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

Cytolytic activity of mineral oil elicited rat peritoneal macrophages activated by lipopolysaccharide (LPS) and/or rIFN-gamma, rIL-2, Zymosan and PMA (4-beta-phorbol-12-beta-myristate 13-alpha-acetate) was detected in the presence of various concentrations of L-arginine. This paralleled the NO2- production in the presence, but not in the absence, of L-arginine. Significant amount of NO2- was detected in the peritoneal macrophages cultured with 0.4 mmol of L-arginine 8 days and the last 24 h with LPS at a concentration of 1 microgram/ml. No significant differences were found between activated peritoneal macrophages obtained from normal (healthy) and/or from tumor bearing rats to induce tumoricidal activity and NO2- production under the same experimental conditions. The results showed that the major cytolytic mechanism against BP6-Tu2 and U 937 tumor cell lines is L-arginine-dependent nitrogen oxide synthesis of activated rat peritoneal macrophages.
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PMID:Tumoricidal properties of rat peritoneal macrophages activated with various activators depend on nitrogen oxid synthesis. 152

Coculture of purified murine T cells with anti-CD3 monoclonal antibody (145-2C11) results in the induction of nonspecific cytotoxic T lymphocytes (CTL) with MHC-unrestricted cytolytic activity against a range of tumor targets. Serine proteases associated with effector cell granules are among the molecules postulated to play a role in cell-mediated cytolysis. The present study examines the ability of exogenous serine protease substrates to inhibit anti-CD3-activated cytotoxic T (ACT) cell-mediated killing of P815 mastocytoma and YAC1.2 lymphoma target cells. The chymotrypsin substrate N-acetyl-L-tyrosine ethyl ester (ATEE) was found to significantly inhibit ACT cell-mediated cytolysis. In contrast, the trypsin substrate N-benzoyl-L-arginine ethyl ester (BAEE) had little, if any, effect on ACT cell-mediated cytolysis. These effects were observed with both target cell populations. Conjugate inhibition studies performed with ATEE indicated that a chymotrypsin-like serine protease is involved in a postbinding event during cytolysis. Pretreatment of either target or effector cells with ATEE prior to cytolytic assay revealed that the chymotrypsin-like serine protease involved in cytotoxicity is of effector cell origin. Northern blot analysis of total RNA extracted from ACT cells revealed the presence of transcripts coding for CCP1 and CCP2 serine proteases known to be involved in antigen-specific CTL function, but little or no expression of the HF serine protease which has also been implicated in antigen-specific CTL killing. CCP2 exhibits chymotrypsin-like activity while HF displays trypsin-like activity. On the other hand, the CCP1 gene product has protease activity which resembles neither chymase nor tryptase activities. Thus, the level of mRNA expression for these serine proteases is consistent with our earlier observations, using the serine protease substrates, that a chymotrypsin-like serine protease but not a trypsin-like serine protease is involved in ACT cell-mediated cytolysis. "Lymphocyte panning" of ACT cells revealed abundant CCP1 and moderate CCP2 mRNA expression in CD4- and CD8+ anti-CD3-activated T cells with strong tumoricidal activity. CD8- anti-CD3-activated T cells with moderate cytolytic activity also expressed substantial levels of CCP1 and CCP2 mRNA, suggesting that both CD4- CD8- and CD4- CD8+ ACT cells participate in killing tumor targets. In contrast, CD4+ anti-CD3-activated T cells lacked both cytolytic activity and significant CCP1 and CCP2 mRNA expression. These findings are consistent with the involvement of chymotrypsin-like, as well as other, serine proteases in CTL-mediated lysis.
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PMID:Expression and utilization of chymotrypsin-like but not trypsin-like serine protease enzymes by nonspecific T killer cells activated by anti-CD3 monoclonal antibody. 153 39

Nutrient substrates have been shown to enhance cell-mediated immunity, but their role as adjuvants to immunotherapy has not been previously determined. This study evaluated L-arginine as an essential substrate for optimal generation of lymphokine-activated killer (LAK) cells. This experiment also assessed supplemental dietary L-arginine as a means to potentiate the host antitumor response to interleukin-2 (IL-2) in a murine neuroblastoma (NRB) model. A/J mice received 1% arginine or isonitrogenous 1.7% glycine in addition to a regular diet 14 days before subcutaneous inoculation with C1300 NRB cells. Twenty-four hours later, animals received low (1 x 10(6) U/kg three times a day) or high (3 x 10(6) U/kg three times a day) doses of IL-2 or saline intraperitoneally for 4 days. On days 4 and 10 post-C1300 NRB inoculation, mice were killed for assessment of natural killer cell and tumor specific cytotoxicity. Remaining animals were followed for tumor incidence, tumor growth, and duration of host survival. Interleukin-2 therapy in mice receiving dietary arginine compared with those receiving glycine resulted in significantly augmented natural killer cell cytotoxicity (day 4) and generation of specific tumoricidal mechanisms (day 10). The addition of dietary arginine to low-dose IL-2 therapy significantly diminished C1300 NRB engraftment (p less than 0.05) and growth (p less than 0.001) and prolonged the duration of host survival (p less than 0.05) compared with the glycine treatment group. In vitro studies demonstrated that L-arginine is an essential substrate for optimal generation of LAK cells. Thus, supplemental dietary L-arginine enhances lymphocyte cytotoxic mechanisms and potentiates IL-2 immunotherapy.
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PMID:Enhancement of interleukin-2 immunotherapy with L-arginine. 154 2

