Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism by which the murine fibrosarcoma clone PAK 17.15 induces platelet aggregation [tumor cell-induced platelet aggregation (TCIPA)] was studied because platelet activation by this clone is necessary for metastasis to the lungs. PAK 17.15 TCIPA was completely inhibited by ADP-clearing enzymes, such as apyrase, or a mixture of creatine phosphate and creatine phosphokinase. Thrombin and collagen were not involved in PAK 17.15 TCIPA. Further studies showed that ADP is most likely secreted from activated platelets and that membrane protein(s) on PAK 17.15 cells are responsible for platelet activation. Inasmuch as ADP-dependent platelet aggregation requires fibrinogen and can be inhibited by the Gly-Arg-Gly-Asp-Ser (GRGDS) synthetic peptide, the effect of this peptide on PAK 17.15 TCIPA was studied. PAK 17.15 TCIPA was completely inhibited by the GRGDS peptide (0.4 mM) but not by a control peptide, Gly-Arg-Gly-Glu-Ser (0.8 mM). In addition, the GRGDS peptide inhibited adhesion of PAK 17.15 cells to immobilized fibronectin. As expected, the GRGDS peptide almost completely inhibited lung colonization by iv injected PAK 17.15 cells in C57BL/6 mice. Our results indicate that GRGDS may inhibit pulmonary metastases by interfering with TCIPA as well as with tumor cell adhesion to extra-cellular matrix components in the host.
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PMID:Inhibition of tumor cell-induced platelet aggregation and experimental tumor metastasis by the synthetic Gly-Arg-Gly-Asp-Ser peptide. 318 95

To investigate the effect of arginine-enriched solution on tumor growth and metastasis, rats were infused with solutions containing 5.5 and 0.66% arginine for 8 days. Infusions were started at the same time of subcutaneous transplant of Yoshida sarcoma. Arginine-rich solution suppressed tumor growth at an early stage and prevented metastases to the liver and kidney. In addition, arginine supplements enhanced the phagocytic activity of alveolar macrophages. It also resulted in maintenance of a positive nitrogen balance and prevented the increases in the levels of several amino acids observed in the control group. The suppressive effect of arginine-enriched solution on tumor growth may be due to its activation of the immunologic system, in which the phagocytic activity of macrophages probably participates.
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PMID:Evaluation of the effect of arginine-enriched amino acid solution on tumor growth. 392 15

This retrospective study deals with 168 patients with small cell lung cancer (SCLC) who were treated at the NCI March 1973 and July 1977 with intensive chemotherapy. Results showed that 12 per cent of all the patients were disease-free for more than 40 months (25% of the limited disease and 3% of the extended stage disease patients which were treated. Complete remission was essential to prolonged survival. The development of a complete remission was favored by a satisfactory initial general condition, localised disease or presence of only one site of metastatic disease. Initial treatment included the following combinations: cyclophosphamide, methotrexate and CCNU. High doses are necessary. However, above a certain level, the toxicity increased without a corresponding increment in activity. Addition of another association without cross-resistance (vincristine-adriamycine-natulan or VP-16 and isophosphamide) may induce a complete remission in cases where only a partial remission was obtained initially. In limited disease, radiotherapy seemed to prolong disease-free survival. This lead the authors to study the use of initial radiotherapy, at the rate of 40 grays in 3 weeks in 15 fractions, at the same time as chemotherapy. The radiotherapist must take certain precautions in the use of this double treatment: reshaped fields and insertion of a spinal cord block above 2 000 rads. In extended disease, thoracic irradiation seemed to be of no benefit. Pilot studies are not underway using intensive chemotherapy with multiple tumor site irradiation and autologous marrow implants 48 per cent of all patients with SCLC will develop cerebral metastatic disease (44% intracranial, 13% leptomeningeal, 9% epidural). At 30 months, 75 percent of those who did not receive prophylactic irradiation developed cerebral disease whereas only 40 per cent of the patients who received a prophylactic dose of 30 grays developed cerebral disease. Inspite of the indisputable but incomplete local benefit of prophylactic brain irradiation, it did not prolong survival. Important biological studies are underway at the NCI. - Cell clone cultures have been established. These were enhanced by the addition of arginine vasopressive (AVP) and bombesine. These two substances may be considered as markers of APUD system and are secreted by the SCLC. Bombesine has been isolated in all the cultures tested. This possible marker was perhaps responsible for the anorexia and cachexia in these patients. - These cultures have allowed for identification of deletion 3p (14-23) chromosome anomalies in all the samples examined. - In vitro chemotherapy studies of these cultures have been carried out. Their correlation with clinical results were encouraging (100% negative p/n; 75% positive p/n). - Lastly, monoclonal AC have been prepared. Inspite of their imperfect specificity and heterogeneity with regard to tumor cells, their potential advantages were considerable.
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PMID:Experience of the National Cancer Institute (USA) in the treatment and biology of small cell lung cancer. 628 Jul 95

