Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acivicin is an investigational amino acid antitumor antibiotic currently being evaluated in Phase II clinical trials. In humans acivicin causes reversible, dose-limiting central nervous system (CNS) effects including somnolence, ataxia, personality changes, and hallucinations. We have observed and reported previously that acivicin-treated cats exhibit symptoms (ataxia, sedation, somnolence) resembling CNS toxicity reported in humans. We hypothesized that if acivicin uptake into brain were mediated by a saturable transport system common to endogenous amino acids, drug uptake and CNS toxicity might be blocked by elevation of normal amino acid concentrations in circulating plasma. To test this hypothesis, cats received constant-rate i.v. infusions of either saline or Aminosyn, 10% (a commercially available mixture of 16 amino acids not containing glutamine, glutamate, aspartate, or cysteine) for 4 h prior to and 18 h subsequent to administration of acivicin at a dose producing marked behavioral changes in control cats. Presence or absence of ataxia and sedation were noted at intervals after acivicin treatment. Results showed that Aminosyn infusion prevented CNS symptoms in six of eight cats. Subsequent experiments showed that acivicin levels in brain tissue of Aminosyn-treated cats were 13% of the drug levels in saline-infused cats. Acivicin levels in most peripheral tissues were also decreased significantly by Aminosyn infusion but not to the extent observed in brain. Decreased brain uptake was shown to be due to a combination of amino acid blockade of drug transport into that organ and of increased total body clearance of drug. Concomitant Aminosyn treatment did not alter the efficacy of acivicin in mice bearing L1210 leukemia or MX-1 human mammary carcinoma. Further studies demonstrated that a solution containing only four large neutral amino acids (leucine, isoleucine, phenylalanine, and valine) could also protect cats from acivicin-induced CNS toxicity, apparently without increasing acivicin total body clearance. However, a mixture of several other amino acids contained in Aminosyn (alanine, arginine, tyrosine, histidine, proline, serine, and glycine) failed to prevent CNS toxicity. We conclude that cotreatment with Aminosyn or a mixture of large neutral amino acids could protect cancer patients from acivicin-induced CNS toxicity without ablating antitumor efficacy.
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PMID:Prevention of central nervous system toxicity of the antitumor antibiotic acivicin by concomitant infusion of an amino acid mixture. 238 52

The McDonough strain of the feline sarcoma virus contains a transforming gene (v-fms) which contains partial nucleotide homology with proto-oncogenes encoding tyrosine kinases. One of the v-fms-encoded products, gp140fms, is a cell surface transmembrane glycoprotein that may function as a growth factor receptor. Although c-fms transcripts have been detected in placental trophoblasts and normal human bone marrow, the role of the c-fms gene product is unknown. We now report that induction of monocytic, but not granulocytic, differentiation of human HL-60 leukaemic cells is associated with expression of c-fms, preceded by that of c-myc and c-fos. Because c-fms transcripts are also detectable in peripheral blood monocytes and in blasts from certain patients with myelomonocytic leukaemia, the c-fms gene product may play a role in monocytic differentiation.
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PMID:Expression of the c-fms proto-oncogene during human monocytic differentiation. 240 50

Rous sarcoma virus-transformed BHK cells (RSV/B4-BHK) adhere to a fibronectin-coated substratum primarily at specific dot-shaped sites. Such sites contain actin and vinculin and represent close contacts with the substratum as revealed by interference reflection microscopy. Only a few adhesion plaques and actin filament bundles can be detected in these cells as compared to untransformed parental fibroblasts. In thin sections examined with transmission electron microscopy (TEM) these adhesion sites correspond to short protrusions of the ventral cell surface that contact the substratum at their apical portion. These structures, which may represent cellular feet, are therefore called podosomes. By screening a number of different transformed fibroblasts plated on a fibronectin-coated substratum we find that podosomes are common to mammalian and avian cell lines transformed either by Rous sarcoma virus (RSV) or by Fujinami avian sarcoma virus (FSV), whose oncogenes encode specific tyrosine kinases. Using antibodies reacting with phosphotyrosine in immunofluorescence experiments, we show that phosphotyrosine-containing molecules are concentrated in podosomes. Podosomes are not detected in fibroblasts transformed by other retroviruses (Snyder-Theilen sarcoma virus, Abelson leukemia virus and Kirsten sarcoma virus) or by DNA tumor viruses (polyoma, SV40), indicating that podosome-mediated adhesion in transformed fibroblasts is related to the peculiar properties of some oncoproteins and possibly to their tropism for adhesion systems. Podosomes and adhesion plaques, although similar in cytoskeletal protein composition, have different mechanisms and kinetics of formation. Assembly of podosomes, in fact (i) does not require fetal calf serum (FCS) in the adhesion medium, that is necessary for the organization of adhesion plaques; (ii) does not require protein synthesis; and (iii) is insensitive to the ionophore monensin, that prevents adhesion plaque formation. Moreover, during attachment to fibronectin-coated dishes, podosomes appear in the initial phase (60 min) of attachment, while adhesion plaques require a minimum of 180 min. In conclusion podosomes of RSV- and FSV-transformed fibroblasts represent a phenotypic variant of adhesion structures.
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PMID:Rous sarcoma virus-transformed fibroblasts adhere primarily at discrete protrusions of the ventral membrane called podosomes. 241 76

