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

The ability to metastasize requires that tumor cells be able to degrade matrix. Nontoxic compounds that inhibit matrix digestion might be useful as anti-metastatic agents. We have investigated whether phenytoin, a drug commonly used in clinical practice that inhibits the production of collagenase by some cells, inhibits metastases in a standard animal model of metastasis: In vitro, phenytoin inhibited the proliferative response of B16 F10 melanoma cells to serum-containing media (75% inhibition at 25 micrograms/ml) but had no effect on their ability to degrade a type I collagen gel (1-100 micrograms/ml). Treatment of these cells with phenytoin prior to inoculation in vivo did not inhibit tumor growth, implantation in a surgical wound, or incidence of spontaneous metastases from a primary tumor growing in the foot. Pretreatment of mice with phenytoin (15, 40, and 75 mg/kg/day) diminished pulmonary metastases following tail vein injection in a minimal but dose dependent fashion; mean number of pulmonary colonies 4.6 +/- 3.1 (75/mg/kg/day) vs. 10.2 +/- 9.9 (control). However, tumor growth, implantation, and spontaneous metastases were not inhibited by pretreating the mice with the same doses of phenytoin. It is concluded that phenytoin has an insignificant inhibitory effect on tumor growth and metastasis.
 ...
PMID:Search for anti-metastatic therapy: effects of phenytoin on B16 melanoma metastasis. 173 31

C57BL/6 mice with syngeneic B16-F10 melanomas were treated 7 days after tumor inoculation into the footpad with local hyperthermia (HT) of 43.5 degrees C for 90 min. A combination of local 30 Gy X-irradiation (XRT) given 2, 4 or 12 h after HT cured the primary tumor in 34/35 mice, with irreversible damage to normal foot tissues in most of the animals. When 7.5, 10 or 15 Gy XRT were delivered 4, 18 or 24 h after HT, there were only a small number of cures and also a much smaller incidence of irreversible normal tissue damage. HT alone resulted in a significant (P less than 0.001) increase in metastases to regional lymph nodes (RLN) and the lungs. The 'curative' doses of combined XRT and HT resulted in a significant (P less than 0.001) decrease in metastasis to RLN and to the lungs. Conversely, subcurative doses of combined therapy resulted in an increase in RLN and lung metastasis (P less than 0.001). Abdominal lymph node metastasis, not usually seen in control mice, is markedly increased after HT alone or in combination with subcurative XRT (P less than 0.001). The overall survival of mice treated with HT alone is decreased (P less than 0.0028). The survival of mice treated with HT followed 4, 18 or 24 h later with 10 Gy XRT is further decreased (P less than 0.0025). These data show that subcurative HT, or XRT plus HT, increases the incidence of spontaneous metastasis in this syngeneic mouse melanoma model. Curative doses prevent this effect on metastasis, but there is an unacceptable incidence of irreversible damage to the tumor-bearing foot. The cause(s) of this phenomenon are not known.
Clin Exp Metastasis
PMID:Development of lymph node and pulmonary metastases after local irradiation and hyperthermia of footpad melanomas. 186 28

The currently available antitumoral therapeutic modalities are most often inefficient against metastatic disease. The metastatic phenotype has been shown to be largely determined by cell membrane properties. The cell membrane could therefore be considered as a possible target for antimetastatic drugs. In the present study we examined the effect of hyperthermia (the antitumoral effect of which is based, at least partly, on an action on the cell membrane) on the F1 and F10 variants of B16 melanoma. Cells of the more malignant variant, F10, were found to be markedly more sensitive to hyperthermic treatment than those of the less malignant one, F1. One hour in-vitro treatment by supranormal temperatures (ranging from 40 to 46 degrees C) resulted in a differential effect with regard to both proliferating capacity of the cells in vitro and tumorigenic ability following inoculation to mice. Our present results in the B16 melanoma corroborate data obtained by us in another tumour system, the AKR lymphoma. Study of the effect of membrane-acting agents on tumour variants differing in degree of malignancy might result in the finding of antitumoral agents efficient against advanced cancer.
 ...
PMID:Differential sensitivity to hyperthermia of the F1 and F10 B16 melanoma variants. 201 98

A selective pattern of metastasis, not accountable by a simple mechanical trapping mechanism, is exhibited by many primary tumors and appears to be controlled by properties of both the tumor cell and the host organ. This organotropism may be regulated, in part, by the migration of an invading tumor cell toward chemotactic factors present in the extracellular matrix which may be released as a result of proteolytic digestion. To test this hypothesis we have examined 4 M guanidine extracts of liver extracellular matrix, prepared by high salt extraction, for organ-specific chemotactic activity. The murine cell lines B16-L4b and M5076, which preferentially metastasize to the liver in an experimental metastasis model, demonstrated preferential motility toward the liver matrix extract while the lung-colonizing lines B16, B16-F10 and B16-BL6 did not. The liver specific chemotactic activity eluted as four fractions of Mr much less than 250,000, Mr approximately 245,000, Mr approximately 120,000 and Mr approximately 30,000 by gel filtration chromatography.
Clin Exp Metastasis
PMID:Chemotactic activity present in liver extracellular matrix. 201 16

