Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A procedure has been developed for the preparation of large (10- to 80-microns-diameter) multivesicular liposomes that contain magnetic resonance contrast agent (DTPA and either manganese or gadolinium). Blue dextran was observed to induce the formation of the large liposomes with dioleoylphosphatidylcholine and cholesterol (1:1 molar ratio) and with dipalmitoylphosphatidylcholine and cholesterol (1:1 molar ratio). The formation of the large liposomes is dependent upon mixing the blue dextran with the lipid films at temperatures above the transition point of the lipids. Tracer amounts of 153Gd were added to the aqueous phase to permit quantitation of the recovery of encapsulated materials. Liposomes that were prepared using equimolar ratios of phospholipid and cholesterol were stable in serum for more than 12 h. The ultrastructure of the large multivesicular liposomes reveals the existence of individual vesicles (greater than 2 micron diameter) bound together by a multilamellar coating. When injected into the internal carotid artery of the rabbit, the large liposomes became entrapped in the vascular bed primarily in the frontal and occipital regions of brain. The resulting emboli may provide a means to deliver drugs to a specific site in brain, such as a tumor, if the vascular bed of the site can be cannulated precisely.
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PMID:Magnetic resonance imaging of rabbit brain after intracarotid injection of large multivesicular liposomes containing paramagnetic metals and DTPA. 339 65

The kinetics of endogenous protein phosphorylation and resultant phosphoprotein patterns were investigated in well-differentiated (DMTC) and undifferentiated (AMTC) medullary thyroid carcinomas of the rat. Cytosolic or particulate fractions from these tumors were incubated with gamma-32P-ATP in the presence of various effectors. Phosphorylation appeared to be predominantly independent of exogenously added cyclic AMP. Magnesium and manganese were equally effective cofactors. For both tumor types 32P incorporation into cytosolic proteins was maximal within 3-4 min after addition of ATP and subsequently decreased gradually within 1 h. In contrast, in particulate preparations maximal incorporation was reached within 30 s and remained constant over a relatively long time span. In both cases, however, 32P incorporation in extracts from DMTCs were 50-100% higher as compared to AMTCs. Comparison of the phosphoprotein patterns of each tumor after in vitro phosphorylation showed some significant differences. A phosphoprotein with molecular weight of 90 kilodalton (90 kD) was exclusively expressed in the cytosol of DMTC, whereas 99- and 84-kD phosphoproteins were only present in the cytosol of AMTC. The DMTC particulate fraction contained two phosphoproteins (with molecular weights of 40 and 37 kD), which were absent from that of AMTC. In addition, a number of proteins were more intensely phosphorylated in one of the tumors, e.g. proteins of 94 and 33 kD in DMTC cytosol and a protein of 78 kD in AMTC cytosol. Calcium induced phosphorylation of five proteins in DMTC cytosol (with molecular weights of 69, 55, 49, 43 and 32 kD), which were less intensely or not phosphorylated in AMTC. Tyrosine kinase activity was investigated using exogenously added poly(glutamine:tyrosine, 4:1) as an artificial substrate. Cytosolic tyrosine kinase activity in DMTC was +/- 50% higher than in AMTC (11.9 +/- 0.6 and 8.2 +/- 1.7 pmol/mg/min, respectively). The enzyme activities in the particulate preparations were much higher than in the cytosols (+/- 100 pmol/mg/min), although considerable variations in enzyme activity between different tumors of either type were observed. Quantitative differences in tyrosine kinase activity between AMTC and DMTC particulate fractions did not seem to exist using this substrate. Phosphoamino acid analysis of endogenously phosphorylated proteins in both AMTC and DMTC showed phosphotyrosine to be present only in cytosolic proteins within the 50-kD molecular weight region, the majority of 32P being on serine and some on threonine.(ABSTRACT TRUNCATED AT 400 WORDS)
Tumour Biol 1987
PMID:Protein phosphorylation and tyrosine kinase activity in medullary thyroid carcinomas of the rat. 344 67

