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: EC:3.2.1.36 (hyaluronidase)
4,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various tumors secrete tumor-specific substances capable of producing signs and symptoms in host organs not caused by direct tumor invasion or organ destruction. These symptoms are collectively referred to as "remote effects" or "paraneoplastic syndromes" of malignancy. Paraneoplastic syndromes are uncommon in childhood cancer. In Wilms tumor several distinct paraneoplastic syndromes have been reported: hypertension, erythrocytosis, hypercalcemia, Cushing syndrome, and acquired Von Willebrand disease. In addition some tumor-specific substances are known to be elevated in patients with a malignancy without causing specific symptoms. These so called "tumor markers" can be used to detect early recurrence in previously treated patients, or in the evaluation of patients undergoing adjuvant therapy. Five of particular interest are erythropoietin, neuron-specific enolase (NSE), hyaluronic acid (HA), hyaluronic acid-stimulating activity (HSA), and hyaluronidase.
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PMID:Serum biological markers and paraneoplastic syndromes in Wilms tumor. 838 82

Previous studies have suggested that mucin gene expression is tissue-specific; however, the relationship between unique mucin gene products and the biochemical properties of mucins is unknown. The purpose of this study was to determine the biochemical and molecular characteristics of mucin synthesized by adenocarcinoma cell lines derived from breast (ZR-75-1), stomach (MGC-803), pancreas (Capan-2), and lung (Chago K-1). Mucin was quantitated by [3H]glucosamine labeling and Sepharose CL-4B chromatography. The mucinous nature of the labeled high molecular weight glycoproteins (HMG) was verified by alkaline borohydride treatment, cesium chloride density gradient ultracentrifugation, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Specific mucin gene expression was determined using cDNA probes for 2 distinct intestinal mucins (MUC-2 and MUC-3) and one breast cancer mucin (MUC-1). Specific core mucin proteins were confirmed by immunoblots using antibodies that recognize MUC-1, MUC-2, and MUC-3 core peptides. These experiments demonstrate that all cell lines contained HMG in the medium, cytosol, and membrane fractions. The HMG was mucinous in breast, pancreatic, and lung cell lines. In contrast, most of the HMG secreted by the gastric cell line was proteoglycan-like, due to its susceptibility to hyaluronidase, heparinase, and chondroitinase avidin-biotin complex. Ion-exchange (DEAE-Sephacel) chromatography of [3H]glucosamine-labeled HMG demonstrated that the acidic or basic nature of the mucin was different in all cancer cell lines tested. Despite these differences, mRNA and immunoblot analysis suggest that all cell lines predominantly express MUC-1 apomucin, small amounts of MUC-2 apomucin, and no MUC-3. Immunoprecipitation of MUC-1-type mucin using the 139H2 monoclonal antibody demonstrated that different sizes of mucin peptides were present in all cell lines, corresponding to the known length polymorphism of this mucin. The amount and nature of carbohydrate epitopes were analyzed by immunoblots using anti-T (peanut lectin), anti-Tn (91S8 monoclonal antibody), and anti-sialosyl Tn (JT10e monoclonal antibody). T and Tn antigens were significantly higher in breast and pancreatic cells as compared with lung and gastric cell lines. These findings correlated with increased activities of polypeptidyl N-acetylgalactosaminyl transferase and beta-1,3-galactosyltransferase.(ABSTRACT TRUNCATED AT 400 WORDS)
Cancer Res 1993 Mar 15
PMID:Mucin synthesis and secretion in various human epithelial cancer cell lines that express the MUC-1 mucin gene. 844 22

The purpose of this randomized, double-blind study was to compare 300 units of hyaluronidase per one-half liter to 150 units per one-half liter in patients receiving brief infusions for subcutaneous hydration. Twenty-five evaluable patients were randomized to receive a local injection of 300 units of hyaluronidase or 150 units of hyaluronidase immediately before two 1-hr infusions of two-thirds dextrose 5% and one-third normal saline solution (500 cc volume). The following day a crossover took place, and patients received the alternate treatment before each of the two 1-hr infusions. The intensity and swelling as reported by the patient (visual analogue scale 0-100), and the intensity of edema and rash as assessed by the investigator (score 0-4) were not significantly different between groups. The patients' and investigators' final choice was also not significantly different. Patients could not distinguish between bolus and their previous experience with overnight clysis. Our results suggest that brief infusions are well tolerated for subcutaneous hydration of patients with advanced cancer. A concentration of 150 units of hyaluronidase per one-half liter is well tolerated in this population.
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PMID:Comparison of two different concentrations of hyaluronidase in patients receiving one-hour infusions of hypodermoclysis. 880 76