Unselected F9 murine embryonal carcinoma cells preferentially colonize the liver upon injection into tail veins of syngeneic mice, while the lungs are only very rarely colonized. Here we show that F9 cells attach better to fibronectin than to laminin in an adhesion assay, like other liver-colonizing cell lines. Moreover, assays of adhesion to extracellular matrix (ECM) prepared from rat organs (liver, lung and kidney) demonstrate that, in the absence of serum, F9 cells adhere better to liver- than to kidney- or lung-derived ECM. Even in the presence of FCS, the adhesion to lung ECM remains very low. This very low adhesiveness of F9 cells to lung-derived ECM correlates well with the finding that, in an organ distribution assay, tail-vein-injected F9 cells are very rapidly released from the lungs, when compared to the retention times of the lung-specific murine melanoma cell line B16-F10. Yet another property appears to contribute to organ-specific colonization of these cells: extracts of liver promote the growth of F9 cells, in contrast to extracts of lung or kidney which have no effect. These data suggest that preferential formation of metastases in the liver following the intravenous injection of F9 cells is the result of both their adhesive abilities and their growth response to local microenvironment.
 ...
PMID:The role of both specific cellular adhesion and growth promotion in liver colonization by F9 embryonal carcinoma cells. 204 May 39

Systemic administration of swainsonine, an indolizidine alkaloid, inhibits the experimental metastasis of B16-F10 murine melanoma cells. This activity can be attributed primarily to swainsonine-mediated enhancement of host natural killer cell activity. As one next step towards investigating the potential therapeutic utility of this drug, its efficacy in enhancing host survival in the same B16-F10 model system has been assessed. In studies employing intravenously injected tumor cells, pretreatment of mice with swainsonine-containing drinking water provided a reproducible protective effect for the host. This prolongation of survival was substantially enhanced when swainsonine was administered in combination with either of two other immunomodulators, polyinosinic: cytidylic acid (poly-IC) or interleukin-2. In studies in which combinations of these agents were administered after intravenous injection of tumor cells, or after subcutaneous implantation, a greatly reduced effect on host survival was observed. However, when used in combination with cyclophosphamide (to block the effects of suppressor T cells), swainsonine did increase mean survival time. The implications of these results for the use of swainsonine in treatment of metastatic or localized disease, together with its potential mechanism(s) of action, are discussed.
Clin Exp Metastasis
PMID:An assessment of the effects of swainsonine on survival of mice injected with B16-F10 melanoma cells. 210 78

Using B16 F10 murine melanoma cells and sublines generated from the JB/MS melanoma which exhibit various degrees of melanogenesis, the relationships among differentiation, tumorigenicity, and metastatic potential were examined. The effect of melanocyte-stimulating hormone (MSH), which specifically stimulates differentiation of melanocytes, was also studied. All melanoma lines tested were capable of growing as experimental pulmonary metastases but, surprisingly, the undifferentiated and amelanotic JB/MS-w cells failed to grow as primary subcutaneous tumors. JB/MS-w cells, which had few surface MSH receptors, did not respond to MSH with an increase in melanin production, unlike the other cell lines. Although in vitro treatment with MSH did not change the rates of growth of primary tumors by these cell lines, such treatment decreased the number of pulmonary metastases from B16 F10, JB/MS cells, JB/MS-b1 cells and JB/MS-w cells. Conversely, MSH treatment significantly increased the rates of pulmonary metastases from JB/MS-p cells. The expression of surface melanoma antigens, urokinase-type plasminogen activity and susceptibility to natural killer cells were examined. MSH did not significantly alter surface melanoma antigen expression, but increased the natural killer cell susceptibility of B16 F10, JB/MS and JB/MS-b1 cells, cells which possess abundant surface MSH receptors. There was an inverse correlation between differentiation (pigmentation) and proliferation in vitro, and the more pigmented melanoma cells (B16 F10, JB/MS and JB/MS-b1) expressed relatively lower levels of class-I MHC, relatively higher levels of class-II MHC and the highest metastatic capacity. These results demonstrate that MSH possesses the capacity to regulate not only melanogenesis, but also other factors critical to the metastatic growth of the cells.
 ...
PMID:Differentiation and the tumorigenic and metastatic phenotype of murine melanoma cells. 216 2

