Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GD3 is the most prominent ganglioside on the surface of human melanoma cells, and therefore it has been considered by several investigators as a potential tool for active immunotherapy of melanoma. The main obstacle to this goal is that GD3 is poorly immunogenic in mice and in humans. Several approaches have been described for increasing the GD3 immunogenicity. Here, the immunogenicity of GD3 ganglioside was investigated by vaccination of Balb/c x C57B1/6 F1 mice with several types of GD3-bearing liposomes. The humoral immune response was analyzed by ELISA and tumor cell recognition. Several liposome formulations were assayed in order to increase the immunogenicity of GD3. We also tested vaccinations with GD3-Salmonella minnesota, Freund's complete adjuvant and Bordetella pertussis antigen. Immunization of mice with sphingomyelin:cholesterol:dicetyl-phosphate:GD3, molar ratio 40:40:10:10, liposomes resulted in good IgM and IgG3 anti-GD3 response, with a maximum titer of 1:1200 and absence of significant cross-reactivity with other gangliosides. In immunofluorescence assays, the antisera induced showed high capacity of recognition of melanoma cells with no reactivity against other tumor cells. The results clearly showed a high positive correlation between liposomes with sphingomyelin and GD3 immunoreactivity. The incorporation of muramyl-dipeptide or Lipid A in the liposome formulation increased the secretion of IgM and IgG as well as the nonspecificity of the response.
 ...
PMID:Specific serological response by active immunization with GD3-bearing liposomes. 881 93

Water-soluble paclitaxel may cause less side effects and be less costly to administer in comparison to a taxol formulation using a cremophor EL/alcohol vehicle. In this study, polyethylene glycol (PEG; MW 5000) was conjugated to the 2' position of paclitaxel through a spacer succinyl group. PEG-paclitaxel as a non-ionic paclitaxel prodrug was highly water soluble (> 20 mg equiv. paclitaxel/ml). The release of paclitaxel from phosphate-buffered solution was pH dependent. The half-life of PEG-paclitaxel was 7.6, 54 and 311 min at pH 9.0, 7.4 and 6.0, respectively. PEG-paclitaxel inhibited the growth of B16 melanoma cells to an extent similar to that of paclitaxel. In MCA-4 mammary tumor-bearing mice, a single dose of PEG-paclitaxel (40 mg equiv. paclitaxel/kg body weight) significantly delayed tumor growth. The average number of days for the tumor to reach 12 from 8 mm in diameter increased from 6.5 days for control animals to 8.5 days for PEG-paclitaxel-treated animals and 9.4 days for paclitaxel-treated animals. These studies demonstrated that PEG may be used as an effective solubilizing carrier for paclitaxel.
 ...
PMID:Synthesis and evaluation of water-soluble polyethylene glycol-paclitaxel conjugate as a paclitaxel prodrug. 891 32

Autotaxin (ATX) is an extracellular enzyme and an autocrine motility factor that stimulates pertussis toxin-sensitive chemotaxis in human melanoma cells at picomolar to nanomolar concentrations. This 125-kDa glycoprotein contains a peptide sequence identified as the catalytic site in type I alkaline phosphodiesterases (PDEs), and it possesses 5'-nucleotide PDE (EC 3.1.4.1) activity (Stracke, M. L., Krutzsch, H. C., Unsworth, E. J., Arestad, A., Cioce, V., Schiffmann, E., and Liotta, L. (1992) J. Biol. Chem. 267, 2524-2529; Murata, J., Lee, H. Y., Clair, T., Krutsch, H. C., Arestad, A. A., Sobel, M. E., Liotta, L. A., and Stracke, M. L. (1994) J. Biol. Chem. 269, 30479-30484). ATX binds ATP and is phosphorylated only on threonine. Thr210 at the PDE active site of ATX is required for phosphorylation, 5'-nucleotide PDE, and motility-stimulating activities (Lee, H. Y., Clair, T., Mulvaney, P. T., Woodhouse, E. C., Aznavoorian, S., Liotta, L. A., and Stracke, M. L. (1996) J. Biol. Chem. 271, 24408-24412). In this article we report that the phosphorylation of ATX is a transient event, being stable at 0 degrees C but unstable at 37 degrees C, and that ATX has adenosine-5'-triphosphatase (ATPase; EC 3.6.1.3) and ATP pyrophosphatase (EC 3.6.1.8) activities. Thus ATX catalyzes the hydrolysis of the phosphodiester bond on either side of the beta-phosphate of ATP. ATX also catalyzes the hydrolysis of GTP to GDP and GMP, of either AMP or PPi to Pi, and the hydrolysis of NAD to AMP, and each of these substrates can serve as a phosphate donor in the phosphorylation of ATX. ATX possesses no detectable protein kinase activity toward histone, myelin basic protein, or casein. These results lead to the proposal that ATX is capable of at least two alternative reaction mechanisms, threonine (T-type) ATPase and 5'-nucleotide PDE/ATP pyrophosphatase, with a common site (Thr210) for the formation of covalently bound reaction intermediates threonine phosphate and threonine adenylate, respectively.
 ...
PMID:Autotaxin is an exoenzyme possessing 5'-nucleotide phosphodiesterase/ATP pyrophosphatase and ATPase activities. 899 94