Components of extracellular matrix and the matrix-degrading enzymes are some of the key regulators of tumor metastasis and angiogenesis. Hyaluronic acid (HA), a matrix glycosaminoglycan, is known to promote tumor cell adhesion and migration, and its small fragments are angiogenic. We have compared levels of hyaluronidase, an enzyme that degrades HA, in normal adult prostate (NAP), benign prostate hyperplasia (BPH) and prostate cancer (CaP) tissues and in conditioned media from epithelial explant cultures, using a sensitive substrate(HA)-gel assay and an ELISA-like assay. The results show a significant elevation (3-10-fold) of this enzyme in tumor tissues compared to that in NAP and BPH tissues. Furthermore, the hyaluronidase levels in tissues correlates well with the tumor grade. For example, the concentrations in a locally extended CaP lesion (191 +/- 7.9 milliunits/mg protein), and low-grade tumors (9.4 +/- 1.4 milliunits/mg protein), respectively. Among the primary epithelial explant cultures, CaP cultures secrete at least 10-fold higher levels of hyaluronidase that those secreted by NAP and BPH cultures. Furthermore, among the established prostate cancer cell lines, DU145, an androgen-unresponsive metastatic line, secretes 4-fold more hyaluronidase than LNCaP, an androgen-responsive and relatively well-differentiated cell line. We also show that prostatic hyaluronidase has an apparent M(r) approximate to 55,000, a pH optimum of 4.6, and is distinct from other well-characterized hyaluronidases.
Cancer Res 1996 Feb 01
PMID:Association of elevated levels of hyaluronidase, a matrix-degrading enzyme, with prostate cancer progression. 856 86

Preclinical and clinical observations suggest that the administration of hyaluronidase (Hyase) shortly before that of chemotherapy increases the access and, thus, the effectiveness of anticancer drugs in tumors. To examine this hypotheses as well as the selectivity of such a therapeutic approach potentially beneficial in isolated limb perfusion, the Hyase-induced distribution of melphalan was measured in tumor-bearing nude mice with respect to the mode of drug administration using RP-18 ion-pair high-performance liquid chromatography (HPLC) with fluorimetric detection. Melphalan alone (50 micromol/kg) or a combination of melphalan (50 micro mol/kg) and Hyase (100,000 IU/kg) was injected either i.p. or s.c. in the vicinity of the tumors. The s.c. melphalan injection caused a 4-fold rise in melphalan concentration (59 microM) in the tumors as compared with i.p. application (15 microM). Only minor effects were observed with respect to the route of melphalan application on its distribution in other tissues (ca. 13 microM in plasma, 15 microM in muscle, 30 microM in the liver, 26 microM in the kidney, and 21 microM in the testicle). Irrespective of the route of Hyase coadministration, the enzyme increased the concentration of i.p. injected melphalan in all tissues to ca. 20 microM in the tumor, 15 microM in plasma, 27 microM in muscle, 40 microM in the liver, 29 microM in the kidney, and 28 microM in the testicle. In contrast, s.c. injected melphalan was selectively accumulated by the tumors after both s.c. and i.p. Hyase administration (462 and 388 microM, respectively). Melphalan enrichment in the tumors was higher (16- to 32-fold higher than in the other tissues) after i.p. administration of Hyase since, in contrast to s.c. injection of the enzyme, its i.p. administration caused a decrease in the concentration of the cytostatic in all other tissues as compared with the s.c. administration of melphalan alone.
Cancer Chemother Pharmacol 1996
PMID:Hyaluronidase pretreatment produces selective melphalan enrichment in malignant melanoma implanted in nude mice. 860 57

