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)

A mutant of Moloney murine leukemia virus was generated in which the UAG termination codon at the 3' end of the gag gene was changed to a CAG codon encoding glutamine. Cells carrying the mutant provirus constitutively express the gag-pol fusion protein and no detectable gag protein. The precursor is stable, is not processed by the protease domain within the precursor, and does not induce assembly and release of virion particles.
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PMID:Expression of the gag-pol fusion protein of Moloney murine leukemia virus without gag protein does not induce virion formation or proteolytic processing. 245 1

Avarol is a sesquiterpenoid hydroquinone, which displays no inhibitory potencies on mammalian DNA polymerases alpha, beta, and gamma, on mammalian RNA polymerases I, II, and III, or on reverse transcriptases from Moloney murine leukemia virus (Mo-MuLV) and from HIV. For a further elucidation of the antiviral effect of Avarol, we used NIH-3T3 cells infected with Mo-MuLV as a model system. The results show that in uninfected NIH-3T3 cells Avarol (i) causes a 50% reduction of the growth rate only at the high concentration of 29.6 microM and (ii) is accumulated in the cytoplasm close to the nucleus. At the much lower concentrations of 1-3 microM, Avarol causes an almost complete inhibition of viral progeny release. Moreover, it is shown that at 3 microM Avarol, the increase of the Mo-MuLV-induced UAG suppressor glutamine tRNA (tRNA(UmUGGln) was reduced to the normal level. Dot blot hybridization studies revealed that Avarol displays no inhibitory activity on cellular and viral mRNA synthesis. Taking the processing pathway of viral polyprotein Pr180gag,pol to p80 (reverse transcriptase) as an example, our Western blotting experiments showed that the final maturation process, conversion of p110 to p80, is inhibited in Avarol-treated cells. From these data we conclude that Avarol prevents the suppression of the UAG termination codon at the gag-pol junction of the retroviral genome. The functional consequence of this event is very likely an inhibition of the readthrough of the retroviral protease gene which overlaps the pol and gag genes, resulting in the reduction of the protease synthesis which is necessary for the viral proliferation.
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PMID:Selective inhibition of formation of suppressor glutamine tRNA in Moloney murine leukemia virus-infected NIH-3T3 cells by Avarol. 245 80

We have examined the effects of various inhibitors of the lipoxygenase pathway of arachidonic acid metabolism on the growth of three well-characterized human leukemia cell lines, HL-60, K-562, and KG-1. An intact lipoxygenase pathway, and the synthesis of leukotriene C4 (LTC4), which requires reduced glutathione, is essential for in vitro growth of normal myeloid progenitors (CFU-GM). We tested the effects of nordihydroguiaretic acid (NDGA) and caffeic acid (CA), inhibitors of lipoxygenase; buthionine sulfoximine (BSO), which inhibits glutathione synthesis; and Acivicin, a glutamine antagonist, on these cell lines and compared the effects with those seen on CFU-GM. In semisolid culture, all three cell lines were inhibited by NDGA, CA, and BSO in a dose-dependent manner similar to that in CFU-GM but were relatively resistant to Acivicin. In liquid culture, all three cell lines exhibited relative resistance to inhibition by both BSO and Acivicin, with KG-1 also demonstrating relative resistance to inhibition by NDGA and CA. The inhibition of HL-60 by CA could be completely reversed by the addition of exogenous leukotriene D4. The dependence on the lipoxygenase pathway may be altered to varying degrees in different leukemic lines and may depend on culture conditions. Whether these changes may contribute to the pathogenesis of leukemia or merely represent secondary metabolic changes is yet to be determined.
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PMID:Effects of lipoxygenase and glutathione pathway inhibitors on leukemic cell line growth. 249 78

A human histiocytic lymphoma cell line, U937, is highly sensitive to L-asparaginase with an ID50 of about 0.0001 U/ml after 72 hr of culture. When U937 cells were made resistant to either L-asparaginase (1 U/ml) or asparagine deprivation, the activity of asparagine synthetase increased to 80- or 7-fold of the wild type, respectively. The phenotype of the resistance to L-asparaginase turned out to be stable under nonselective conditions for over several months. The hybrids between L-asparaginase sensitive (Molt4) and resistant (HL-60) cell lines revealed the latter phenotype in terms of L-asparaginase sensitivity and the activity of asparagine synthetase. Furthermore, U937 cells resistant to L-asparaginase could survive in glutamine-free media with 1.5-fold elevation of glutamine synthetase activity. These results altogether clarify the role of asparagine synthetase in L-asparaginase toxicity and have a good implication for the clinical use of L-asparaginase.
Leukemia 1989 Apr
PMID:Biochemical characterization of U937 cells resistant to L-asparaginase: the role of asparagine synthetase. 256 53

