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)

Phytohemagglutinin isolectins L4 and E4 inhibit the growth and proliferation of cultured L1210 murine leukemia cells. L1210 cells were incubated with L4 or E4, and the metabolic and morphological characteristics of the cells were assessed. Dose-dependent inhibition of up to 90% occurs for [3H]thymidine and [14C]uridine incorporation. L4 is 30 to 50 times more potent an inhibitor than is E4. Inhibition begins 2 to 3 hr after exposure of L1210 cells to L4 and persists for as long as the cells are exposed to this isoleuctin. Total DNA and oxygen consumption in L4-treated cultures is also decreased. Whereas protein synthesis assessed by [14C]valine incorporation is less affected, glucose utilization remains unchanged. The binding of L4 and E4 to L1210 cells and human lymphocytes is similar and is reversible by porcine thyroglobulin. Porcine thyroglobulin also reverses L4-induced inhibition of nucleotide incorporation. Cell aggregation is the major morphological consequence of isoleuctin treatment observed by light or electron microscopy. L1210 cells are agglutinated at lower doses of isoleuctins than are normal murine lymphocytes. No evidence of cell death as estimated by 51Cr release or trypan blue uptake has been noted. Our data indicate that L4 and E4 have cytostatic properties and demonstrate that the reversible binding of a macromolecule to the surface of a malignant cell can modulate synthetic pathways and the rate of proliferation.
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PMID:Inhibitory effects of phytohemagglutinin isolectins L4 and E4 on L1210 cells. 56 79

The objective of the present investigation was to screen a series of new N'-oxides of N',N'-dimethylaminoalkylamides of dodecanoic acid for activity in vitro and to investigate the biochemical mode of action. On the basis of primary screening, one of the most active compounds, namely the N'-oxide of 10-(N',N'-dimethylaminodecyl)amide of dodecanoic acid (n = 10) was chosen for detailed biochemical study. This compound inhibited the incorporation of 14C-precursors (adenine, valine, thymidine, uridine) into appropriate macromolecules of P388 murine leukemia and Ehrlich ascites carcinoma cells. The amine oxide also interfered with energy-yielding processes (aerobic glycolysis, endogenous respiration). Cytotoxicity is a consequence of the cytolytic activity of the compounds mentioned above. Membranous effects were demonstrated by the measuring of the release of cytoplasmic materials absorbing at 260 and 280 nm, marker enzyme activities (LDH, MDH), release of protein from the cells into the culture medium, as well as by morphological examination. It is evident that the site of action of the amine oxides investigated was the biological membrane which, after interaction with the amine oxides, showed changes in molecular organization and osmotic and permeability characteristics.
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PMID:Biochemical basis of cytotoxic activity of some new N'-oxides of N',N'-dimethylaminoalkylamides of dodecanoic acid. 142 44

VLA-1 to VLA-6 are cell-surface molecules binding to matrix molecules such as collagen, fibronectin, epiligrin, and laminin. In addition, VLA-4 binds to VCAM-1 and ICAM-2, thus mediating intercellular adhesion prerogative for lymphocyte extravasation or 'homing'. Using frozen tissue of normal lymphoid organs and of 100 morphologically and immunologically typed B cell neoplasias, monoclonal antibodies to all six VAL-alpha and to the common beta-chain were applied to serial sections. VLAs were found differentially expressed in cytologically and microtopographically defined B-cell subsets [follicular mantle zone cells (MZ), follicular center cells (FC), extrafollicular cells (EF), and plasma cells (PC)] of normal spleen, lymph node, and thymic medulla (which contains an EF compartment). Thus, these cell types, which correspond to discrete stages of B cell development, can also be defined by their VLA status. Acute B lymphoblastic leukemia (ALL) was VLA-1-, 2-, 3 +/-, 4 +/-, 5 +/-, 6-. The VLA-1-, -2 +/-, 3+, -4+, -5+, -6-phenotype of chronic B lymphocytic leukemia (CLL) resembled that of MZ. Hairy cell leukemia (HCL) differed from CLL in its tendency to lack VLA-2, in its consistent lack of VLA-3, and altogether resembled splenic EF in its VLA profile. Mantle zone lymphoma (MZL) consistently expressed VLA-3 and -4 and frequently VLA-5. Nodal follicular center cell lymphomas (FCCL) were VLA-1- and -2- and very rarely expressed VLA-5 and -6. Thus, FCCL although roughly corresponding to FC, tended to aberrantly express VLA-3 and/or VLA-4. Burkitt's lymphoma resembled FCCL but expressed VLA-4 more frequently and at higher levels. Mediastinal clear cell lymphoma of B-cell type differed from FCCL in its regular lack of VLA-3, -5, and -6 and in frequently lacking VLA-4. Medullary plasmacytoma was VLA-1-, -2-, -3 +/-, -4 +/-, -5-, -6+, thus being the only B cell neoplasia which was consistently VLA-6+. With respect to the well-known clinical characteristics of the B cell malignancies examined, the leukemic phenotype might crucially depend on the presence of VLA-5.
Leukemia 1992 Apr
PMID:Adhesion molecules VLA-1 to VLA-6 define discrete stages of peripheral B lymphocyte development and characterize different types of B cell neoplasia. 158 89

