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)

Mouse P388 and L1210 leukemia cells grown in vitro were found to be 4 to 10 times more sensitive to 6-diazo-5-oxo-L-norleucine and 3 to 5 times more sensitive to Acivicin than were 3T3 and C57BL x DBA/2 F1 embryonic fibroblasts. The combined actions of succinylated Acinetobacter glutaminase-asparaginase and 6-diazo-5-oxo-L-norleucine or Acivicin produced synergistic inhibition of nucleic acid synthesis in P388 tumor cells. An uptake system for Acivicin is described. Its properties in P388 and 3T3 cells are similar in their strong temperature dependence, utilization of the "L" transport system, presumably competitive inhibition by glutamine, similar Km's (about 200 microM), and potent inhibition by p-chloromercuribenzene sulfonate, NA+. However, Acivicin uptake was inhibited in 3T3 (but not in P388) cells by KCN or 2,4-dinitrophenol. At equilibrium in P388 cells, the intracellular level of Acivicin was approximately 57-fold greater than was the extracellular concentration. The accumulated Acivicin was not metabolized by P388 cells, nor does exchange of 3H label into water occur. Rapid efflux of Acivicin occurred with both cell lines at 37 degrees, but efflux from 3T3 cells was greatly diminished at 0 degrees. The rate of efflux was accelerated by including glutamine or unlabeled Acivicin in the extracellular medium.
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PMID:Enhancement of antitumor activity of glutamine antagonists 6-diazo-5-oxo-L-norleucine and acivicin in cell culture by glutaminase-asparaginase. 721 22

Melphalan uptake by human ovarian carcinoma cells obtained from patients with clinically documented disease was significantly reduced by ascitic fluid. Examination of the ascitic fluid revealed physiologic concentrations of a number of amino acids, notably leucine (100-150 microM) and glutamine (500-600 microM). These two amino acids, when used at concentrations found in the ascitic fluid, significantly reduced melphalan uptake to levels which approximated those obtained with ascitic fluid. The possible effect of high concentrations of these amino acids on melphalan therapy for this neoplasm is discussed with particular reference to the model melphalan transport system in the murine L1210 leukemia cell. Specific emphasis is placed on the rationale for combining melphalan with arginine and a glutamine-depleting enzyme.
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PMID:Uptake of melphalan by human ovarian carcinoma cells and its relationship to the amino acid content of ascitic fluid. 722 65

Acivicin, an inhibitor of L-glutamine-dependent amidotransferases, is active against the murine L1210 and P388 leukemia models. Cytidine triphosphate synthetase has been proposed as the primary target for this agent. Our results demonstrate that Acivicin is also an inhibitor of de novo pyrimidine biosynthesis. This inhibition results in the depletion of pyrimidine deoxyribonucleoside triphosphate pools and explains the effect of this agent on DNA synthesis. Further, Acivicin is synergistic with N-(phosphonacetyl)-L-aspartic acid, another inhibitor of de novo pyrimidine synthesis. The combination of these agents results in a more than additive depletion of deoxycytidine triphosphate pools which may account for their synergism in inhibiting cellular growth. Thus, the inhibition of de novo pyrimidine synthesis by Acivicin may be useful in modulating the effects of certain antimetabolites or other inhibitors of this pathway.
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PMID:Synergistic effects with inhibitors of de novo pyrimidine synthesis, acivicin, and N-(phosphonacetyl)-L-aspartic acid. 726 Sep 7

Succinylated Acinetobacter glutaminase-asparaginase (SAGA) has broader antitumor activity than Escherichia coli L-asparaginase in experimental systems; moreover, drug resistance does not develop in tumor cell lines initially sensitive to this enzyme. We have investigated the pharmacology and toxicology of SAGA after both single-dose and serial daily dose injections in 20 adult patients. Glutaminase activity in plasma after i.v. injection of single doses did not follow simple first-order kinetics (half-life during the initial 24 hr was 21 +/- 9 hr. A linear relation was observed between increasing doses of SAGA and resultant levels of plasma enzyme activity and blood glutamate. Assay of whole blood which had been deproteinized immediately following phlebotomy showed that single doses of SAGA lowered glutamine only transiently to nondetectable levels; serial daily doses were required to achieve and maintain continuous glutamine depletion. Reversible depression of the central nervous system, ranging from encephalopathy to coma, occurred in a dose-related manner and was dose limiting. Other prominent reactions included respiratory alkalosis, hyperglycemia, nausea, and vomiting. Transient antitumor effects were noted in two patients with solid tumors and in two patients with leukemia. SAGA causes considerable neurotoxicity in adults which requires close patient monitoring. Phase II studies in leukemic patients are in progress.
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PMID:Phase I evaluation of succinylated Acinetobacter glutaminase-asparaginase in adults. 743 89