Several studies have demonstrated a correlation between the expression of CD44 variant isoforms and the ability of tumor cells to metastasize. The CD44 proteins carry amino acid sequence motifs that confer the ability to bind to the extracellular matrix component hyaluronate (HA). In this study, we investigated whether a CD44 variant previously shown to stimulate metastasis in a rat pancreatic carcinoma model (BSp73AS) is capable of binding to HA, and whether such binding is critical for metastasis. We show that transfection of this CD44 variant into BSp73AS cells increases the HA-binding capacity of the cells in a dose-dependent manner. Transfection of the same CD44 variant isoform into BDX2 cells also conferred strong HA-binding properties on these cells, but was insufficient to cause them to metastasize. Transfection of a surface-bound hyaluronidase into metastasizing BSp73AS cells bearing variant CD44 efficiently ablated the ability of these cells to bind to HA. However, in metastasis assays, these hyaluronidase-transfected cells showed patterns of metastasis similar to those of the parental cell line. We also show that the HA-binding capacity of a variety of tumor cells is not correlated with their metastatic proclivity, and that an antibody previously shown to block metastasis of the pancreatic carcinoma cells does not interfere with their ability to bind to HA. We conclude that although CD44 variant expression does promote metastasis formation, HA binding by tumor cells is not rate limiting for metastasis in the BSp73AS system and probably also in other metastasizing tumors. Furthermore, for metastasis by CD44 variant-expressing BSp73AS cells to occur, contact of the CD44 variant protein with a ligand other than HA Is required.
Cancer Res 1996 Jul 01
PMID:Hyaluronate-independent metastatic behavior of CD44 variant-expressing pancreatic carcinoma cells. 867 73

Expression of CD44 and of specific splice-variants of CD44 has been causally related to metastatic behaviour in a variety of carcinomas and lymphomas. To elucidate whether, in principle, similar splice-variants could be involved in glioma cell invasion we examined the expression of CD44 and its splice-variants in a series of 38 primary human brain tumors (28 astrocytomas, WHO grade I-III and 10 glioblastomas, WHO grade IV) and in cell lines derived from 9 glioblastomas. All brain tumors examined showed strong immunoreactivity for an N-terminal epitope present on all CD44 isoforms known. Using a polyclonal antiserum raised against the complete sequence encoded by variant exons v3 to v10, CD44 splice-variants could be detected irrespective of the grade of malignancy in many of the tumor samples at a low level and often restricted to only a few clustered tumor cells. Thus, the N-terminal epitope probably indicates the presence of the smallest and most ubiquitous isoform CD44s. Interestingly, all glioblastomas expressed CD44 variants whereas expression in astrocytomas WHO grade I, II, and III could only be detected in about half of the tumor samples. Using reverse transcriptase-PCR we were able to detect different CD44 splice-variants in the glioblastoma cell lines and in cultured primary astrocytic cells. Glioblastoma cells analyzed by flow cytometry showed the expected binding capacity for hyaluronic acid which could be increased twofold after pretreatment with hyaluronidase. The results presented show that there is low expression of CD44 variants in human tumors of astrocytic origin. Expression of CD44 and its splice-variants could contribute to the migration capacity of neoplastic astrocytes, and may be considered as a target for new diagnostic and therapeutic approaches in the clinical management of brain tumors.
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PMID:Expression of variant CD44 epitopes in human astrocytic brain tumors. 875 Jan 82

Excessive production of airway mucus is a characteristic feature of many chronic inflammatory lung diseases. Although current pharmacological approaches to excessive mucus production are limited, glucocorticoids appear to be the most effective among a few useful drugs. The exact evidence for the effectiveness of glucocorticoids on mucus production has not been fully elucidated to date. The purpose of this study is to clarify the effect of dexamethasone on mucus production and mucin gene expression in a human pulmonary mucoepidermoid carcinoma cell line (NCI-H292). NCI-H292 cells produced hyaluronidase-resistant high-molecular-weight glycoconjugates (HMWG), which elute in the void volume on Sepharose CL-4B column chromatography. Dexamethasone significantly suppressed the basal production of [3H]glucosamine-or [3H]serine-labeled HMWG in NCI-H292 cells. In Northern blot analysis, dexamethasone attenuated steady-state mRNA levels of MUC-2 and MUC-5AC mucin genes. These data indicate that dexamethasone suppresses the basal production of HMWG and decreases steady-state mRNA levels of mucin genes in airway mucus-producing cancer cells.
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PMID:Dexamethasone suppresses mucus production and MUC-2 and MUC-5AC gene expression by NCI-H292 cells. 884 99