The nature of the relationship between agonist-stimulated cyclic AMP production and metastatic potential was examined in detail for four B16 melanoma cell lines of varying metastatic potential. Highly metastatic cells (B16 F10C1) appeared to differ from cells of low metastatic potential (B16 F1C29) in the degree to which cyclic AMP production in intact cells was stimulated by protein kinase C activation. No significant difference was found in the adenylate-cyclase enzyme activities of the broken cells, irrespective of the agonist used, or in the distribution of cyclic AMP between the intracellular and extracellular compartment. Although B16F1, F10 and F10C1 cells all produced equally pigmented tumors in vivo, the cells differed in their melanogenic response to cyclic AMP elevating agents in vitro: the least metastatic cells produced least agonist-induced cyclic AMP but this induced greatest tyrosinase activation and melanin production in vitro; conversely, the more metastatic cells produced more cyclic AMP but less tyrosinase activation and melanin production in response to agonist stimulation. Thus, agonist-stimulated cyclic AMP production does not appear to be coupled to the differentiated function of melanogenesis for highly metastatic B16 melanoma cells.
Clin Exp Metastasis
PMID:The regulation of cyclic AMP production and the role of cyclic AMP in B16 melanoma cells of differing metastatic potential. 216 82

Recognition of the carbohydrate part of cellular glycoconjugates by cell-surface sugar receptors may contribute to interactions, essential to the establishment of metastases. Comparison of the properties of strongly metastatic variants to their related, less metastatic counterparts offers a generally accepted approach to the discovery of metastasis-associated characteristics. The chemically induced murine lymphoma line Eb and its spontaneously arising variant ESb with increased potential for lung and liver colonization, the virally induced lymphosarcoma cell line RAW117-P and its in vivo selected variant H10 with increased potential for liver colonization, and the B16-F1 melanoma line and its in vivo selected variant F10 with increased potential for lung colonization, were chosen. A panel of 12 types of chemically glycosylated E. coli beta-galactosidase, exposing the pivotal carbohydrate residues for specific carbohydrate-dependent cell binding, was employed to study the expression of respective cell-surface sugar receptors on these cell lines. Specific binding occurred in a non-uniform manner for the individual probes. Systematic measurements at a non-saturating ligand concentration revealed quantitative differences between the 2 cell lines of each system. However, there were no consistent changes associated with the metastatic phenotype. A similar result was obtained employing Scatchard analyses for quantitative evaluation of binding characteristics in several cases. Surface receptor expression was responsive to chemical induction of differentiation in the lymphosarcoma model. Analyses of sugar-inhibitable cell adhesion to neoglycoprotein-coated plastic wells for the lymphoma and lymphosarcoma cells revealed that the presence of cell-surface sugar receptors, even at similar densities to those defined by neoglycoenzyme binding, will not necessarily translate into an identical adhesive response. Several carbohydrates, especially N-acetyl-D-galactosamine, can differentially affect this interaction at a non-toxic concentration in both model systems.
 ...
PMID:Analysis of cell-surface sugar receptor expression by neoglycoenzyme binding and adhesion to plastic-immobilized neoglycoproteins for related weakly and strongly metastatic cell lines of murine tumor model systems. 216 45

Drug resistance, which so often accompanies tumor progression, has been shown to be related to changes in membrane properties which may result in decreased drug accumulation in the tumor cell. A correlation between sensitivity to thermochemotherapy and degree of malignancy was found in the AKR lymphoma system. Hyperthermia increased adriamycin (ADR) uptake and concomitantly its cytotoxicity to AKR lymphoma cells. Moreover, these effects were more pronounced on a variant of high malignancy (HM) than on a low malignancy (LM) one. Fluorescent microscopy, as well as cytofluorometry, indicated that lymphoma cells treated by ADR at 43 degrees C were more permeable to the cytotoxic agent than those exposed to the chemotherapeutic substance at 37 degrees C. Cytofluorometry indicated the presence of a minor cell subpopulation with low ADR uptake in the HM variant, not found in the LM one. Fluorocytometry also showed that the temperature-dependent increased ADR uptake was more marked in the HM than in the LM variant, explaining the differential effect of thermochemotherapy on the two lymphoma variants. However, correlation between degree of malignancy and sensitivity to thermochemotherapy is not a general feature. In contrast to the results obtained in the AKR lymphoma system, in the B16 melanoma the low malignancy variant, F1, was more markedly affected by the combined treatment than the F10 variant. The increased cytotoxic effect of ADR by supranormal temperatures in the F1 variant was shown to be due to an augmented drug uptake. The results suggest that drug resistance in late stages of tumor progression can be overcome by an agent acting on the cell membrane. However, the data also indicate the necessity of assaying cancer treatment modalities, including those designed to circumvent drug resistance, on various tumor system models.
Clin Exp Metastasis
PMID:Sensitivity to thermochemotherapy of AKR lymphoma and B16 melanoma variants of malignancy. 229 12


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>