The spreading and colonization of tumor cells require their migration to metastatic sites via blood vessels. To penetrate blood-vessel walls, cells, including malignant ones, must recognize and associate with the sub-endothelium extracellular matrix (ECM) and its glycoproteins. Recognition of ECM-glycoproteins, such as fibronectin (FN) and vitronectin (VN), is mediated by integrin receptors expressed on various cell types, including platelets, leukocytes and tumor cells. The Arg-Gly-Asp (RGD)-containing peptide, a major adhesive ligand of ECM, is present in various plasma and matrix glycoproteins, such as FN and VN. Non-peptidic mimetics of RGD, consisting of carboxylate and guanidinium groups of Asp and Arg divided by a linear atom spacer, express a high affinity for the alpha IIb-beta 3 integrin and inhibit platelet aggregation. Herein, the ability of RGD mimetics to inhibit adhesive interactions between tumor cells and RGD, and tumor progression in vivo, was examined. RGD-containing peptides and the RGD mimetic, compound SF-6,5, but not the Arg-Gly-Glu (RGE) peptide or the corresponding mimetic, specifically inhibited B16-F10 melanoma cell adhesion to immobilized VN and FN. Daily administration in vivo of SF-6,5 to mice inhibited the formation of B16-F10 colonies in experimental and spontaneous models of metastases. Moreover, SF-6,5 could prevent mouse death caused by massive colonization of tumor cells in the lungs. The therapeutic effect of RGD-containing peptides on tumor metastasis formation was marginal, probably due to the small amounts used, and its susceptibility to proteolysis in situ. Thus, non-peptidic mimetics of small adhesive epitopes may provide a novel therapeutic tool to prevent an adverse pathological event involving integrin-dependent cell-cell and cell-ECM interactions.
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PMID:Inhibition of metastatic cell colonization in murine lungs and tumor-induced morbidity by non-peptidic Arg-Gly-Asp mimetics. 750 56

The purpose of this study was to determine whether the activation of inducible nitric oxide synthase (iNOS) can serve as a target for immunotherapeutic agents for treatment of murine reticulum cell sarcoma metastases. Liver metastases were established by the i.v. injection of M5076 cells into syngeneic C57BL/6 mice. Multiple systemic administrations of multilamellar vesicle-liposomes (MLV) containing the lipopeptide CGP 31362 (MLV-31362) or MLV-31362 combined with murine IFN-gamma eradicated the metastases. Tumor regression correlated with iNOS expression within the tumor lesions detected by Northern blot and immunohistochemistry techniques and with increased production of nitric oxide (NO). The administration of a specific iNOS inhibitor, NG-methyl-L-arginine, significantly decreased NO production and diminished the antitumor activities of the immunomodulators. Consistent with the regression of hepatic metastases, the combination of MLV-31362 and IFN-gamma synergistically induced iNOS gene expression, NO production, and apoptosis in the tumor cells under in vitro and in vivo conditions. The addition of NMA prevented the production of NO and apoptosis. These data imply that multiple systemic administrations of MLV-31362 plus IFN-gamma activate endogenous iNOS in sarcoma cells, which then undergo apoptosis, leading in turn to the regression of M5076 sarcoma hepatic metastases.
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PMID:Direct correlation between expression of endogenous inducible nitric oxide synthase and regression of M5076 reticulum cell sarcoma hepatic metastases in mice treated with liposomes containing lipopeptide CGP 31362. 754 13