Peripheral blood cells and bone marrow cells from patients with various types of leukemia, but not those from healthy persons, were brightly immunofluorescent (IF) after staining with monoclonal antibody reactive to O-phosphotyrosine. All the IF-positive cells observed in peripheral blood were judged to be leukemic in morphology, and the IF-positive cells comprised 40-90% of total leukemic cells present in blood. Similar bright fluorescence was observed in the K562 human leukemic cell line. The results raise the possibility that leukemic cells can be distinguished from normal hematologic cells by their increased contents of phosphorylated tyrosine residues.
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PMID:Immunofluorescent staining of human leukemic cells with monoclonal antibody to phosphotyrosine. 241 4

We have used a high-affinity polyclonal antibody directed against phosphotyrosine (P-Tyr) to localize P-Tyr-containing proteins in normal and transformed cells in culture by immunofluorescence microscopy experiments. The distribution of the proteins with modified tyrosine was compared with that of F-actin in these cells. Cells infected with Abelson murine leukemia virus were found to contain elevated levels of P-Tyr, as expected. Various permanent lines of fibroblastic and epithelial cells exhibited lower, but easily detectable, levels of P-Tyr. The P-Tyr in fibroblasts was concentrated at the focal contacts at the termini of actin-containing microfilament bundles and, in the epithelial cells examined, at the intercellular junctions. Early passages of primary cultures of chicken embryo fibroblasts and chicken embryo heart cells also showed detectable levels of P-Tyr in focal contacts and cell-cell junctions. However, P-Tyr was not detectable in later passages of chicken embryo fibroblasts. The concentration of P-Tyr-containing proteins in intercellular junctions in normal cells suggests that these are sites of significant biochemical regulatory activities which may be important in the control of normal cell adhesivity, motility, and shape.
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PMID:Phosphotyrosine-containing proteins are concentrated in focal adhesions and intercellular junctions in normal cells. 241 41

The NH2-terminal amino acid sequence of Moloney murine leukemia virus reverse transcriptase was determined to be Thr-Leu-Asn-Ile-Glu-Asp-Glu-Tyr-Arg-Leu-His-Glu-. The comparison of the amino acid analysis data obtained after carboxypeptidase Y digestion with the published nucleotide sequence (T. M. Shinnick, R. A. Lerner, and J. G. Sutcliffe, Nature (London) 293, 543-548, 1981) led to the conclusion that the COOH-terminus is Leu coded by CTC in nucleotide positions 4608-4610, and the tentative COOH-terminal sequence is Pro-Asp-Thr-Ser-Thr-Leu-Leu-OH. In light of these and previously reported results the complexity and map order of the pol gene are discussed.
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PMID:Amino- and carboxyl-terminal sequence of Moloney murine leukemia virus reverse transcriptase. 241 14

For direct identification of phosphotyrosine-containing proteins in lysates of various cells, phosphotyrosine (P-Tyr) was coupled to carrier proteins and anti-P-Tyr antibodies were raised in rabbits and mice. The antibodies were highly specific for P-Tyr and did not cross-react with phosphoserine or phosphothreonine. The mean association constant of rabbit anti-P-Tyr antibody to N-acetyl-P-Tyr was about four times that of rabbit anti-azobenzene phosphonate antibody. In addition, anti-P-Tyr antibody scarcely cross-reacted with the 5'-monophosphate of ribosyladenine or the 5'-monophosphate of ribosylinosine, whereas anti-azobenzene phosphonate antibody cross-reacted appreciably with these compounds. Anti-P-Tyr antibody immunoprecipitated three oncogenic gene products from cells transformed with Rous sarcoma virus, Fujinami sarcoma virus, and Abelson murine leukemia virus, respectively. The immunoprecipitates with anti-P-Tyr antibody from cells transformed with these three retroviruses all manifested tyrosine kinase activity including activity for phosphorylations of oncogene products. In addition to the proteins reported previously, the following new phosphotyrosine-containing proteins were immunoprecipitated from the respective retrovirus-transformed cells by anti-P-Tyr antibody: Mr 230,000, 74,000, and 24,000 proteins (Rous sarcoma virus); Mr 230,000, 69,000, and 24,000 proteins (Fujinami sarcoma virus); and Mr 230,000, 62,000, and 54,000 proteins (Abelson murine leukemia virus).
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PMID:Direct identification of phosphotyrosine-containing proteins in some retrovirus-transformed cells by use of anti-phosphotyrosine antibody. 241 36