One or more mevalonate derivatives of non-sterol type have been proposed to be of indispensable importance for cell growth. Conceivable mevalonate-dependent mechanisms involved in growth control are farnesylation of Ras proteins, regulation of c-myc expression, and N-linked glycosylation of the IGF-1 receptor. The latter mechanism might be rate-limited by dolichyl phosphate, which acts as a donor of oligosaccharides in glycoprotein synthesis in the endoplasmic reticulum. In order to study the significance for cell proliferation of the three aforementioned mevalonate-dependent processings, their inhibitory response due to mevalonate deprivation was explored and compared with the effect on DNA synthesis in the malignant melanoma cell line SK-MEL-2. We found that mevalonate depletion due to treatment with 3 microM lovastatin for 24 h, which efficiently growth-arrested the cells, hardly at all affected the expression of c-myc, and although Ras prenylation was inhibited by 50%, the most pronounced effect of lovastatin was seen on N-linked glycosylation of IGF-1 receptors, which was inhibited by more than 95%. The order and magnitude of the decreased IGF-1 receptor glycosylation, which was followed by a decreased expression of IGF-1 receptors at the cell membrane, correlated well with the inhibition of DNA synthesis. We investigated whether dolichol, and in particular dolichyl phosphate, through its participation in N-linked glycosylation, act as regulators of IGF-1 receptor expression. First, we could confirm that exogenous dolichol became phosphorylated and in this form took part in the glycosylation processing. Secondly, we showed that dolichyl phosphate, in a dose-dependent manner, could increase the number of IGF-1 receptors at the cell membrane, simultaneously as DNA synthesis was stimulated. Taken together, our results provide direct evidence for an important role of dolichyl phosphate as a regulator of cell growth through limiting N-linked glycosylation of the IGF-1 receptor.
 ...
PMID:Mevalonate-regulated mechanisms in cell growth control: role of dolichyl phosphate in expression of the insulin-like growth factor-1 receptor (IGF-1R) in comparison to Ras prenylation and expression of c-myc. 925 45

Our previous work showed that sphingosine 1-phosphate (Sph-1-P) inhibits the cell motility of mouse melanoma B16/F10, and other types of cells at 10-100 nM concentrations. In the present paper, we have identified and characterized specific cell surface binding sites for Sph-1-P in F10 cells. Sph-1-P immobilized on controlled pore glass beads inhibited the motility of F10 cells, suggesting that Sph-1-P acts on the cells from the outside. Binding assays with [3H]Sph-1-P revealed the presence of specific cell surface binding sites for Sph-1-P in F10 cells. Scatchard analysis demonstrated a single class of binding sites for Sph-1-P. The binding of [3H]Sph-1-P to F10 cells was inhibited by the addition of excess unlabeled Sph-1-P but not other natural sphingolipids. The specific binding was also sensitive to treatment with a protease. Using Sph-1-P-immobilized affinity chromatography, we, for the first time, identified 41-kDa and 79-kDa Sph-1-P binding proteins on the melanoma cell surface, although the 41-kDa protein was less specific to Sph-1-P. We demonstrated that pertussis toxin (PTX) treatment did not abolish the motility inhibition by Sph-1-P, suggesting that no PTX-sensitive G-protein is involved in the signaling. Furthermore, Sph-1-P was found to be specifically released from mouse BALB/3T3 clone A31 cells and F10 cells. Collectively, these results strongly suggest that Sph-1-P regulates melanoma cell motility through an extracellular action by specific binding to cell surface receptor protein(s), which is independent of PTX-sensitive G-protein.
 ...
PMID:Sphingosine 1-phosphate regulates melanoma cell motility through a receptor-coupled extracellular action and in a pertussis toxin-insensitive manner. 927 6

