Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.36 (hyaluronidase)
 4,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Decarbazine (DTIC) is reported to exhibit enhanced clinical toxicity and increased antitumor activity in vitro when exposed to light. Since it was unclear whether light exposure enhanced DTIC antitumor activity or local toxic effects in vivo, a series of experiments was performed in mice given DTIC solutions exposed to light for 2 hours at room temperature. Adenocarcinoma 07/A was implanted by trocar in adult female BALB/c mice. DTIC (50 and 100 mg/kg) was given ip three times per week for 2 weeks. Both drug doses significantly inhibited tumor growth. However, there was no significant difference between light-exposed and -protected drug treatments. In vitro clonogenic assays in L1210 leukemia and Chinese hamster ovary (CHO) cells demonstrated that DTIC cytotoxicity was not increased with light exposure (0.8 J/m2/sec). Both cell lines showed a dose-response relationship to DTIC after 1- or 6-hour exposures in the presence or absence of light. Normal dehaired BALB/c mice were given single intradermal injections of 0.5, 1.75, 5.0, or 10 mg of DTIC in 0.05 ml of saline. Dose-dependent skin ulceration was produced at the 1.75-, 5.0-, and 10.0-mg dose levels. Again, there was no consistent statistical difference in skin ulceration between treatments using light-exposed and -protected DTIC vials. However, when mice were exposed to light following intradermal DTIC, increased skin toxicity was produced (P less than 0.05 by Student-Neuman-Keuls multiple range test). A number of potential local antidotes to DTIC skin ulceration were found to be ineffective. These included: L-cysteine, dimethyl sulfoxide, hyaluronidase, hydrocortisone, and 0.9% saline. Sodium thiosulfate (0.3 M) significantly reduced DTIC skin ulcers as did pre-exposure of DTIC to S-9 rat liver enzymes and NADPH. Neither mild skin heating nor cooling reduced DTIC ulcerations. DTIC appears to synergize with light in vivo to produce increased toxicity. Patients receiving DTIC should avoid intense light exposure after drug injection. However, elaborate precautions to prevent light exposure of DTIC solutions during preparation or injection appear to be unnecessary.
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PMID:Experimental dacarbazine antitumor activity and skin toxicity in relation to light exposure and pharmacologic antidotes. 381 94

The Hyal-1 locus, which we have previously described and mapped to mouse chromosome 9, influences the serum levels and molecular weight forms of hyaluronidase. We have also shown that the growth of two transplantable tumors, the 3LL carcinoma and the B16F10 melanoma, is influenced by the alleles at Hyal-1, in that the tumors develop more slowly in congenic B6.C-Hyal-1a (also called HW23) mice than in the parental Hyal-1b C57BL/6 mice. Here we present evidence that tumor development is stimulated and mortality is accelerated in B6.C-Hyal-1a mice grafted with 3LL carcinoma cells when treated with alpha/beta interferon (IFN-alpha/beta) or with IFN-beta, whereas in IFN-treated C57BL/6 mice 3LL tumor growth is inhibited. Likewise, in B6.C-Hyal-1a mice grafted with B16F10 melanoma cells, IFN-alpha/beta treatment results in stimulation of tumor growth, whereas in IFN-treated C57BL/6 mice tumor growth, whereas in IFN-treated C57BL/6 mice tumor growth is inhibited and mortality delayed. Thus, IFN-alpha/beta treatment of B6.C-Hyal-1a mice results in stimulation of tumor development and sometimes in accelerated mortality. This is the opposite of the usually described effect of IFN treatment in mice, which is inhibition of tumor development and delayed mortality, as was indeed observed in the C57BL/6 mice in the present experiments. These results provide the first indication that host genes can up- or down-regulate the antitumor activity of IFN and that, on some genetic backgrounds, IFN treatment enhances rather than inhibits tumor development. This may help to explain the apparent discordance between mouse model studies, which hitherto have consistently reported inhibition of tumor formation by IFN, and the clinical trials, in which only a limited percentage of individuals show tumor regression while others have no beneficial effect or even have progression of disease in spite of the IFN treatment.
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PMID:Accelerated tumor development in interferon-treated B6.C-Hyal-1 a mice. 851 20

