobilized peripheral blood. 976 8

A 60-year-old woman was admitted in August 1995 complaining of abdominal pain. A diagnosis of essential thrombocythemia had been made in 1987, and myelofibrosis developed in the patient thereafter. Physical examination revealed massive hepatosplenomegaly, and the peripheral blood showed leukoerythroblastosis with chromosomal abnormalities in peripheral blood cells. In May, 1996, blastic transformation occurred. Based on the findings of surface marker analysis, the blasts met the diagnostic criteria for acete myelogenous leukemia because they were negative for peroxidase and positive for CD13. In June, the patient died of multiple organ failure. Postmortem examination revealed multiple tumor emboli.
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PMID:[Transformation of myelofibrosis into acute myelogenous leukemia (M0) with multiple tumor emboli]. 978 83

We describe a case of acute myeloid leukemia in a 2 1/2-year-old boy presenting with a mediastinal tumor causing respiratory distress, and lymph node enlargement in the cervical and inguinal regions. Apart from myeloid markers CD13 and CD33, blast cells also expressed stem cell marker CD34 and megakaryocytic marker CD61. Cytogenetically, inv(7)(p21q31) was found in 9/25 and 15/25 analyzed metaphases from short-term cultures of lymph node and bone marrow cells, respectively. The patient is in continued complete remission 26 months post diagnosis. The case demonstrates that chromosome aberrations other than inv(16), t(8;21), and t(9;11) may be associated with extramedullary disease, and that not all chromosome 7 aberrations are prognostic adverse findings.
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PMID:A case of childhood acute myeloid leukemia associated with inversion (7)(p21q31). 997 43

An acute leukemia with an unusual immunophenotype developed in a 17-year-old girl. At the initial presentation, extramedullary involvement was not evident, but with advancing disease, massive splenomegaly and an osteolytic rib tumor developed. The disease was aggressive and refractory to intensive chemotherapeutic regimens for myeloid and lymphoid malignancies, and the patient died 3 months after the initial presentation. The leukemic cells were of irregular shape and variable size; they had deeply indented or bi-lobed nuclei and relatively fine, azurophilic granules in their cytoplasm. They were positive for acid phosphatase and beta-glucuronidase in granular staining, but they were negative for myeloperoxidase. The leukemic cells had a unique immunophenotype: it was positive for T-cell antigens (CD1a, CD2, cytoplasmic CD3, CD4), myeloid antigens (CD13 and CD33), NK-cell antigen (CD56), CD19 and CD30. DNA analysis revealed no gene rearrangement in the T-cell receptor beta, gamma and delta, or immunoglobulin heavy chain genes. The leukemic cells of our patient are thought to have arisen from the transformation of a putative precursor cell common to both the T- and NK-cell lineage in the bone marrow. The current literature on precursor NK-cell malignancy is reviewed, and its clinicopathological feature is discussed.
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PMID:Acute leukemia with the phenotype of a natural killer/T cell bipotential precursor. 1003 70


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