Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The functioning of the Golgi complex in protein intracellular transport is most simply understood in terms of its being composed of a sequence of functionally distinct subcompartments. For example, the influence of perturbation of cellular Na+-K+ balance on the transport of secretory and membrane glycoproteins is to greatly slow their passage from relatively proximal to relatively distal subcompartments. To further the understanding of the nature of these subcompartments a rat IgM myeloma has been subjected to analytical subcellular fractionation. Fractions selectively enriched in distinct Golgi-associated activities have been prepared and their membrane proteins compared with those of rough microsomal fractions. The subfractionation is extensive and suggests the possibility of obtaining well resolved Golgi subfractions. Myeloma cells stained intracellularly with Concanavalin A- and wheatgerm agglutinin--peroxidase conjugates show distinct labelling patterns. Concanavalin A stains the entirety of the rough endoplasmic reticulum as well as the proximal face of the Golgi stack. Wheatgerm agglutinin stains the distal face of the stack of Golgi cisternae. The staining patterns are not due to immunoglobulin as they are also observed in myeloma variants that fail to synthesize immunoglobulin.
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PMID:The role of subcompartments of the Golgi complex in protein intracellular transport. 613 57

This paper provides an overview of cancer chemotherapy with special reference to the pharmacokinetics of the nitrosoureas. At physiological PH, the chloroethylnitrosoureas can be decomposed into an isocyanate and 2-chloroethyl diazene hydroxide. Therefore, it is clear that they have both alkylation and carbamoylation actions. In addition to the spontaneous chemical dissociation, the nitrosoureas can be metabolized by liver microsomal enzymes to more polar hydroxylated products, and certain nitrosoureas can be denitrosated by these enzymes to the parent urea. Since the lipid-soluble nitrosoureas and some of the water-soluble nitrosoureas such as ACNU and MCNU demonstrated to cross the blood-brain barrier, they have been used in the treatment of primary brain tumors and tumors and tumors of metastatic origin. It has been demonstrated from the results of our study and other reports that the alkylation of DNA by ACNU progresses more slowly as compared with that of other alkylating agents. This is an important finding in relation to the appearance of delayed myelosuppression of the nitrosoureas and in the design of dose schedules of these agents. The major clinical emphasis has been directed towards the more active chloroethylnitrosoureas with reduced myelosuppression, and attempts are now made for this purpose. Unfortunately, the results of phase I and II trials of the newly developed nitrosoureas suggest that these agents produce delayed and cumulative bone marrow toxicity. Antitumor activity of the nitrosoureas is frequestly observed in chronic myelocytic leukemia, malignant lymphoma, brain tumors and small cell carcinoma of the lung, and less frequently in gastrointestinal carcinoma, multiple myeloma and malignant melanoma. In order to enhance clinical effects of the nitrosoureas, further investigation of the design in therapeutic schedules on the basis of their pharmacokinetic characteristics will be needed.
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PMID:[Cancer chemotherapy with special reference to pharmacokinetics of nitrosoureas]. 622 95

BALB/c mice were repeatedly immunized with a galactosyl transferase-rich microsomal fraction of rat myeloma cells. Spleen cells were subsequently fused with Sp2/0 mouse myeloma cells, the resulting hybridomas were cloned, and their secreted Ig was screened for reactivity with antigens belonging to the Golgi complex. One such monoclonal antibody, 6F4C5, gave especially intense immunofluorescent staining of the Golgi area of myeloma cells and fibroblasts. It recognized two proteins bands on immunoblots of gel-fractionated cell lysates: a major one with an estimated Mr of 54,000 and a minor one at 86,000. Both proteins were concentrated in microsomal fractions isolated at low ionic strength. They were hydrophilic judging from partitioning of a Triton X-114 cell lysate. Both were cytoplasmically oriented as demonstrated by protease and high KCl treatments of postmitochondrial supernatants and microsomal fractions. Neither was retained by columns of insolubilized wheat germ agglutinin or concanavalin A, which suggests that they are not glycoproteins. Their more detailed location in the Golgi complex was studied by immunoelectron microscopy, using a saponin permeabilization procedure and peroxidase-conjugated reagents. The observed staining was restricted to two or three cisternae in the medial part of the stack. Nevertheless, differential centrifugation experiments indicated that the two antigens may be recovered in distinct subcellular fractions: this may be related to the unexpected observation that rather low salt concentrations strip the antigens from microsomal fraction.
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PMID:Characterization of cytoplasmically oriented Golgi proteins with a monoclonal antibody. 643 14

