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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Susceptibility of rodent cells to infection by ecotropic murine leukaemia viruses (MuLV) is determined by binding of the virus envelope to a membrane receptor that has multiple membrane-spanning domains. Cells infected by ecotropic MuLV synthesize envelope protein, gp70, which binds to this receptor, thereby preventing additional infections. The consequences of envelope-MuLV receptor binding for the infected host cell have not been directly determined, partly because the cellular function of the MuLV receptor protein is unknown. Here we report a coincidence in the positions of the first eight putative membrane-spanning domains found in the virus receptor and in two related proteins, the arginine and histidine permeases of Saccharomyces cerevisiae (Fig. 1), but not in any other proteins identified by computer-based sequence comparison of the GenBank data base. Xenopus oocytes injected with receptor-encoding messenger RNA show increased uptake of L-arginine, L-lysine and L-ornithine. The transport properties and the expression pattern of the virus receptor behave in ways previously attributed to y+, the principal transporter of cationic L-amino acids in mammalian cells.
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PMID:Transport of cationic amino acids by the mouse ecotropic retrovirus receptor. 187 78

We have examined the effects of Cyclosporin A (CsA) on growth and polyamine metabolism of MOLT-4, human T lymphoblastic leukaemia cells to ascertain the role of the polyamine biosynthetic pathway in the antitumour action of CsA. We observed that CsA had a dose-dependent inhibitory effect on growth of the cells in vitro, decreasing protein content, cell number and the rate of incorporation of 3H-thymidine into the cells. However, CsA treatment had no significant effect on intracellular polyamine levels in the cells. Contrary to previous reports, simultaneous addition of the diamine, putrescine, with CsA did not block or lessen the growth inhibitory effects of CsA. On the other hand, ornithine decarboxylase activity, the rate limiting enzyme of polyamine biosynthesis which converts ornithine to putrescine, was decreased by CsA treatment. This decrease appeared to be reversible and contrasts with the inhibition by alpha-difluoromethyl-ornithine, which is irreversible and can be overcome by addition of putrescine. This suppression of ornithine decarboxylase by CsA is more likely to occur by indirect effects on translation and/or transcription rather than a direct effect on the enzyme. It may be a contributory factor in the overall antiproliferative effects of CsA but is more likely to be a response to these growth inhibitory effects rather than a direct effect of the drug.
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PMID:Effects of cyclosporin A on growth and polyamine metabolism of MOLT-4 T-lymphoblastic leukaemia cells. 189 53

The complementary DNA sequence encoding the cell-surface receptor for ecotropic host-range murine retroviruses (ecoR) shows that it contains 622 amino acids and 14 hydrophobic potentially membrane-spanning sequences. Because this receptor occurs on many or all murine cells and is probably essential for viability of cultured fibroblasts, its normal function might be to transport an essential metabolite. We expressed ecoR in Xenopus laevis oocytes by injecting RNA transcribed from the cloned cDNA. These oocytes specifically bound the gp70 envelope glycoprotein from an ecotropic murine leukaemia virus. An inward current was recorded electrophysiologically when a mixture of amino-acids was applied: this resulted from a stereoselective, saturable uptake of lysine, arginine and ornithine; it was independent of sodium and not substantially altered by gp70. Cysteine and homoserine were also taken up, but sodium was necessary for their transport. These properties of ecoR correspond to those of the y+ amino-acid transporter. Our results demonstrate the subversion of a ubiquitous cell membrane protein, in this case a basic amino acid transporter, for use as a retroviral receptor.
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PMID:Cell-surface receptor for ecotropic murine retroviruses is a basic amino-acid transporter. 187 78

The heretofore unknown gamma-(m-carboxyanilide) and gamma-(m-boronoanillide) derivatives of methotrexate (MTX) and the gamma-(m-carboxyanilide) derivatives of aminopterin (AMT) were prepared and tested as inhibitors of dihydrofolate reductase (DHFR) and as inhibitors of cell growth in culture with the aim of comparing their activity with that of N alpha-(4-amino-4-deoxypteroyl)-N delta-hemiphthaloyl-L-ornithine, a potent antifolate whose side chain likewise contains a hydrophobic aromatic ring with an acid group on the ring. All three anilides were potent DHFR inhibitors, with activity comparable to MTX and AMT. The gamma-(m-boronoanilide) displayed growth inhibitory potency similar to that of the hemiphthaloylornithine analogue, with an IC50 of only 0.7 nM. This compound, which is the most potent of the gamma-amides of MTX tested to date, is also the first reported example of an antifolate with a B(OH)2 group in the side chain and is especially novel because of its potential to form a stable tetrahedral boronate complex by reaction with electron rich OH or NH2 groups in the active site of DHFR or other folate enzymes. In antitumor assays against L1210 leukemia in mice, N alpha-(4-amino-4-deoxypteroyl)-N delta-hemiphthaloyl-L-ornithine gave a T/C of greater than 263% at 20 mg/kg (qdx9) and 300% at 16 mg/kg (bidx10), whereas maximally tolerated doses of MTX of 8 mg/kg (qdx9) and 1 mg/kg (bidx10) gave T/C values of 213 and 188%, respectively. MTX gamma-(m-boronoanilide) was also active, with a T/C of 175% at 32 mg/kg (qdx9), the highest dose tested.
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PMID:Synthesis and biological activity of methotrexate analogues with two acid groups and a hydrophobic aromatic ring in the side chain. 199 80