The value of cathepsin B activity in determining the extent of disease was investigated in 106 patients with carcinoma of the cervix uteri and in 20 women with dysplasia of the cervix uteri. The measurements of serum and tumor cathepsin B activity were performed before treatment. The levels of cathepsin B were estimated by direct fluorimetric assay based on the use of 2-Phe-Arg-NMec as a substrate. The results show that the mean serum and tumor activity of this enzyme increase with progression of neoplastic disease and was closely dependent on clinical stage of cervical carcinoma. Also, we found higher serum and tumor levels of cathepsin B activities in patients with clinical early disease (FIGO Stage Ib and IIa) in whom metastases to pelvic lymph nodes were detected than in patients with disease limited to the cervix uteri (p < 0.001, t-test). Enhanced activity of cathepsin B was observed in 64% of patients with cervical carcinoma.
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PMID:Cathepsin B in predicting the extent of the cervix carcinoma. 761 69

Alteration of expression levels of the nm23 genes has previously been correlated with metastatic status of ovarian epithelial carcinoma. To elucidate the relevance of the qualitative changes of the nm23 genes to progression of ovarian carcinoma and/or to nm23 expression levels of the tumour, 41 samples of epithelial ovarian tumours [three benign, three low malignant potential (LMP), and 35 frankly malignant tumours] were studied for mutation of the nm23-H1 and the nm23-H2 genes using single-strand conformational polymorphism (SSCP) analysis. In addition, loss of heterozygosity (LOH) at the nm23 locus on chromosome 17q was studied by CA repeat polymorphism analysis. Mutation of the K-ras gene was also analysed in the same specimens. A novel mutation of the nm23 gene was found in one case of stage III serous carcinoma without lymph model metastases. Sequencing of the subcloned mutant cDNA revealed a missense mutation from TGG to CGG at codon 133 of the nm23-H2 gene, resulting in a change from Trp to Arg. LOH at the nm23 locus was detected in 5 of 23 (21.7%) informative cases of ovarian carcinoma. Mutation of the K-ras gene was detected in 2 of 35 (5.7%) carcinomas at codons 12 and 13 respectively. There was no correlation between clinical stage or metastatic status of ovarian carcinoma and nm23 mutation, LOH at the nm23 locus or K-ras mutation. The expression levels of both the nm23-H1 and the nm23-H2 genes were lower in the tumour with nm23-H2 mutation and higher in those with K-ras mutation. This suggests that mutation of the nm23 genes and the K-ras gene affects carcinogenesis or progression of ovarian carcinoma by modulating expression of the nm23 genes.
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PMID:Mutation of the nm23 gene, loss of heterozygosity at the nm23 locus and K-ras mutation in ovarian carcinoma: correlation with tumour progression and nm23 gene expression. 766 82