Mutations of signal transducing molecules such as Ras have been shown to confer a growth advantage in leukaemic blasts and contribute to the pathogenesis of the disease. Alterations of signal transducing molecules other than Ras may play a role in leukaemogenesis. Knowledge of such mutations could also further our understanding of the normal signalling processes. We have therefore studied the coding sequence of the GM-CSF receptor alpha chain (GM-CSFR alpha) in patients with acute myeloid leukaemia (AML) and non-AML controls using single strand conformation polymorphism (SSCP) analysis. Abnormalities were detected in 4/32 AML patients (13%) and 2/15 non-AML controls (13%). Direct sequencing of PCR products revealed five different base substitutions. Three were conservative, two caused amino acid changes. The base substitution leading to amino acid change alanine to glycine at position 17 was found in both an AML patient and a control. It lies in the signal sequence and does not affect the mature protein. The other base change altering arginine to glutamine at position 164 is unlikely to influence the receptor structure as this structural position in the chain is not well conserved in members of the cytokine receptor family. Both amino acid changes were constitutive alterations as they could be demonstrated in the patients' children. The base changes described in the AML patients thus represent polymorphisms and do not contribute to the pathogenesis of AML.
Leukemia 1994 Sep
PMID:Analysis of mutations in the GM-CSF receptor alpha coding sequence in patients with acute myeloid leukaemia and haematologically normal individuals by RT-PCR-SSCP. 752 90

TREB5 (hXBP-1) protein is a transcription factor that recognizes the CRE-like element in enhancers of human T-cell leukemia virus and MHC class II gene and activates their transcription. TREB5 is a member of the CREB/ATF family, containing a basic amino acid region and leucine zipper structure (b-Zip structure). To characterize the key domain of TREB5 for transcriptional activation, mutational analysis was carried out. The C-terminal region of 148-221 amino acids was identified as an activation domain and was also active when fused to Gal4 DNA binding domain. This domain contains three unique regions rich in glutamic acid, glutamine, or serine/threonine and is active in both osteosarcoma (HOS) and T (Jurkat) cell lines. All of these three regions are essential; however, a part of the serine/threonine region was dispensable in Jurkat, but not in HOS cells. In addition to the activation domain, the N-terminal region showed activity in conjunction with the b-Zip structure, but not with the Gal4 DNA binding domain. Furthermore, this region showed activity in Jurkat cells, but not in HOS cells. These results suggest that TREB5 has two activational functions in transcription and may provide diversity in cell-type-specific transcriptional activation, possibly through dimerization with other b-Zip proteins and phosphorylation.
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PMID:Identification of transcriptional activation domain of TREB5, a CREB/ATF family protein that binds to HTLV-1 enhancer. 760 16

A chromosomal translocation, t(4;11)-(q21;q23), is associated with an aggressive mixed-lineage leukemia. A yeast artificial chromosome was used to clone the chromosomal breakpoint of this translocation in the RS4;11 cell line. The breakpoint sequences revealed an inverted repeat bordered by a consensus site for topoisomerase II binding and cleavage as well as chi-like elements. The der(11) chromosome encodes a fusion RNA and predicted chimeric protein between the 11q23 gene MLL and a 4q21 gene designated AF4. The sequence of the complete open reading frame for this fusion transcript reveals the MLL protein to have homology with DNA methyltransferase, the Drosophila trithorax gene product, and the "AT-hook" motif of high-mobility-group proteins. An alternative splice that deletes the AT-hook region of MLL was identified. AF4 is a serine- and proline-rich putative transcription factor with a glutamine-rich carboxyl terminus. The composition of the complete MLL-AF4 fusion product argues that it may act through either a gain-of-function or a dominant negative mechanism in leukemogenesis.
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PMID:Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product. 768 31