The recently established, estrogen receptor positive rat endometrial adenocarcinoma cell line RUCA-I was tested for estrogen responsiveness in vivo and in vitro. In vivo, 10(6) RUCA-I cells were injected subcutaneously into intact, ovariectomized, or ovariectomized, estradiol-substituted syngenic DA/Han rats. All animals developed well differentiated endometrial adenocarcinoma, that had metastasized to peripheral lymph nodes and into the lung. Ovariectomy reduced tumor and lymph node weight, as well as number of lung metastases significantly compared to controls. In another series of experiments, treatment with the pure anti-estrogen ZK 119010 basically gave the same results as seen in ovariectomized animals, whereas tamoxifen treatment had no effect on metastasis of RUCA-I cells. These findings clearly demonstrate the estrogen dependency of growth and metastasis of RUCA-I cells in vivo. In vitro, we assessed the estrogenic and anti-estrogenic potency of various anti-estrogens, thereby investigating their effects on the expression of components of the complement C3 complex as an estradiol-induced protein and on the expression of fibronectin as an estrogen-repressed protein. Evaluating the relative anti-estrogenic potency of these anti-estrogens we found that ICI 164384 and ICI 182780 behaved as complete antagonists in vitro. Tamoxifen, like estradiol, stimulated complement C3 production and repressed fibronectin expression and has to be regarded as an agonist in this particular in vitro system. ZK 119010 if given alone had no significant influence on the biosynthesis of complement C3 and of fibronectin if compared to the unstimulated control. In addition, another estrogen dependent parameter was identified. Estrogen and anti-estrogen treatment affected glycosylation of complement C3 components. After estradiol treatment predominantly the higher glycosylated epitope of complement C3 became detectable, which could be transformed into the low molecular weight epitope by treatment with hyaluronidase. Finally, we compared the anti-proliferative effects of ICI 164384 and of tamoxifen in vitro. Both anti-estrogens slightly inhibited the growth of RUCA-I rat endometrial adenocarcinoma cells. In conclusion, RUCA-I cells represent a powerful, endometrial derived experimental model to test the agonistic and antagonistic properties of anti-estrogens on growth and metastasis in vivo and on gene expression in vitro. The effects of the tested anti-estrogens on gene expression of RUCA-I cells were found to be useful in predicting their effectiveness on tumor growth in vivo.
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PMID:The rat endometrial adenocarcinoma cell line RUCA-I: a novel hormone-responsive in vivo/in vitro tumor model. 880 92

Gliomas are highly invasive, invariably fatal intracerebral tumors. It seems that receptors for hyaluronan are required for the invasive process. Hyaluronan is a major component of the extracellular matrix in the brain, and all of the gliomas express CD44, the principal receptor for hyaluronan. To investigate the role of lysosomal hyaluronidases on tumor invasion we overexpressed hyaluronidase-2 (HYAL2) in murine astrocytoma cells. We found that high expression of HYAL2 accelerated intracerebral tumor growth dramatically, whereas the same cells formed s.c. tumors within the same time as the parental cells. The brain tumors were highly vascularized and more invasive than the control tumors. It seems that the interactions of the HYAL2-expressing tumor cells with the hyaluronan-containing extracellular matrix in the brain mediate these effects, whereas the same cells in a s.c. environment, which lacks the high hyaluronan level, behave like the parental cells.
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PMID:Hyaluronidase-2 overexpression accelerates intracerebral but not subcutaneous tumor formation of murine astrocytoma cells. 1062 19

Apigenin is a plant flavonoid that is thought to play a role in the prevention of carcinogenesis. However, its mechanism of action has not yet been elucidated. Because of the importance of angiogenesis in tumor growth, we investigated the effect of apigenin on endothelial and smooth-muscle cells in an in vitro model. Apigenin markedly inhibited the proliferation, and, to a lesser degree, the migration of endothelial cells, and capillary formation in vitro, independently of its inhibition of hyaluronidase activity. In contrast, it strongly stimulated vascular smooth-muscle-cell proliferation. The molecular mechanisms of apigenin activity were analyzed in these 2 types of cells. Our results show that apigenin inhibits endothelial-cell proliferation by blocking the cells in the G(2)/M phase as a result of the accumulation of the hyperphosphorylated form of the retinoblastoma protein. Apigenin stimulation of smooth-muscle cells was attributed to the reduced expression of 2 cyclin-dependent kinase inhibitors, p21 and p27, which negatively regulate the G(1)-phase cyclin-dependent kinase.
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PMID:Apigenin inhibits endothelial-cell proliferation in G(2)/M phase whereas it stimulates smooth-muscle cells by inhibiting P21 and P27 expression. 1069 50