An enzymatic system in rat liver microsomal preparations has been detected that catalyzes the transfer of the 2'-phospho-AMP moiety from NADP to endogenous polypeptides; the major acceptor is a polypeptide of about 40 kDa (p40). Modification of the acceptor by 2'-phospho-AMP residues was deduced from the simultaneous transfer of 2'-[33P]phosphate and [3H]adenine residues from double-labeled NADP, while no incorporation of radioactivity into p40 was seen with NADP species labeled in the NMN moiety. The true substrate of this phosphoadenylylation reaction was 2'-phospho-ADP-ribose rather than NADP, because labeled phospho-ADP-ribose was as efficient as or more efficient than NADP in forming modified p40. Also, NADP was rapidly converted to phospho-ADP-ribose during incubation with microsomes. Furthermore, isonicotinic acid hydrazide, an inhibitor of NADP glycohydrolase, prevented phosphoadenylylation from NADP, but not from phospho-ADP-ribose, and glycohydrolase-resistant NADPH could not substitute for NADP. Transferase activity was found in liver and brain microsomes and, to a smaller extent, in the cytosol fractions. In Ehrlich ascites tumor cells, most of the activity resided in the cytosol, from which it could be partially purified. The apparent Km for phospho-ADP-ribose was about 2 X 10(-4) M, and the pH optimum was around 7. Divalent cations like Mg2+ and Mn2+ inhibited the reaction. In all compartmental preparations, activity was eliminated by heating or short treatment with alkali or acid. In submitochondrial particles from rat liver, a system with different characteristics led to the phosphoadenylylation of several endogenous polypeptides.
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PMID:2'-Phosphoadenylylation of eukaryotic proteins: a type of covalent modification. 346 93

Addition of epidermal growth factor (EGF) to human A431 cells causes a 2-4-fold increase in cytoplasmic free Ca2+ concentration ([Ca2+]i) as measured by quin-2 fluorescence. The EGF effect is rapid but transient: [Ca2+]i reaches a maximum within 30-60 s and then returns to its resting value (182 +/- 3 nM) over a 5-8-min period. The EGF-induced [Ca2+]i rise is completely dependent on extracellular Ca2+, is abolished by La3+ and Mn2+, and is not accompanied by changes in membrane potential (mean values of -64 mV). Serum also elicits a transient [Ca2+]i rise in A431 cells, but this response is not dependent on the presence of extracellular Ca2+. The tumor promoter 12-O-tetradecanoylphorbol 13-acetate completely inhibits the EGF- and serum-induced increases in [Ca2+]i without affecting basal [Ca2+]i levels. Our results, together with previous 45Ca2+ uptake data (Sawyer, S. T., and Cohen, S. (1981) Biochemistry 20, 6280-6286), suggest that while serum factors trigger the release of Ca2+ from internal stores, EGF acts by opening a voltage-independent Ca2+ channel in the plasma membrane. The data further suggest a role for protein kinase C in attenuating the Ca2+-mobilizing mechanisms of EGF and serum.
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PMID:The epidermal growth factor-induced calcium signal in A431 cells. 348 78

NAD-dependent methylenetetrahydrofolate dehydrogenase is expressed in transformed or established mammalian cell lines in vitro but only in the developmental tissues of normal adult animals (Mejia, N. R. and MacKenzie, R. E. (1985) J. Biol. Chem. 260, 14616-14620). The enzyme, which contains methenyltetrahydrofolate cyclohydrolase activity as well, has been purified 6000-fold from Ehrlich ascites tumor cells. The preparation is homogeneous by sodium dodecyl sulfate gel electrophoresis (Mr = 34,000), and results from cross-linking with bis(sulfosuccinimidyl)suberate are consistent with a dimeric structure (Mr = 68,000) for the native bifunctional enzyme. The dehydrogenase is specific for NAD and requires both a divalent cation, Mg2+ or Mn2+, for activity and as well is stimulated by inorganic phosphate. When compared to the usual NADP-dependent methylenetetrahydrofolate dehydrogenase from mouse liver, the NAD-dependent dehydrogenase activity of the murine tumor enzyme shows a greater affinity for the polyglutamate forms of folate.
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PMID:NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase from ascites tumor cells. Purification and properties. 348 46