The effect of a singular amino acid, asparagine (Asn), glutamine (Gln), or proline deletion in a cultured medium (RPMI 1640 supplemented with 10% fetal calf serum and other ingredients) on adriamycin (ADR) cytotoxicity was evaluated in the growth of P388 murine leukemia cells and CEM human acute lymphoblastic leukemia cells over a 3 day period. No enhancement of ADR cytotoxicity was observed in the assay of IC50 values under the amino acid deleted condition. Singular deletion of Gln or Asn from ADR-free medium apparently inhibited the proliferation of both cells, i.e. both cell lines strongly require them. The cytotoxicity of 5 nM ADR was then examined in medium which included one or the other of them in stepwise levels varied at 80, 60, 40, 20 and 0% of the ordinary level. Change of Asn level caused a difference in ADR toxicity; also, the change of Gln level, especially the 60% level caused ADR toxicity of 5 nM, which is less than the IC50 value, in the proliferation of both cells. This suggested the usefulness of glutamine level modification on the enhancement of ADR cytotoxicity.
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PMID:Inhibition of cultured leukemia cell growth by enhanced adriamycin cytotoxicity with reduction of glutamine or asparagine level in medium. 788 97

Rat annexin II cDNA clones were isolated from a rat basophilic leukaemia cell plasmid library by cross-species hybridization with a mouse probe, and fully sequenced using the dideoxy-chain-termination method. Alignment of the derived amino-acid sequence with those of other mammalian annexin II species revealed a high level of conservation, characteristic of the annexin family of proteins. One of the cDNAs isolated contained an additional six nucleotides close to the N-terminus, lying in-frame and at a point corresponding to an intron/exon boundary in the human annexin II gene. As the two rat cDNAs were identical apart from the six nucleotide insert, it is likely that these represent alternatively spliced transcripts of a single gene, rather than the products of two separate genes. The six nucleotides encode serine-glutamine and therefore introduce an additional potential phosphorylation site into a region already containing one tyrosine and two serine phosphorylation sites. The discovery of this novel annexin II variant may have important implications both for p11 binding and for regulation of annexin II function by phosphorylation.
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PMID:Molecular cloning of a novel N-terminal variant of annexin II from rat basophilic leukaemia cells. 809 93

The human T-cell leukemia/lymphotropic virus type I (HTLV-I) induces T-cell leukemia and transforms human T cells in vitro. A recently identified protein with a molecular weight of 12,000 (12K) (p12I), encoded by single- and double-spliced mRNAs transcribed from the 3' end of the HTLV-I genome, has been shown to localize in the perinuclear compartment and in the cellular endomembranes. The p12I protein exhibits significant amino acid sequence similarity to the E5 oncoprotein of bovine papillomavirus type 1 (BPV-1). Both proteins are very hydrophobic, contain a glutamine residue in the middle of a potential transmembrane region(s), and are localized in similar cellular compartments. Because of these observations, we investigated whether the p12I resemblance to E5 correlated with a similarity in their biological behavior. We expressed the p12I protein to evaluate its ability to functionally cooperate with the BPV-1 E5 oncoprotein and to bind to a cellular target of the E5 protein, the 16K component of the vacuolar H+ ATPase. Cotransfection of the mouse C127 cell line with the p12I and E5 cDNAs showed that although p12I alone could not induce focus formation, it strongly potentiated the transforming activity of E5. In addition, the p12I protein bound to the 16K protein as efficiently as the E5 protein. These findings might provide new insight for potential mechanisms of HTLV-I transformation and suggest that p12I and E5 represent an example of convergent evolution between RNA and DNA viruses.
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PMID:The human T-cell leukemia/lymphotropic virus type I p12I protein cooperates with the E5 oncoprotein of bovine papillomavirus in cell transformation and binds the 16-kilodalton subunit of the vacuolar H+ ATPase. 823 Apr 93


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