The detection of high-grade bladder tumors prior to invasion is crucial for a good prognosis. We recently found that the levels of hyaluronic acid (HA), a glycosaminoglycan, are elevated in the urine of bladder cancer patients, and small angiogenic HA fragments are present in the urine of high-grade bladder cancer patients. Hyaluronidase is an enzyme that degrades HA into small angiogenic fragments. We compared the urinary hyaluronidase levels of normal individuals and patients with bladder cancer or other genitourinary conditions, using a substrate (HA)-gel technique and an ELISA-like assay. Among the 139 specimens analyzed, the urinary hyaluronidase levels in patients with G2/G3 tumors (33.4 +/- 4.5 milliunits/mg protein) are 5-8-fold higher than those in normal individuals (4.2 +/- 1.2 milliunits/mg protein) and those in patients with G1 tumors (6.5 +/- 1.7 milliunits/mg protein) or other genitourinary conditions (7.4 +/- 1.4 milliunits/mg protein; P < 0.001). Urinary hyaluronidase measurement shows a sensitivity of 100% and a specificity of 88.8% to detect high-grade bladder (G2/G3) tumors. Thus urinary hyaluronidase measurement is a simple, noninvasive yet highly specific and sensitive method for high-grade bladder cancer detection. The increase in urinary hyaluronidase levels is due to the secretion of a tumor-associated hyaluronidase into the urine because the hyaluronidase levels in G2/G3 tumor tissues are also higher (6-7-fold) than those in normal bladder and G1 tumor tissues (P < 0.001). The bladder tumor-associated hyaluronidase activity is distinct from other hyaluronidases, has a pH optimum of 4.3, and is attributed to two proteins with molecular masses of 65 kD (p65) and 55 kD (p55).
Cancer Res 1997 Feb 15
PMID:Tumor-derived hyaluronidase: a diagnostic urine marker for high-grade bladder cancer. 904 60

Actinomycin D (ActD) enhances the potency of tumor necrosis factor-alpha (TNF-alpha) in killing cancer cells. However, it is determined in this study that murine L929 fibrosarcoma cells, when pretreated with bovine testicular hyaluronidase for 12-24 h, became resistant to the cytotoxic effect of TNF-alpha in the presence of DNA intercalators, such as ActD, doxorubicin, and daunorubicin. Monoclonal anti-Fas antibody-mediated apoptosis in the presence of ActD was also blocked in hyaluronidase-pretreated L929 cells. Hyaluronidase failed to up- or downregulate the expression of apoptosis regulatory proteins, including Bcl-2, Bcl-xL, ICH-1, and TIAR, suggesting that these proteins were not involved in the hyaluronidase-induced resistance to TNF/ActD. A semisynthetic polysulfated hyaluronic acid (HA) inhibited the increased TNF/ActD resistance, whereas unmodified HA, dextran sulfate, and naturally polysulfated glycosaminoglycans had no effect. Evidence is provided here that the induced resistance is related to serum fetuin and a novel intracellular 35-kDa TNF-binding protein (intra TBP). Under serum-free conditions, L929 became refractory to TNF/ActD cytotoxicity and hyaluronidase reversed the resistance. Exogenous fetuin increased L929 cell spreading and proliferation, and restored hyaluronidase-induction of TNF/ActD resistance in these serum-starved cells. Hyaluronidase failed to reduce the expression of TNF-receptors and their binding of TNF-alpha. However, binding and Western-blotting analyses revealed that hyaluronidase downregulated the intra-TBP. Overall, these observations suggest that serum fetuin and intraTBP are involved in the hyaluronidase induction of TNF/ ActD resistance.
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PMID:Hyaluronidase induces murine L929 fibrosarcoma cells resistant to tumor necrosis factor and Fas cytotoxicity in the presence of actinomycin D. 910 95


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