Spleen cells from a BALB/cByJ mouse previously immunized with purified rat liver microsomal cytochrome P-450c were fused with myeloma cells (P3X63Ag8.653) and 10 hybridoma clones secreting antibody against cytochrome P-450c were selected for characterization. The monoclonal antibodies (C1-C10) were purified from mouse ascites fluid and nine were determined to be distinct immunoglobulins. C6 was an IgG2b, whereas the rest were of the IgG1 subclass. A competitive enzyme-linked immunoassay was used to show that the antibodies were directed against at least five spatially distinct epitopes on cytochrome P-450c. Additional evidence for the recognition of distinct epitopes was provided by Ouchterlony immunoprecipitation of cytochrome P-450c with mixtures of appropriate monoclonal antibodies. Differences in antibody reactivity provided evidence for a sixth overlapping epitope that was recognized by two antibodies (C4 and C6). Three monoclonal antibodies to the same epitope on cytochrome P-450c, (CD2, CD3, and CD5) cross-reacted strongly with cytochrome P-450d, another isozyme induced by 3-methylcholanthrene treatment of rats. The antibodies that did not cross-react with cytochrome P-450d contained kappa light chains, whereas the three cross-reacting antibodies contained lambda light chains. None of the monoclonal antibodies cross-reacted with purified cytochromes P-450a, P-450b, P-450e, P-450f, P-450g, or P-450h or any other cytochrome P-450 in "Western blots" of liver microsomes from untreated or 3-methylcholanthrene-treated rats. C8 was a potent inhibitor of metabolism catalyzed by cytochrome P-450c in a reconstituted system as well as microsomes from 3-methylcholanthrene-treated rats. This antibody effected maximal inhibition of catalytic activity at an approximately 0.5:1 molar ratio of IgG to cytochrome P-450c, i.e. one antibody-binding site per epitope on cytochrome P-450c.
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PMID:Characterization of nine monoclonal antibodies against rat hepatic cytochrome P-450c. Delineation of at least five spatially distinct epitopes. 670 86

Monoclonal antibodies were prepared from hybridoma clones isolated by the fusion of myeloma cells and spleen cells derived from mice immunized with either purified rabbit liver microsomal cytochrome P-450LM2 or cytochrome P-450LM4. Seven hybridoma clones produced three kinds of monoclonal antibodies to P-450LM2. The first class bound, precipitated, and inhibited the enzyme activity of P-450LM2 for both benzo[a]pyrene hydroxylation and 7-ethoxycoumarin deethylation. The other two classes either bound and precipitated or only bound the enzyme. These monoclonal antibodies to P-450LM2 showed a precipitin reaction and inhibition of enzyme activity that was specific for cytochrome P-450LM2. Thus, they did not react with or inhibit the enzyme activity of the other isozyme cytochrome P-450LM4, Fraction 1 or Fraction 7. All of the monoclonal antibodies formed against P-450LM2 were mouse immunoglobulin (Ig) subclass IgG1. The most effective monoclonal antibody strongly inhibited the formation of oxygenated metabolites of benzo[a]pyrene at various positions as well as the deethylation of 7-ethoxycoumarin. Four hybridomas were isolated which produced monoclonal antibodies to P-450LM4. One of the four was of the IgM class and three were of the IgG1 type. The four monoclonal antibodies bound to P-450LM4 but did not precipitate the enzyme, and did not bind to P-450LM2. The monoclonal antibody P-450LM4 complexes interacted with protein A, and the enzyme activity for benzo[a]pyrene hydroxylation could be removed by centrifugation. The high specificity and monoclonality of these antibodies suggest their potential usefulness for studying the genetics, regulation, and roles of the different isozymes of P-450LM in drug and carcinogen metabolism.
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PMID:Monoclonal antibodies to rabbit liver cytochrome P-450LM2 and cytochrome P-450LM4. 681 77

Rat liver microsomal 3-hydroxy-3-methylglutaryl-CoA reductase [HMG-CoA reductase; mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34], the key regulatory enzyme in cholesterol biosynthesis, has been purified to apparent homogeneity. Purified HMG-CoA reductase yields a single diffuse band when NaDodSO4/polyacrylamide gels are stained with Coomassie blue and yields two adjacent bands when gels are stained with silver. Purified reductase was used to elicit the production of monoclonal antibodies. Spleen cells from BALB/c mice immunized with purified HMG-CoA reductase were fused with Sp-2/0 myeloma cells. Clones producing monoclonal antibodies to HMG-CoA reductase were identified by using a solid-phase radioimmunoassay and were subcloned in soft agar. The three relatively stable hybridoma lines isolated secrete different Igs as judged by their antibody subclasses and differing abilities to inhibit HMG-CoA reductase in solution. Efficient precipitation of solubilized HMG-CoA reductase was achieved with the two IgG antibodies but not with the IgM. A mixture of all three monoclonal antibodies immunoprecipitates more than 90% of the HMG-CoA reductase activity in solubilized rat liver extracts. These monoclonal antibodies should be useful probes for investigation of the regulation of HMG-CoA reductase and cholesterol synthesis.
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PMID:Production and characterization of monoclonal antibodies to rat liver microsomal 3-hydroxy-3-methylglutaryl-coenzyme A reductase. 695 16