Cell motility is an essential element of tumor dissemination, allowing organ infiltration by cancer cells. Using mouse LB lymphoma cells transfected with standard CD44 (CD44s) cDNA (LB-TRs cells) or with the alternatively spliced CD44 variant CD44v4-v10 (CD44v) cDNA (LB-TRv cells), we explored their CD44-dependent cell migration. LB-TRv cells, but not LB-TRs or parental LB cells, bound soluble hyaluronic acid (HA) and other glycosaminoglycans (GAGs), and exclusively formed, under physiological shear force, rolling attachments on HA substrate. Furthermore, LB-TRv cells, but not LB-TRs cells or their parental LB cells, displayed accelerated local tumor formation and enhanced accumulation in the peripheral lymph nodes after s.c. inoculation. The aggressive metastatic behavior of i.v.-injected LB-TRV cells, when compared with that of other LB-transfectants, is attributed to more efficient migration to the lymph nodes, rather than to local growth in the lymph node. Injection of anti-CD44 monoclonal antibody or of the enzyme hyaluronidase also prevented tumor growth in lymph nodes of BALB/c mice inoculated with LB-TRv cells. The enhanced in vitro rolling and enhanced in vivo local tumor growth and lymph node invasion disappeared in LB cells transfected with CD44v cDNA bearing a point mutation at the HA binding site, located at the distal end of the molecule constant region. These findings show that the interaction of cell surface CD44v with HA promotes cell migration both in vitro and in vivo, and they contribute to our understanding of the mechanism of cell trafficking, including tumor spread.
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PMID:CD44-dependent lymphoma cell dissemination: a cell surface CD44 variant, rather than standard CD44, supports in vitro lymphoma cell rolling on hyaluronic acid substrate and its in vivo accumulation in the peripheral lymph nodes. 1168 6

Hyal2 is one of several hyaluronidases present in vertebrates. The human gene encoding this enzyme is present on chromosome 3p.21.3, close to two additional hyaluronidase genes. cDNAs encoding Hyal2 homologues have been characterized from mouse and Xenopus laevis. These enzymes hydrolyze high molecular mass hyaluronan to intermediates of approximately 20 kDa, a finding which implies that structural domains of this size exist in this polysaccharide which was mostly thought to be a random coil. Hyal2 enzymes have an acidic pH-optimum with an activity that is considerably lower than observed for other types of hyaluronidases. Originally considered to be a typical lysosomal enzyme, more recent evidence has shown that Hyal2 proteins can also be exposed on the cell surface bound to the plasma membrane via a GPI anchor. Hyal2 is present in many tissues, one exception being the adult brain. In this tissue, the gene is silenced after birth by methylation. Current evidence about the role of Hyal2 in tumor growth, inflammation and frog embryogenesis is discussed.
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PMID:Hyal2--less active, but more versatile? 1173 Dec 68

Quantitative determination of newly reported enzymes activity in the crude skin toxin (CST) of catfish revealed highest activities of hyaluronidase and lipase, lesser activities of phospholipase A2, lactate dehydrogenase (LDH), cholinesterase (CE), alkaline phosphatase (ALP), and aspartate transaminase (AST), and least activities of proteinase and 5-nucleotidase (5'-NT). The CST has a hemolytic activity of 54% and no ichthyotoxicity up to 500 ug/ml. The chosen dose of CST (LD12.5) showed a potential cytotoxic activity against solid Ehrlich carcinoma-bearing mice demonstrated by an increase in the mean survival time (238.8%) and tumor growth inhibition ratio (T/C) of 73%. The CST ameliorated the relative weights of heart and liver after three weeks, while modulating the elevation in the relative spleen weight throughout the treatment periods (three, six, and nine weeks). The levels of serum triglyceride, total cholesterol, and liver total lipids were normalized after three weeks, whereas the serum albumin and hepatic glycogen concentrations, as well as ALT, AST, 5'-NT, and G-6-Pase activities were ameliorated after 6 weeks. Serum levels of glucose, LDH, and creatine kinase (CK) activities were significantly modulated throughout the treatment periods. Histological examinations of the tumor and liver tissues of treated tumor-bearing animals were carried out. Tumor tissues showed many cytolytic and cytopathic changes after treatment, while liver tissues showed moderate dysplastic changes after six weeks of treatment, which became more marked after nine weeks.
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PMID:Biological activities of the crude skin toxin of the Suez Gulf oriental catfish (Plotosus lineatus) and its antitumor effect in vivo (mice). 1250 71