It was recently reported (C-W. Chen et al., FEBS Lett. 168, 70 (1984)) that water solutions of Mn3+ (TPPS4) have a surprisingly high relaxivity at 20 MHz and 37 degrees C, greater than most Mn2+ complexes including the hexaaquoion. Because Mn3+ (TPPS4) is highly stable, and porphyrins in general are tumor-seeking, we have sought to understand the origin of the large relaxivity by comparing the 1/T1 NMRD profiles (magnetic field dependence of 1/T1 of solvent protons) of Mn3+ (TPPS4) solutions with those of a number of other small Fe3+ and Mn2+ complexes. By relating the measured NMRD profiles to the theory of relaxation by magnetic dipolar interactions, in a form appropriate for small paramagnetic solute molecules, we establish that the theory affords an excellent quantitative description of the relaxation behavior of all the samples, and confirm that the relaxivity of Mn3+ (TPPS4) is anomalously high. The effect is attributed, in part, to the anisotropy of the ground-state wavefunction of Mn3+ in the porphyrin complex, effectively bringing the spin density of the Mn3+ ions closer to the protons of the coordinated water molecules than would a spherically symmetric S-state ion. In addition, the paramagnetic relaxation time of the Mn3+ spins, though short, is longer than would be anticipated for a non-S-state ion, and increases substantially with magnetic field above about 2 MHz. In this regard, Mn3+ (TPPS4) may be one of a class of molecules with properties particularly favorable for use as contrast-enhancing agents in magnetic resonance imaging.
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PMID:The anomalous relaxivity of Mn3+ (TPPS4). 357 59

Using unselected and selected B16 melanoma cell lines, we examined the relationship between homotypic aggregation properties and the potential to form experimental metastatic lung colonies. The B16 sublines were selected in vitro from a line with relatively low homotypic aggregation kinetics and experimental metastatic potential (B16-F1) by successive steps of cell aggregation, followed by separation of cell aggregates from single cells. The selected sublines possessed significantly higher rates of aggregation than did the parental cell line and, when injected intravenously as single cells, formed greater numbers of lung tumor colonies. The aggregation kinetics of the parental and selected cell lines were dependent on divalent cations, with the following order of selectivity: Ca2+ greater than Mn2+ much greater than Mg2+. Syngeneic and xenogeneic serum components and the protease inhibitor leupeptin enhanced the aggregation kinetics of various B16 cell lines. The results support the proposal that a positive correlation exists between increased homotypic adhesion and experimental metastatic potential.
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PMID:Malignant melanoma cell lines selected in vitro for increased homotypic adhesion properties have increased experimental metastatic potential. 379 26

Mn(III), Fe(III), and Gd(III) complexes of tetrakis(4-sulfonatophenyl)porphyrin (TPPS) and several other porphyrins were evaluated as potential MRI contrast agents. Based on consideration of relaxivity and stability properties in solution, MnTPPS was found to be the compound of choice. At pH 7 the Gd and Mn complexes significantly enhanced the water proton relaxation rate, while the relaxivity of FeTPPS exhibited a significant loss of relaxivity above pH 6 due to oxy-dimer formation. Although GdTPPS exhibited the highest relaxivity in solution, this property was rapidly lost due to dissociation of the metal ion. By contrast MnTPPS remained stable in human plasma after incubation for 9 days. Upon intravenous injection into athymic mice bearing subcutaneous human colon carcinoma xenografts, MnTPPS provided enhanced relaxation of the tissue water in several excised mouse tissues, notably kidney, liver, and tumor. The results at a fixed field (0.25 T) and relaxation dispersion studies showed decreases in water relaxation rates with time for kidney and liver, but an increase for the tumor, with a maximum near 4 days at the highest dose used.
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PMID:Tissue distribution and stability of metalloporphyrin MRI contrast agents. 382 76