Observations during the last several years on the relationships between bone marrow-derived dendritic cells (DC) and the cells which are in direct contact with them led to the idea that DC may have regulatory properties. Such regulatory properties exerted by DC were noted in experimental cancers in murine systems as well as in human cancers. It was noted that patients with the same type of cancer in which DC are present in the tumor survive longer than patients without DC in the tumor. It is not known how DC can abrogate the development of the metastatic tumor cells in the primary tumor, nor how the tumor cells are capable of abrogating the anticancer activity of the DC and allowing the development of tumor metastases. Studies on the anticancer activity of macrophages revealed that these cells have an inducible Nitric Oxide (NO) synthase (NOS) which utilizes arginine to produce NO. Suppressor macrophages release NO, which inhibits the ribonucleotide reductase and mitochondrial oxidation in tumor cells in vitro. It was also reported (4) that Interferon gamma (IFN-gamma), produced by murine T helper 1 cells, induces NOS activity in macrophages, while T helper 2 cells which produce Interleukin-4 (IL-4) inhibit the expression of NOS in macrophages. The hypothesis presented in this paper suggests that DC have a gene for NOS which is inducible by immunomodulators (e.g. IFN gamma, OK432, LPS) and can be suppressed by cytokines produced by tumor cells (e.g. IL-4, IL-10).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Success and failure of dendritic cell (DC) anticancer activity may be modulated by nitric oxide synthetase (NOS) gene expression: a hypothesis. 768 49

Hepatic parenchymal vasoconstriction increases cytotoxic drug uptake into hepatic metastases by increasing the tumour to liver blood flow ratio. Prolonged infusion of the vasoconstrictor vasopressin does not result in sustained vasoconstriction, and this may limit the benefit of vasopressin in infusional chemotherapy. We have assessed whether loss of vasopressin-induced vasoconstriction is mediated by nitric oxide. Hepatic and tumour blood flow were continuously monitored, in an animal hepatic tumour model, by laser Doppler flowmetry. The response to regionally infused vasopressin and the nitric oxide inhibitor N-nitro-L-arginine methyl ester (L-NAME) were assessed over a 30 min infusion period. The vasopressin-induced vasoconstrictor effect diminished after 15 min despite continued infusion. Vasoconstriction was significantly prolonged when L-NAME was infused in addition to vasopressin. The increase in tumour to normal blood flow ratio was greater over the infusion period when L-NAME was co-administered with vasopressin. Our results suggest that the loss of vasopressin-induced vasoconstriction seen in liver parenchyma after regional infusion is prevented by the nitric oxide synthase inhibitor L-name and may be mediated by nitric oxide.
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PMID:Nitric oxide inhibition sustains vasopressin-induced vasoconstriction. 773 17

We investigated the role of signal transduction systems in the attachment of human uveal melanoma cells to matrix proteins. Ocular melanoma cells established from primary tumours attached rapidly to all substrates examined. Preferred substrates of attachment were collagens type I, III and IV and fibronectin rather than laminin, gelatin, arginine-glycine-aspartine, vitronectin, poly-L-lysine or plastic. All cells showed rapid attachment to the preferred substrates (80% within 10 min). Manipulation of intracellular cyclic AMP or protein kinase C activity had relatively little effect on cell attachment. In contrast, attachment was significantly reduced by manipulating either intracellular calcium or calmodulin. After 15 min at 37 degrees C, the calcium ionophore ionomycin (5 microM) reduced attachment to 25%, and TMB8 (50 microM), which can reduce intracellular calcium, reduced attachment to 60%. The experimental calmodulin antagonist J8 (25 microM), a substituted naphthalene sulphonamide, reduced attachment to 40%. Similarly tamoxifen (25 microM), which has calmodulin antagonist activity in vitro, reduced attachment to 55%. Both J8 and tamoxifen inhibited cell attachment to a wide range of matrix proteins, suggesting that this effect on attachment is not dependent on the presence of specific adhesion receptors. Reduction of ocular melanoma tumour cell/matrix interactions through manipulation of intracellular calcium or calmodulin may therefore merit further investigation as a possible approach to reducing metastatic spread.
Clin Exp Metastasis 1994 Nov
PMID:Investigation of the role of signal transduction in attachment of ocular melanoma cells to matrix proteins: inhibition of attachment by calmodulin antagonists including tamoxifen. 792 90


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