The p53 gene was examined in primary lymphoblasts of 25 pediatric patients with acute lymphoblastic leukemia by the RNase protection assay and by single strand conformation polymorphism analysis in 23 of 25 cases. p53 mutations were found to occur, but at a low frequency (4 of 25). While all four mutations were identified by single strand conformation polymorphism, the comparative sensitivity of RNase protection was 50% (2 of 4). Heterozygosity was retained at mutated codons in 3 of 4 cases. One pedigree was consistent with the Li-Fraumeni syndrome, and bone marrow from both diagnosis and remission indicated a germline G to T transversion at codon 272 (valine to leucine). Although members of another family were affected with leukemia, a 2-bp deletion in exon 6 was nonhereditary. The other two nonhereditary p53 mutations included a T to G transversion at codon 270 (phenylalanine to cysteine) and a G to C transversion at codon 248 (arginine to proline). These data support the role of both hereditary and acquired p53 mutations in the pathogenesis and/or progression of some cases of childhood acute lymphoblastic leukemia.
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PMID:Hereditary and acquired p53 gene mutations in childhood acute lymphoblastic leukemia. 173 52

Cancer morbidity was investigated in a cohort of 2,170 ethylene oxide (EO)-exposed workers from 2 plants producing disposable medical equipment. The subjects had been employed for at least 1 year during the periods 1970-1985 and 1964-1985, respectively. The exposure to EO was assessed for each of six job categories in the plants with respect to each calendar year, on which basis values for individual cumulative exposure to EO (ppm-years) were calculated. The levels of hydroxyethyl adducts to N-terminal valine (HOEtVal) in hemoglobin fitted well with the values estimated for airborne exposure to EO. No increased cancer incidence was found [standardized morbidity ratio (SMR), 0.78; 95% CI, 0.49-1.21)]. No leukemia was observed, but one case of non-Hodgkin's lymphoma, one case of myeloma, and one case of polycythemia vera were diagnosed as compared with two expected hematopoietic and lymphatic tumors (SMR, 1.54; 95% CI, 0.32-4.5). No stomach cancer was detected as compared with the 0.5 case expected. There were no significant exposure-response associations between estimates of exposure to EO and cancer morbidity.
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PMID:An epidemiological study of cancer risk among workers exposed to ethylene oxide using hemoglobin adducts to validate environmental exposure assessments. 174 69

Primary screening in vitro and study on the mode of action of 9-hydroxybenfluron (HBF) in both murine P388 leukemia and Ehrlich ascites carcinoma cells have been performed. Metabolite HBF is approximately twice as effective as a reference drug (benfluron). To elucidate the biochemical mode of action, the effect of HBF on the biosynthesis of macromolecules indicated by the incorporation rate of [14C]adenine (in DNA and RNA), [14C]thymidine (in DNA), [14C]uridine (in RNA) and [14C]valine (in protein) was studied in concentration and time dependence. HBF inhibited incorporation of all four precursors into the trichloroacetic acid-insoluble fraction of Ehrlich ascites cells. The fact that incorporation of these four precursors is inhibited suggests that the effect of HBF lies at an underlying level of energy generation or transfer rather than at specific reactions in the biosynthesis of DNA and proteins.
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PMID:9-Hydroxybenfluron: cytostatic effects and inhibition of macromolecular biosynthesis in Ehrlich ascites and P388 murine leukemia cells. 180 25

The presence of activated transforming genes was investigated in four patients with therapy-related leukemia and in three with therapy-related myelodysplastic syndrome. DNA of bone marrow cells from six of the patients exhibited transforming activity in the tumorigenicity assay. Five of the six patients who were positive in the tumorigenicity assay contained activated N-ras oncogenes, and three contained activated K-ras oncogenes. Thus, concurrent activation of N-ras and K-ras oncogenes was observed in two patients. In vitro DNA amplification followed by oligonucleotide dot-blot analysis was used to investigate mutations in codons 12, 13, and 61 of the N-ras and K-ras oncogenes. Two patients exhibited an N-ras mutation, substituting aspartic acid (GAT) for glycine (GGT), and three patients exhibited an N-ras codon 13 mutation, substituting valine (GTT) for glycine. Two patients exhibited K-ras codon 12 mutations, substituting aspartic acid (GAT) or cysteine (TGT) for glycine (GGT), respectively, and one case exhibited a K-ras codon 61 mutation, substituting lysine (AAA) for glutamic acid (CAA). Cytogenetic analysis revealed that loss of chromosome 7 was frequent (four patients: 57%). Our data indicate that activation of N-ras and K-ras genes, as well as loss of heterozygosity for specific alleles on chromosome 7, plays a more important role in the leukemogenesis of both therapy-related leukemia and myelodysplastic syndrome.
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PMID:Transforming genes and chromosome aberrations in therapy-related leukemia and myelodysplastic syndrome. 185 83