The p53 gene was examined in primary or metastatic tumors from six patients with rhabdomyosarcoma (RMS) and in five RMS cell lines by screening methods including single-strand conformation polymorphism analysis, the RNase protection assay, sequencing of complementary DNA subclones, and Southern blotting. Six original tumors were of embryonal histology, four alveolar, and one mixed. p53 mutations were identified in four of the six tumors or cell lines derived from tumors with embryonal histology and in one of the four with alveolar histology. Consistent with p53 allele loss, each mutation was found in the homo- or hemizygous state. One tumor showed a G to C transversion at p53 codon 213 (arginine to proline), and another showed deletion of the entire gene. The p53 mutations in cell lines included a codon 248 C to T transition (arginine to tryptophan) in RD and a codon 280 A to T transversion (arginine to serine) in RH30. The cell line CTR contained a 4-base pair deletion at codons 219/220 in exon 6 with resultant frame shift and premature termination in exon 7. These data support the role of diverse types of p53 mutations in the pathogenesis and/or progression of a significant proportion of cases of childhood RMS.
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PMID:Frequency and diversity of p53 mutations in childhood rhabdomyosarcoma. 155 27

We have previously shown that transfection of NIH 3T3 cells with the T24 H-ras oncogene converts the cells to a tumorigenic and metastatic phenotype, in proportion to levels of ras expression. We hypothesize that ras-induced increases in malignancy occur via altered expression of various genes. We have identified OPN (osteopontin; also known as Secreted Phosphoprotein, 2ar, Eta-1, and transformation-associated phosphoprotein) as a ras-induced gene in these cells. We report here that expression of OPN RNA and secretion of OPN protein are increased in a series of ras-transformed NIH 3T3 cells, in proportion to levels of expression of ras. Detection of secreted OPN protein was facilitated by a barium citrate precipitation procedure. Although the function of this protein in tumor cells is not known, OPN contains a conserved GRGDS (glycine-arginine-glycine-aspartic acid-serine) amino acid sequence, which may function as a cell attachment site for this protein. We speculate that increased expression of OPN contributes to the increased malignancy of ras oncogene-transformed NIH 3T3 cells, perhaps by alterations in either adhesive properties or integrin-mediated signal transduction pathways.
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PMID:Induction of expression of osteopontin (OPN; secreted phosphoprotein) in metastatic, ras-transformed NIH 3T3 cells. 156 80

Arginine deiminase (EC 3.5.3.6) was purified to homogeneity from the cell extract of Mycoplasma arginini by molecular-sieve, anion-exchange and arginine-affinity chromatographies. The purified enzyme was composed of 2 identical sub-units with a molecular weight of 45.000 and had a pI of 4.7. Its Vmax value and Km value for L-arginine were estimated to be 50 units/mg protein and 0.2 mM, respectively. It exerted maximal enzyme activity at pH 6.0-7.5 and at 50 degrees C. The arginine deiminase was stable at neutral pH. When injected i.v. into mice, the half-life of the arginine deiminase in blood was about 4 hr. In culture, the enzyme strongly inhibited the growth of 6 kinds of mouse tumor cell lines by depleting L-arginine in the culture media. When the in vivo growth-inhibitory activity of arginine deiminase was tested for the 6 tumor cell lines, i.p. administration of the purified enzyme effectively prolonged the survival time of the mice injected with all kinds of the tumor cell lines. Especially, the in vivo growth of a hepatoma cell line, MH134, was completely prevented by the daily administration at a dose of 0.2 mg/mouse for 14 days. These results raise the possibility of the use of the arginine deiminase derived from Mycoplasma arginini as a new anti-tumor drug.
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PMID:In vivo anti-tumor activity of arginine deiminase purified from Mycoplasma arginini. 156 92