The A375 cell line, derived from human malignant melanoma, has characteristics of interleukin-6 (IL-6) production. By using this cell line, we have investigated a murine metastasis model of IL-6-producing tumors to the brain by injecting A375 cells directly into the left cardiac ventricle. Nude mice were anesthetized with intraperitoneal injection of pentobarbital sodium. Next, A375 cells suspended in phosphate-buffered saline (PBS) were injected into the left cardiac ventricle of mice. An intracardiac injection of 10(5) cells developed tumor colonies in the brain after 4 to 6 weeks. Metastatic cells were found in every lobe of the brain. An immunocytochemical study revealed IL-6 production by A375 cells at the metastatic sites in the brain. By the transfection of genes encoding proteins into A375 cells, a novel model of protein expression in the brain in vivo could be constructed. Our system does not require great skill. Our experimental model will facilitate future studies of the local effects of proteins in the brain.
 ...
PMID:Establishment of a murine model for metastasis of cytokine-producing tumor to the brain. 935 26

We previously reported the synthesis of a series of doxorubicin analogue prodrugs that give rise to intensely cytotoxic metabolites in the presence of carboxylate esterases. We now report studies on structurally related beta-glucuronide prodrugs that are converted to similar potent metabolites in the presence of beta-glucuronidases. These prodrugs were prepared by reductive condensation of daunomycin or doxorubicin with methyl 1-O-[(1'RS)-1'-ethoxy-4'-oxobutyl]-2,3,4-tri-O-acetyl-beta-D- glucopyranosyluronate in the presence of sodium cyanoborohydride followed by base-mediated cleavage of the glucuronate protective groups. The doxorubicin derivatives were isolated in very low yield, most likely because of the inherent base lability of the parent aglycone. By contrast, fairly good yields of the more base-stable daunomycin analogues were obtained. The target daunomycin glucuronide, N-[(4"RS)-4"-ethoxy-4"-(sodium 1"'-O-beta-D-glucopyranuronate)butyl]daunorubicin (6a), had a half-life of 30 h when incubated at a concentration of 12 microM in aqueous 0.05 M phosphate buffer, pH 7.4, at 37 degrees C. Under identical conditions in the presence of 197 units/mumol of Escherichia coli beta-glucuronidase, 6a was hydrolyzed with a half-life of 1.7 h. The single metabolite observed was chromatographically identical with that formed from the hydrolysis of N-(4,4-diacetoxybut-1-yl)daunomycin by carboxylate esterases. 6a was approximately 10,000-fold more toxic to human A375 melanoma cells in the presence of E. coli beta-glucuronidase than in the absence of the enzyme. These findings indicate the therapeutic potential of anthracycline glucuronide prodrugs as independent entities or four use in conjunction with enzyme tissue-targeting strategies such as antibody-directed enzyme prodrug therapy (ADEPT) or gene-directed enzyme prodrug therapy (GDEPT).
 ...
PMID:Intensely cytotoxic anthracycline prodrugs: glucuronides. 940 92