Microsomes prepared from several animal sources were analyzed for the presence of proteins corresponding to the ribophorins (I and II) which have been previously characterized in rat liver rough microsomes and appear to be involved in the binding of polysomes to endoplasmic reticulum membranes. In rough microsomal membranes from rat lacrimal gland, rabbit liver, dog and chicken pancreas, and mouse myeloma, ribophorin-like polypeptides with similar electrophoretic mobilities were detected by sodium dodecyl sulfate/polyacrylamide gel electrophoresis. In all cases the polypeptides remained associated with sedimentable polysomes after solubilization of the microsomal membranes with nonionic detergents. Ribophorin-like polypeptides were absent from smooth microsomes. Antibodies raised against each rat liver ribophorin, purified by preparative sodium dodecyl sulfate/polyacrylamide gel electrophoresis, immunoprecipitated only the corresponding polypeptide, indicating no crossreactivity between ribophorins I and II. These antibodies also immunoprecipitated the homologous ribophorins found in microsomal preparations from other organs and species.
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PMID:Identification of ribophorins in rough microsomal membranes from different organs of several species. 708 28

L-Phenylalanine mustard (L-PAM), a bis-choroethylamine, is an important drug in the treatment of multiple myeloma and ovarian cancer. It undergoes rapid hydrolysis in vitro and in vivo, forming the mono-and dihydroxy degradation products. L-PAM's first-order disappearance rate in a phosphate-buffered solution did not differ statistically according to the presence or absence of activated rat liver microsomal enzymes. Furthermore, L-PAM's disappearance rate in a rat whole liver perfusion system was not greater than its hydrolysis rate in water. In vitro plasma recovery studies showed that up to 85% of the 14C L-PAM drug equivalents could be recovered as the parent compound and the mono- and dihydroxy degradation products. Thus, L-PAM in in vitro degradation was similar qualitatively and quantitatively to its reported in vivo degradation in animals and man. It is concluded that L-PAM does not undergo important, active in vivo metabolism.
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PMID:In vitro degradation of L-phenylalanine mustard (L-PAM). 710 81

Rat liver microsomal membranes were purified in order to remove membrane-associated secretory products. Measurements of the decay of the newly synthesized protein of these membranes in vivo were carried out at short time intervals after the protein was labeled by the administration of radioactive leucine. The result of these measurements suggest that the membranes are synthesized and degraded at approximately the same rapid rate as the synthesis and secretion of membrane-associated secretory products. Evidence that the highly dynamic protein of the purified membranes is indeed membrane protein is provided by the observations indicating: that this protein is immunochemically distinct from serum proteins, which are the major secretory product of liver; that many different protein components of the membranes turn over at similarly rapid rates; and that the biosynthesis of these proteins is specifically stimulated by the administration of phenobarbital, which is known to stimulate biosynthesis of hepatic endoplasmic reticulum. These findings suggest that in liver, as had been proposed earlier for the myeloma cell, unidirectional membrane flow, accompanied by rapid synthesis at the origin of flow and rapid degradation of the membranes at or near the terminus of flow, may be the mechanism for the intracellular transport of secretory product.
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PMID:Evidence for rapid turnover of hepatic endoplasmic reticulum and its possible relationship to secretion. 720 94

Newly synthesized microsomal membrane phospholipids of actively secreting myeloma cells all appear to decay rapidly, with initial half-lives of less than 1 h. Their rates of decay are similar to each other and to the rates observed earlier for the decay of the protein components of the membrane and also for the intracellular turnover of immunoglobulin light chain, the predominant secretory product of these cells. This evidence, which suggests that many different components of the membrane and, therefore, presumably the membrane itself turn over rapidly, provides support for the hypothesis that unidirectional membrane flow, accompanied by rapid synthesis of the membranes at the origin of flow and their rapid degradation at or near the terminus of flow, is the mechanism of intracellular transport of secretory product by the myeloma cell. An attractive feature of this mechanism is that rapid synthesis and degradation of the membranes could provide the driving force for membrane flow.
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PMID:Evidence for rapid and concerted turnover of membrane phospholipids in MOPC 41 myeloma cells and its possible relationship to secretion. 735 29


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