Avian c-erbB is activated to a leukemia oncogene following truncation of its amino-terminal, ligand-binding domain by retroviral insertion. The insertionally activated transcripts encode protein products that have constitutive tyrosine kinase activity and that can induce erythro-leukemia but not sarcomas. We have found that a single point mutation within the ATP-binding pocket of the tyrosine kinase domain in this truncated molecule can increase the ability of this oncogene to induce anchorage-independent growth of fibroblasts in vitro and fibrosarcoma formation in vivo. Associated with this increased transforming potential is a corresponding increase in the kinase activity of the mutant erbB protein product. The mutation, which converts a valine to isoleucine at position 157 of the insertionally activated c-erbB product, is at a residue that is highly conserved within the protein kinase family. To our knowledge, this is the first demonstration of a point mutation in the ATP-binding pocket that activates a tyrosine kinase.
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PMID:Tissue-specific transformation by epidermal growth factor receptor: a single point mutation within the ATP-binding pocket of the erbB product increases its intrinsic kinase activity and activates its sarcomagenic potential. 197 68

Heterogeneity of p53 protein expression is seen in blast cells of patients with acute myelogenous leukemia (AML). p53 protein is detected in the blasts of certain AML patients but not in others. We have identified p53 protein variants with abnormal mobility on gel electrophoresis and/or prolonged half-life (t 1/2). We have sequenced the p53 coding sequence from primary blast cells of five AML patients and from the AML cell line (OCIM2). In OCIM2, a point mutation in codon 274 was identified that changes a valine residue to aspartic acid. A wild type p53 allele was not detected in these cells. Two point mutations (codon 135, cysteine to serine; codon 246, methionine to valine) were identified in cDNA from blasts of one AML patient. Both mutations were present in blast colonies grown from single blast progenitor cells, indicating that individual leukemia cells had sustained mutation of both p53 alleles. The cDNAs sequenced from blast samples of four other patients, including one with prolonged p53 protein t 1/2 and one with no detectable p53 protein, were fully wild type. Thus, the heterogeneity of p53 expression cannot be explained in all cases by genetic change in the p53 coding sequence. The prolonged t 1/2 of p53 protein seen in some AML blasts may therefore reflect changes not inherent to p53. A model is proposed in which mutational inactivation of p53, although not required for the evolution of neoplasia, would confer a selective advantage, favoring clonal outgrowth during disease progression.
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PMID:Mutation of the p53 gene in human acute myelogenous leukemia. 200 69

S 12363 is a new highly potent vinca alkaloid derivative characterized by the grafting of an a-aminophosphonate, bioisoster of the valine, at the C23 position of O4-deacetyl vinblastine. Using a cell image processor Samba 200 (System for Analytical Microscopic Biomedical Applications), we have studied the effect of S 12363 on cell proliferation of four mammary (MXT, MCF-7, T47-D and MDA-MB231) and two melanoma (HBL and DRD 3) tumor cell lines, and on cell cycle kinetic parameters on human T47-D and HBL tumor cell lines. S 12363 significantly inhibited the growth of these 6 tumor cell lines in a time- and concentration-dependent manner. Three concentrations were tested for 24, 48, 72 and 96 hours incubation times. The human breast T47-D, MCF-7 and melanoma DRD3 and HBL tumor cells were the most sensitive to S 12363. This compound was effective at all doses tested (0.1, 1 and 10 ng/ml) after at least a 24 hour incubation period. The murine MXT and human MDA-MB231 tumor cells were about 10 fold less sensitive than the other cell lines. S 12363 disturbed the cell cycle of T47-D and HBL cell lines and induced a significant accumulation of cells in the G2 + M phases to the detriment of the G0 + G1 phases. The antitumor activity of S 12363 was confirmed in vivo on 2 disseminated murine tumor models, i.e. P388 leukemia implanted subcutaneously and M5076 reticulum-cell sarcoma inoculated intraperitoneally. S 12363 was at least as active as reference compounds vinblastine or vincristine with active doses 5 to 20 times lower.
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PMID:Characterization of the pharmacological antitumor effects of S 12363, a new vinca alkaloid. 206 54


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