This study examined the role of fibronectin in promoting particulate attachment to sites of urothelial injury. Variables influencing adherence of the rat transitional carcinoma cell line 4909 and "non-cellular" styrene-divinylbenzene microspheres to fibronectin were studied in an in vitro system. A soluble synthetic peptide fragment (Gly-Arg-Gly-Asp-Ser [GRGDS]) duplicating the receptor binding domain of fibronectin (RGD) was used to determine whether cell adherence could be inhibited by fibronectin receptor blockade. In vitro findings were correlated with an in vivo assay of both cellular and non-cellular particulate adherence to injured urothelium. Time, plated cell density, substrate concentration, GRGDS concentration, and cell viability, were all found to be significant independent variables influencing in vitro cellular adherence (p less than 0.0001). Receptor blockade with GRGDS significantly decreased in vitro tumor cell adherence to fibronectin. In vitro microsphere binding increased as a direct function of fibronectin concentration but was not time dependent (p less than 0.0001 and p = 0.14 for fibronectin concentration and time respectively). The in vivo adherence of both tumor cells and microspheres was significantly increased in injured bladders compared to controls (p less than 0.01). Receptor blockade with GRGDS failed to inhibit in vivo cell adherence to sites of urothelial injury. Microspheres proved to be competitive inhibitors of cellular adherence in competitive binding assays. In vitro microsphere binding demonstrated a pH dependence with maximal binding at pH 7.2. These data suggest that in vitro tumor cell adherence to fibronectin differs from in vivo tumor cell adherence to sites of urothelial injury. Manipulations which inhibit in vitro adherence, specifically fibronectin receptor blockade and cell death, fail to effect in vivo binding to the extreme that non-cellular particulate appears to bind to the same site, and with similar affinity, as cellular particles.
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PMID:In vitro particulate adherence to fibronectin: correlation with in vivo particulate adherence to sites of bladder injury. 156 98

Matrix-bound fibronectin (FN) appears to be involved in cell adhesion and motility mediated by integrin receptors. Although lymphoid cells and other cell types are capable of producing and secreting FN, the precise role of this secreted FN-like factor in regulating immune reactions is unclear. In the present study we analyzed the adhesive properties of FN secreted by rat CD4+ T cells and clone cells activated by the T cell mitogen concanavalin A (Con A), antigen, or via the CD2 pathways, or by macrophages (M phi) activated by lipopolysaccharide (LPS). Immobilized culture supernatant (CS) from the activated T cells or M phi supports the adhesion of activated rat or human CD4+ T cell or murine tumor cell. These CS contained FN and were more potent at facilitating cell adhesion then plasma FN. The adhesion activity of CS was attributed to FN because (a) gelatin columns depleted the FN present in the CS and (b) pretreating the cells with peptides of the cell-binding domain of FN abrogated their ability to bind CS. CS-mediated adhesion appears to occur primarily via the recognition of the Arg-Gly-Asp (RGD) by the beta 1-integrin-specific receptors of the adhesive cells. Thus, we postulate that FN secreted by various types of leukocytes is involved in promoting essential cell-matrix interactions, possibly affecting cell-adhesive and migratory processes at inflammatory or extravasation sites.
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PMID:Activated T lymphocytes and macrophages secrete fibronectin which strongly supports cell adhesion. 157 55

The injection of B16F10 melanoma cells with recombinant human tumor necrosis factor alpha (TNF-alpha) into the tail vein of C57BL/6 mice resulted in 2- to 25-fold more metastatic foci in the lungs than the injection of tumor cells alone. Clearly, TNF-alpha significantly enhanced experimental tumor metastasis. Furthermore, it enhanced the metastasis of Lewis lung carcinoma cells. In contrast, a mutein of TNF-alpha, designated as F4236, having the cell-adhesive sequence (Tyr-Ile-Gly-Ser-Arg) at the N-terminus of the TNF molecule did not enhance metastasis, but rather exhibited similar antitumor activity to wild-type TNF-alpha in fibrosarcoma-bearing mice.
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PMID:A YIGSR-containing novel mutein without the detrimental effect of human TNF-alpha of enhancing experimental pulmonary metastasis. 161 34

Certain waterblooms of toxic cyanobacteria (blue-green algae) are a health threat because of their production of toxic peptides, termed microcystins, which cause liver damage in wild and domesticated animals. The most widely studied microcystin is microcystin-LR, a heptapeptide containing the two L-amino acids, leucine and arginine. The inhibition of protein phosphatase type 1 and type 2A activities by microcystin-LR is similar to that of the known protein phosphatase inhibitor and tumor promoter okadaic acid. We show in this report that microcystin-LR, applied below the acute toxicity level, dose-dependently increases the number and percentage area of positive foci for the placental form of glutathione S-transferase in rat liver, which was initiated with diethylnitrosamine. The result was obtained independently through two animal experiments. This observation indicates that microcystin-LR is a new liver tumor promoter mediated through inhibition of protein phosphatase type 1 and type 2A activities. This provides further evidence that the okadaic acid pathway is a general mechanism of tumor promotion in various organs, such as mouse skin, rat glandular stomach and rat liver.
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PMID:Liver tumor promotion by the cyanobacterial cyclic peptide toxin microcystin-LR. 161 89


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