A human cell culture system is described for biological testing of potent new folate-targeted antileukemic drugs that are poorly transported. Basic amino acid (lysine and ornithine) polymers were employed as carriers for increasing the uptake of folate analogs by human leukemia cell lines. In growth inhibition assays, the lymphocytic CCRF-CEM line displayed sensitivities to covalent methotrexate (MTX) conjugates of poly-L-lysine (Mr = 15,000, 50,000, or 100,000) or poly-L-ornithine (Mr = 35,000) which were identical to the sensitivities of these cells to the unconjugated polymers during continuous (120 hr) and pulse (24 hr) exposures; both polymers and conjugates were 50-fold less toxic than unconjugated MTX. The growth inhibitory effects of the polymers or MTX-conjugates were not reversed by simultaneous inclusion of leucovorin, while those of MTX were reversed. In contrast, the nonlymphocytic K562 line showed toxicity by the MTX-conjugates at nontoxic levels of the polymers during continuous, but not pulse, exposures. During continuous exposure the conjugates were only 10-fold less toxic than unconjugated MTX. Toxicities of the MTX-conjugates for the K562 line under continuous exposure conditions were reversed by the simultaneous presence of leucovorin or the lysosomotropic agent leupeptin and thus appeared to be a true antifolate effect which required uptake and lysosomal degradation. This human cell line is thus a suitable system in which to study the effects of antifolates which can be coupled to basic polymers.
Leukemia 1990 Jan
PMID:A human leukemia cell culture system for testing new antifols: differential sensitivity of lymphoid and nonlymphoid cell lines to unconjugated and methotrexate-conjugated polymers of basic amino acids. 229 1

The properties of a series of methotrexate analogs containing 2,omega-diaminoalkanoic acids have been investigated. The compounds were potent inhibitors of dihydrofolate reductase but, unlike methotrexate, they were also inhibitors of mammalian folylpolyglutamate synthetases. The potency of synthetase and reductase inhibition increased with increasing length of the 2,omega-diaminoalkanoate moiety. The most cytotoxic compound and the most potent inhibitor of both dihydrofolate reductase (I50 = 2.5 to 4 nM) and folylpolyglutamate synthetase (Ki ca. 4 microM) contained 2,5-diaminopentanoic acid (ornithine). These compounds were 70- to 100-fold less cytotoxic than methotrexate to human leukemia cell lines; however, they retained their potency against sublines resistant to methotrexate via defective transport. Their dual loci of enzyme inhibition and their efficacy against methotrexate transport-defective cell lines indicate that these compounds may be an important new class of antifol.
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PMID:Folylpolyglutamate synthetase inhibition and cytotoxic effects of methotrexate analogs containing 2,omega-diaminoalkanoic acids. 242 84

It has previously been demonstrated that decarboxylation of ornithine in tumors, and the oxidative splitting of N1-acetylspermidine in tumor and normal tissues, are important sources of putrescine. Both these sources are utilised by tumors and other tissues with a high demand for polyamines to ensure their polyamine requirement. Consequently, combined treatment of tumor-bearing animals with an inhibitor of ornithine decarboxylase (e.g. alpha-difluoromethylornithine) and polyamine oxidase (e.g. N,N'- bis-allenylputrescine) has an antitumoral effect superior to that of either drug alone. In the present work, it was demonstrated that the alimentary tract is a third important source of polyamines which maintains tumor growth. Gastrointestinal polyamines are of alimentary origin, and are also formed by aerobic and anaerobic microorganisms. They can be reduced by feeding a polyamine deficient diet together with antibiotics that are suitable for decontaminating the gastrointestinal tract. This treatment combined with the administration of the mentioned inhibitors of ornithine decarboxylase and polyamine oxidase completely prevents Lewis lung carcinoma from growing, and prolongs considerably the average life span of L1210 leukemia mice. The results of the polyamine analyses of tumors, leukemia cells and tissues are compatible with the notion that the effective blocking of the three main putrescine sources (intracellular decarboxylation of ornithine, formation of putrescine from N1-acetylspermidine, and the gastrointestinal tract) produces a very strong cytostatic effect. It is expected that the clinical efficacy of polyamine antimetabolites can be considerably improved by measures analogous to those applied in this pilot study.
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PMID:The gastrointestinal tract as polyamine source for tumor growth. 249 54