31P-magnetic resonance spectroscopy (MRS) has been shown to be a promising method for monitoring tumor response to radiation therapy. The purpose of the work reported here was to investigate whether the usefulness of 31P-MRS might be enhanced by measurement of spin-lattice relaxation times (T1s) in addition to resonance ratios. The work was based on the hypothesis that tumors having a high probability of being controlled locally would show shortened T1s during the treatment course due to reoxygenation and development of necrosis. BEX-t human melanoma xenografts, which show efficient reoxygenation and development of necrosis following single dose irradiation, were used as tumor models. Tumors were treated with single doses of 5.0 or 15.0 Gy and the T1s of the inorganic phosphate and nucleoside triphosphate beta resonances were measured as a function of time after irradiation by using the superfast inversion recovery method. Fractional tumor water content was determined by drying excised tumors at 50 degrees C until a constant weight was reached. The T1s in irradiated tumors were either longer than or not significantly different from those in unirradiated control tumors. The increase in the T1s following irradiation coincided in time with a radiation-induced increase in tumor water content, suggesting a causal relationship. The effects of reoxygenation and development of necrosis on T1s were probably overshadowed by the effects of tumor water content. Consequently, the usefulness of 31P-MRS in monitoring tumor response to radiation therapy might not be significantly enhanced by measurement of T1s.
 ...
PMID:Radiation-induced changes in phosphorus T1 values in human melanoma xenografts studied by 31P-MRS. 940 39

In previous studies, we reported that sphingosine 1-phosphate (Sph-1-P) inhibits the chemotactic motility of some cancer cell lines such as mouse melanoma cells, as well as human smooth muscle cells, at a very low concentration, as demonstrated by a transwell migration assay method (Proc. Natl. Acad. Sci. USA 89, 9698, 1992; J. Cell Biol. 130, 193, 1995). In this study, we investigated the effect of Sph-1-P on the chemotactic motility and invasiveness of human neutrophils, utilizing three different assay systems: (a) a transwell migration assay where IL-8 or fLMP was added as a chemotactic factor, (b) a phagokinetic assay with gold colloids, and (c) a trans-endothelial migration assay with human umbilical vein endothelial cells (HUVECs) plated on collagen layers. We found that among various sphingosine derivatives, Sph-1-P specifically inhibited the IL-8- or fLMP-induced chemotactic migration of neutrophils at concentrations below 1 microM. Phagokinetic activity of neutrophils was also suppressed by Sph-1-P, but more moderately than by the PKC inhibitory sphingosine analog, trimethylsphingosine. Finally, Sph-1-P inhibited trans-endothelial migration and invasiveness of neutrophils into HUVEC-covered collagen layers, whereas no effect on their adhesion to HUVECs was observed. These observations strongly suggest that Sph-1-P can act as a specific and effective motility regulator of human neutrophils, raising the possibility of future applications of Sph-1-P, or its analogs, as anti-inflammatory agents regulating invasive migration of neutrophils through endothelial layers at injured vascular sites.
 ...
PMID:Inhibition of chemotactic motility and trans-endothelial migration of human neutrophils by sphingosine 1-phosphate. 945 9

A 36-month-old girl had a 3-week history of proptosis of the right eye. Computed tomography showed an ill-defined homogeneous mass filling the intraconal space. Histopathologic examination and immunohistochemistry findings of an incisional biopsy specimen were consistent with malignant undifferentiated tumor with rhabdoid features. Despite chemotherapy (a combination of vincristine sulfate and dactinomycin) and radiotherapy, massive orbital recurrence occurred 6 months later and orbital exenteration was performed. The recurrent tumor was composed entirely of pleomorphic epithelial cells with prominent nucleoli and many filamentous cytoplasmic inclusions. Immunohistochemical staining showed positive immunoreactivity for vimentin, cytokeratin, and epithelial membrane antigen, and negative immunoreactivity for muscle-specific antigen, melanoma, neural, and histiocytic markers. Electron microscopy excluded myogenic differentiation and showed that the filamentous cytoplasmic inclusions were composed of whorls of intermediate filaments. Aggressive chemotherapy with a combination of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide phosphate was continued after exenteration. At 17 months' follow-up, orbital debulking surgery with externalization of the maxillary sinus was performed because of massive tumor recurrence in the right orbit and growth into the maxillary sinus. The child died 23 months after initial diagnosis from tumor invasion into the central nervous system. Extrarenal rhabdoid tumor is a rare orbital mass that carries a poor prognosis.
 ...
PMID:Malignant rhabdoid tumor of the orbit. 948 82


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