Acivicin [L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid; NSC 163501] is a fermentation-derived amino acid antibiotic antagonistic to L-glutamine which exhibits potent oncolytic properties. We have developed a variant of P388 leukemia resistant to acivicin (P388/ACIA) and compared its properties with those of the parent line (P388/S). An examination of the enzymes utilizing L-glutamine revealed that the basal specific activities of L-asparagine synthetase and L-glutaminase were 1-to 3-fold higher in the parent line. The activities of carbamoyl phosphate synthetase II, L-asparagine synthetase, formylglycinamide ribonucleotide amidotransferase, and guanosine monophosphate synthetase were about equally inhibited in the two cell lines, while there was a partial inhibition of 5-phosphoribosyl-1-pyrophosphate amidotransferase, fructose-6-phosphate amidotransferase, and L-glutaminase activities, found only in the sensitive line. Cytidine triphosphate synthetase activity was not inhibited in either line. There was no difference in the dose response or restitution of L-glutamine utilizing enzyme activities between the two lines. Acivicin treatment produced a 2- to 3-fold augmentation of the L-glutamine pools only in the sensitive line. Drug injection induced increased 5-phosphoribosyl-1-pyrophosphate levels in both lines. Acivicin perturbed guanosine nucleotide pools only in the sensitive line, indicating that the primary mechanism of action of acivicin in P388 leukemia may be directed at guanosine monophosphate synthetase. Transport studies demonstrated a restricted uptake of acivicin by the resistant cells. These studies suggest that the transport of acivicin and L-glutamine plays an important role in determining the sensitivity or resistance to acivicin in these tumors.
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PMID:Mechanism of resistance of a variant of P388 leukemia to L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin). 257 92

The replication of Moloney murine leukemia virus (MMuLV) in chronically infected mouse cells arrested at the G0/G1 phase of the cell cycle by different procedures was investigated. MMuLV production was inhibited in glutamine- and isoleucine (Gln-Ile)-deprived G0/G1 cells. In contrast, butyric acid treatment, which efficiently arrested the cells at the G0/G1 phase of the cell cycle, did not inhibit MMuLV production. Furthermore, the inhibition of MMuLV production caused by either Gln-Ile deprivation or by interferon (IFN) treatment was overcome by butyric acid treatment. Thus, the replication of MMuLV could be dissociated from cell proliferation. The inhibition of MMuLV production in Gln-Ile-deprived cell cultures was compared to the inhibitory effect of IFN, which is known to affect budding and release of the virus. Rates of MMuLV protein synthesis were not affected in both the IFN-treated and Gln-Ile-deprived cells. However, processing of the viral polyprotein Pre65gag into p30 was blocked in the Gln-Ile-deprived cells. Furthermore, whereas in IFN-treated cells, MMuLV accumulated on the cell surface and could be released upon treatment with trypsin, in Gln-Ile-deprived cells, no virions were released by such treatment. These results indicate that in cells arrested by Gln-Ile deprivation, MMuLV is inhibited at a posttranslation step. This step appears to precede the anti-MMuLV block induced by IFN.
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PMID:Regulation of Moloney murine leukemia virus replication in chronically infected cells arrested at the G0/G1 phase. 258 48