Hyaluronan is a negatively charged, high molecular weight glycosaminoglycan found predominantly in the extracellular matrix. Intracellular locations for hyaluronan have also been documented in cytoplasm, nucleus, and nucleolus. The polymer has an extraordinarily high rate of turnover in vertebrate tissues. The focus here is to formulate a metabolic pathway for hyaluronan degradation using all available data, including the recently acquired information on the hyaluronidase gene family. Such a catabolic scheme has defied explication up to now. In somatic tissues, stepwise processing occurs, from the extracellular high molecular weight space filling, antiangiogenic approximately 107-kDa polymer, to intermediate sized highly angiogenic, inflammatory, and immune-stimulating fragments, and ultimately to tetrasaccharides that are antiapoptotic and potent inducers of heat-shock proteins. It is proposed that the high molecular weight extracellular polymer is tethered to the cell surface by the combined efforts of hyaluronan receptors and hyaluronidase-2 (Hyal-2). The hyaluronan is cleaved to a 20-kDa intermediate-sized fragment, the limit product of Hyal-2 digestion. These fragments are delivered to endosomal- and ultimately lysosomal-like structures. Further catabolism occurs there by Hyal-1, coordinated with the activity of two lysosomal beta-exoglycosidases, beta-glucuronidase and beta-N-acetyl-glucosaminidase. A membrane-associated mini-organelle is postulated, the hyaluronasome, in which coordinated synthetic and catabolic enzyme reactions occur. The hyaluronasome can respond to the physiological states of the cell by a series of membrane-bound and soluble hyaluronan-associated receptors, binding proteins, and cofactors that trigger enzymatic events and signal transduction pathways. These in turn can be modulated by the amounts and sizes of the hyaluronan polysaccharides generated in the catabolic cascade. Most of these highly dynamic interactions remain to be determined. It is also proposed that malignant cells can commandeer some of these interactions for facilitating tumor growth and spread.
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PMID:Devising a pathway for hyaluronan catabolism: are we there yet? 1451 8

Hyaluronidases are enzymes that degrade hyaluronan, an important component of the extracellular matrix. The mammalian hyaluronidases are considered to be involved in many (patho)physiological processes like fertilization, tumor growth, and metastasis. Bacterial hyaluronidases, also termed hyaluronate lyases, contribute to the spreading of microorganisms in tissues. Such roles for hyaluronidases suggest that inhibitors could be useful pharmacological tools. Potent and selective inhibitors are not known to date, although L-ascorbic acid has been reported to be a weak inhibitor of Streptococcus pneumoniae hyaluronate lyase (SpnHL). The x-ray structure of SpnHL complexed with L-ascorbic acid has been elucidated suggesting that additional hydrophobic interactions might increase inhibitory activity. Here we show that L-ascorbic acid 6-hexadecanoate (Vcpal) is a potent inhibitor of both streptococcal and bovine testicular hyaluronidase (BTH). Vcpal showed strong inhibition of Streptococcus agalactiae hyaluronate lyase with an IC(50) of 4 microM and weaker inhibition of SpnHL and BTH with IC(50) values of 100 and 56 microM, respectively. To date, Vcpal has proved to be one of the most potent inhibitors of hyaluronidase. We also determined the x-ray structure of the SpnHL-Vcpal complex and confirmed the hypothesis that additional hydrophobic interactions with Phe-343, His-399, and Thr-400 in the active site led to increased inhibition. A homology structural model of BTH was also generated to suggest binding modes of Vcpal to this hyaluronidase. The long alkyl chain seemed to interact with an extended, hydrophobic channel formed by mostly conserved amino acids Ala-84, Leu-91, Tyr-93, Tyr-220, and Leu-344 in BTH.
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PMID:L-Ascorbic acid 6-hexadecanoate, a potent hyaluronidase inhibitor. X-ray structure and molecular modeling of enzyme-inhibitor complexes. 1532 7


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