Phosphotyrosine antibodies were employed to immunodecorate and immunoprecipitate proteins phosphorylated at tyrosine residues in cells transformed by Abelson murine leukemia virus (A-MuLV). In pre-B and pre-T lymphoma cells transformed by A-MuLV, the major phosphotyrosine-containing protein has an MW of 160 kDa and shares immunologically detectable sequences with the v-abl oncogene product. Moreover, two different proteins of approximately 100 and 68 kDa, heavily phosphorylated at tyrosine, were identified. Lack of immunological cross-reactivity with viral products and phosphopeptide mapping showed that the 100 and 68 kDa proteins are coded by cellular genes. Phosphoproteins were undetectable in control resting lymphocytes. The 68 and the 100 kDa proteins were phosphorylated to different extents in proliferating lymphocytes, either stimulated by the growth factor IL-2, or transformed by M-MuLV (lacking the oncogene coded kinase). In fibroblasts transformed by A-MuLV, phosphotyrosine antibodies identified 2 proteins of 120 and 70 kDa. By immunological cross-reaction and by phosphopeptide mapping, the first was identified as a 120 kDa form of the v-abl coded kinase. The 70 kDa protein is coded by a cellular gene, is not structurally related to the 120 kDa v-abl kinase, and is different from any phosphotyrosine-containing protein detected in A-MuLV-transformed lymphocytes. These data show that, upon v-abl-induced transformation, phosphorylation at tyrosine takes place also on proteins other than the 160 or 120-kDa oncogene products. In lymphocytes and fibroblasts these proteins are different, suggesting that the cascade of events triggered by the v-abl gene in different cell types involves tyrosine phosphorylation of different specific proteins.
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PMID:Protein phosphorylation at tyrosine residues in v-abl transformed mouse lymphocytes and fibroblasts. 242 Jul 27

About 1.5% of phosphorylated amino acid residues of HL-60 promyelocytic leukemia cells are phosphotyrosine. Induction of granulocytic differentiation by exposure to dimethylsulfoxide decreased tyrosine phosphorylation to 0.2%. A maximum 3-fold increase in tyrosine kinase activity and a 7-fold increase in protein phosphotyrosine phosphatase activity accompanied this change. Monocytic differentiation induced by 12-O-tetradecanoylphorbol-13-acetate, caused a decrease in phosphotyrosine levels to 0.1%; tyrosine kinase activity maximally increased 2-fold, and protein phosphotyrosine phosphatase activity increased 11-fold in these differentiated cells. Thus, although total tyrosine kinase activity markedly increased during differentiation, this was counteracted by an even greater elevation in protein phosphotyrosine phosphatase activity. The findings support the concept that tyrosine phosphorylation is important in the regulation of growth and differentiation of leukemia cells.
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PMID:Regulation of protein phosphotyrosine content by changes in tyrosine kinase and protein phosphotyrosine phosphatase activities during induced granulocytic and monocytic differentiation of HL-60 leukemia cells. 243 May 65

Antibodies against phosphotyrosine are a powerful tool with which to identify proteins phosphorylated on tyrosine residues, such as viral oncogene-encoded transforming proteins and their cellular protein substrates. Probed on human leukemia cell lines, phosphotyrosine antibodies recognized a 210,000-molecular-weight protein (p210) in K562 cells, a cell line derived from a Philadelphia (Ph)'-positive chronic myelogenous leukemia (CML), but recognized no protein in control Ph'-negative non-CML leukemia cells. The p210 protein was also recognized by antisera against v-abl-encoded polypeptides and displayed kinase activity, phosphorylating itself on tyrosine, in an immunocomplex kinase assay. These data are consistent with reported findings of the expression of a recombined bcr-abl gene in Ph'-positive CML cells, leading to the synthesis of an altered p210c-abl protein endowed with tyrosine kinase activity. Phosphotyrosine antibodies also detected the expression of the p210c-abl protein in fresh bone marrow cells harvested from CML patients in blast crisis. Besides the p210c-abl protein kinase, phosphotyrosine antibodies recognized other proteins with molecular weights of 110,000, 68,000, and 36,000 (p110, p68, and p36) in K562 cells. When [gamma-32P]ATP was added to nonionic detergent-extracted cells, these proteins became phosphorylated on tyrosine, as confirmed by phosphoamino acid analysis. A comparison with fibroblasts transformed by the v-abl, v-src, and v-fps oncogenes suggested the identity of the p36 protein with the common 36-kilodalton protein substrate of viral oncogene-encoded tyrosine kinases. Enhanced tyrosine phosphorylation of cellular proteins is thus a feature shared by cells transformed by v-abl and cells expressing a rearranged bcr-abl gene.
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PMID:Phosphotyrosine antibodies identify the p210c-abl tyrosine kinase and proteins phosphorylated on tyrosine in human chronic myelogenous leukemia cells. 243 Dec 86


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