Pyrazofurin (NSC 143095) as the monophosphate derivative is a potent inhibitor of orotidine 5'-monophosphate (OMP) decarboxylase of the pyrimidine pathway and has been proposed to inhibit 5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylase (EC 2.1.2.3) of the purine pathway (J. F. Worzalla, and M. J. Sweeney, Pyrazofurin inhibition of purine biosynthesis via 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-monophosphate formyltransferase. Cancer Res., 40: 1482-1485, 1980). Measurement of levels of pyrimidine and purine intermediates in cultured mouse L1210 leukemia cells has shown that 25 microM pyrazofurin induces an 8-fold accumulation of OMP and large accumulations of intermediates proximal to the blockade with abrupt decreases in uridine and cytidine nucleotides. Considerable increases in the cellular concentrations of N-succino-AICAR (SAICAR), AICAR, 5-formamidoimidazole-4-carboxamide ribotide (FAICAR), IMP, XMP, and GMP at later times indicate that AICAR transformylase is not significantly inhibited in cultured cells; rather the purine pathway and the GMP branch are stimulated. However, addition of 25 microM 3-deazauridine (NSC 126849) to leukemia cells did result in inhibition of AICAR transformylase: AICAR and SAICAR accumulated, IMP disappeared and there was a large accumulation of guanosine nucleotides. Blockade of pyrimidine biosynthesis by derivatives of pyrazofurin or 3-deazauridine spares 5-phosphoribosyl-1-pyrophosphate and L-glutamine, elevated concentrations of which may stimulate initial reactions of purine biosynthesis and the reaction XMP----GMP.
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PMID:Dual effects of pyrazofurin and 3-deazauridine upon pyrimidine and purine biosynthesis in mouse L1210 leukemia. 271 48

The relationship between proliferation and metabolism of four leukemia cell lines (BALL-1, JOK-1, Jurkat, and MOLT-4) in batch culture was studied. The maximum cell density (1.5-2.3 x 10(6) cells/ml) without change of medium was observed on days 6-8 of cultivation. At the same time, the original concentration of glucose in the medium (10 mmol/l) fell to 3.5-4 mmol/l. While BALL-1 and MOLT-4 cells, on day 4 of cultivation, converted 82% of glucose into lactate, on day 7 this value was 50%, or there was no lactate production (MOLT-4), respectively. On the other hand, the values of the coefficient of glycolysis showed that Jurkat and JOK cells converted also other compounds into lactate. Part of the utilized glutamine was employed by all four cell lines: 1. as a precursor of glutamic acid, and 2. as a source of energy. BALL-1 and JOK-1 cells converted part of arginine into ornithine. At the time when the proliferation of the cells ceased, the level of ammonia reached a toxic concentration of 2.0-3.6 mmol/l. Since these cell lines utilized only a part of carbon and nitrogen sources in the medium, it was suggested that the final cell density was limited by a growth inhibitor (i.e. ammonia) and not by a lack of nutrients.
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PMID:Study of metabolism and growth limitation of human leukemia cell lines. 273 7

An in vitro system to assay translational readthrough of the UAG termination codon at the murine leukemia virus (MuLV) gag-pol junction was developed by using rabbit reticulocyte lysates programmed by SP6-generated Moloney MuLV gag-pol mRNA. Under conditions in which the suppressor activity of the lysate was dependent on addition of tRNA, it could be shown that readthrough synthesis was stimulated to approximately the same extent by equivalent amounts of tRNA from MuLV-infected and uninfected NIH 3T3 cells. Analysis of glutamine tRNA, which mediates suppression in vivo, showed that the level of glutamine acceptor activity and the chromatographic profile of glutamine isoacceptors were unchanged following virus infection. On the basis of these results, we conclude that the suppressor tRNA occurs normally within the tRNA population of uninfected cells and need not be induced in response to virus infection.
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PMID:Translational readthrough of the murine leukemia virus gag gene amber codon does not require virus-induced alteration of tRNA. 278 37

Nucleotide sequences of the region that corresponds to the site of tRNA primer binding for a functional retrovirus were determined in five murine leukemia virus-related sequence clones from mouse chromosomal DNA, which contain a unique 170 to 200-base-pair additional internal segment in the long terminal repeats. The 3'-terminal 18-nucleotide sequence of a major glutamine tRNA isoacceptor was found to match well with the putative primer binding site: 18 of 18 in three clones, 17 of 18 in one clone, and 16 of 18 in one clone. This implies that most of these endogenous proviral sequences of the mouse genome, if replicated as retroviruses, will be different from ecotropic murine leukemia viruses and most mammalian type C retroviruses in using glutamine tRNA, rather than proline tRNA, as a primer.
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PMID:Nucleotide sequence analysis of endogenous murine leukemia virus-related proviral clones reveals primer-binding sites for glutamine tRNA. 298 43


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