alpha-N-(3-Acyloxyacyl)-ornithine (or -serine) is the structure of lipoamino acids obtained by us previously from some gram-negative bacteria (Y. Kawai and I. Yano, Eur. J. Biochem. 136:531-538, 1983; Y. Kawai, I. Yano, and K. Kaneda, Eur. J. Biochem. 171:73-80, 1988; Y. Kawai, I. Yano, K. Kaneda, and E. Yabuuchi, Eur. J. Biochem. 175:633-641, 1988). The 3-acyloxyacylamide structure is present in both the lipoamino acids and lipid A of lipopolysaccharide (endotoxin). The efficacy of lipoamino acids (an ornithine-containing lipid and a serine-containing lipid) in activating C3H/HeSlc mouse peritoneal exudate macrophages was compared with that of bacterial lipopolysaccharide, because the two types of substances were expected to exhibit similar biological activities and physiological functions on the basis of their structural similarities. Actually, the lipoamino acids, as well as lipopolysaccharide, strongly activated the macrophages to generate the immunoregulatory substances prostaglandin E2 and interleukin-1, but their effect on the induction of L929 cell cytolytic factor (a possible tumor necrosis factor), another immunoregulatory substance, was weaker than that of lipopolysaccharide. The effect of lipoamino acids on the cytotoxicity of macrophages for EL-4 leukemia cells was very weak. However, all of these activities, as far as tested, were strongly enhanced by synergistic action with gamma interferon. Only the serine-containing lipid killed both C3H/HeSlc and C3H/HeJ macrophages to almost the same degree as endotoxin killed C3H/HeSlc macrophages. On the other hand, lethal toxicity for mice was not found with either the ornithine-containing lipid or the serine-containing lipid, even when 7 mg of compound was injected into a mouse. These studies suggest that the lipoamino acids are nontoxic characteristic immunoactivators.
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PMID:Macrophage activation by an ornithine-containing lipid or a serine-containing lipid. 249 44

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

The effects of alpha-difluoromethylornithine (DFMO), an ornithine analogue which is an ornithine decarboxylase inhibitor, on the actions of the topoisomerase II-reactive agents 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and etoposide (VP-16) were investigated in 2 murine L1210 leukemia lines and 2 human HL-60 leukemia lines. One of the human lines was resistant to the cytotoxic and DNA cleaving effects of m-AMSA (HL-60/AMSA). In all 4 lines, alpha-DFMO depleted cellular putrescine and spermidine to nondetectable levels. VP-16-induced DNA cleavage (quantified using alkaline elution) was decreased in all lines following alpha-DFMO treatment. The m-AMSA-induced DNA cleavage was decreased in one of the L1210 lines and in the HL-60 line sensitive to m-AMSA; m-AMSA-induced DNA cleavage was increased in the other L1210 line. The low frequency of m-AMSA-induced DNA cleavage produced in HL-60/AMSA was unaffected by alpha-DFMO treatment. Alterations in drug-mediated DNA effects induced by alpha-DFMO could not be uniformly explained by alpha-DFMO-induced alterations in m-AMSA or VP-16 cellular uptake, as indicated by direct measurements of cell-associated drug or results of DNA cleavage assays in nuclei isolated from alpha-DFMO-treated cells. Exogenous putrescine prevented the effects of alpha-DFMO on drug-induced DNA cleavage, substantiating polyamine depletion as the cause of the altered frequency of DNA cleavage. Cytotoxicity assays in 2 of the lines demonstrated that drug-induced reductions in colony-forming ability paralleled drug-induced DNA cleavage. (2R,5R)-6-heptyne-2,5-diamine, a putrescine analogue which is also an ornithine decarboxylase inhibitor, was also used to deplete polyamine levels in HL-60. (2R,5R)-6-heptyne-2,5-diamine was more potent than alpha-DFMO and produced effects on m-AMSA- and VP-16-induced DNA cleavage and cytotoxicity identical to those produced by alpha-DFMO.
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PMID:Effect of polyamine depletion by alpha-difluoromethylornithine or (2R,5R)-6-heptyne-2,5-diamine on drug-induced topoisomerase II-mediated DNA cleavage and cytotoxicity in human and murine leukemia cells. 282 33


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