Treatment of 3T3-L1 cells with 0.1-1.0 nM insulin results in rapid (5-15 min) activation of a soluble protein kinase that phosphorylates serine residues in ribosomal protein S6. The insulin-stimulated kinase activity is detectable in confluent, nongrowing preadipocytes and adipocytes. In the presence of 2 micrograms of cycloheximide per ml, preconfluent 3T3-L1 cells also respond to insulin by acquiring an S6 kinase activity whose properties are the same as those of the enzyme activity elicited by insulin alone in growth-inhibited cells. The principal insulin-stimulated S6 kinase has a Mr of approximately equal to 50,000-60,000; there is a variable amount of activity that sediments with a Mr of about 80,000. The soluble enzyme exhibits optimal activity between pH 8 and pH 9, requires Mg2+ (10-20 mM), and is inhibited by Ca2+ (0.5 mM), Mn2+ (0.05 mM), and NaF (30 mM). GTP cannot substitute for ATP in the phosphotransferase reaction; cAMP, cGMP, phosphatidylserine plus diolein, the cAMP-dependent protein kinase inhibitor, and heparin (0.7 micrograms/ml) are without effect. Although treatment of 3T3-L1 cells with insulin does not influence the activity or the subcellular distribution of the phospholipid and Ca2+-dependent protein kinase C, exposure to the phorbol tumor promoter phorbol 12-myristate 13-acetate (PMA) results in translocation of protein kinase C to the membrane and activation of a soluble phospholipid and Ca2+-independent S6 protein kinase that has the same magnitude of activity and sedimentation behavior as the insulin-induced activity. Trypsin treatment of either 3T3-L1 cytosolic extracts or partially purified 3T3-L1 protein kinase C generates a small amount of S6 kinase activity of Mr 50,000. This activity, resolved by sucrose gradient centrifugation, is less active than that elicited by either insulin or PMA and, unlike the activities generated by insulin and PMA, is associated with histone kinase activity. The data suggest that the S6 kinase elicited by either insulin or PMA is neither protein kinase C, its phospholipid, and Ca2+-independent proteolytic derivative nor the result of proteolytic activation of an inactive proenzyme that can be reproduced by trypsin treatment of cell extracts in vitro.
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PMID:Activation of S6 kinase activity in 3T3-L1 cells by insulin and phorbol ester. 389 33

Galactosyltransferases (GTs) are one of the members of a family of enzymes called glycosyltransferases involved in the biosynthesis of complex carbohydrates. These enzymes catalyze the transfer of galactose from UDP-galactose to an acceptor (glycoprotein, glycolipid) containing terminal N-acetylglucosamine or N-acetylgalactosamine residue. GTs occur in soluble (milk, serum, effusions, etc.) and insoluble (membrane) forms. The GT activities on the outer surface of the cells have been correlated with a host of cellular interactions, including fertilization, cell migration, embryonic induction, chondrogenesis, contact inhibition of growth, cell adhesion, hemostasis, intestinal cell differentiation, and immune recognition. GTs have been purified to homogeneity using affinity chromatography. Most GTs are found active in the pH range 6 to 8 and at temperatures between 35 to 40 degrees C. Manganese is an essential co-factor for GT activity. Isoenzymes of GT have been recognized, especially in tumor tissues, malignant effusions, and sera of cancer patients using polyacrylamide gel electrophoresis in the presence and absence of SDS. Depending on the source of the enzyme, the molecular weights of GTs range between 40,000 to 80,000 daltons. Carcinoma-associated GT isoenzyme has been reported to have a higher molecular weight than the normal GT isoenzyme. Development of monoclonal antibody against the cancer-specific GT isoenzyme will provide help in the development of an immunoassay for the measurement of this isoenzyme in the sera and an aid in the radioimmunolocalization of the tumors in cancer patients.
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PMID:Galactosyltransferases: physical, chemical, and biological aspects. 392 3


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