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)

The synthesis and biological evaluation of N-[4-[[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]- benzoyl]-L-glutamic acid (1) (5-DACTHF, 543U76), an acyclic analogue of 5,6,7,8-tetrahydrofolic acid (THFA), are described. The key intermediate, hemiaminal 8, was prepared in four stages from 3-chloropropionaldehyde diethyl acetal. Reaction of 8 with dimethyl N-(4-aminobenzoyl)-L-glutamate gave the 2,4-bis(acetylamino) derivative 11, which was hydrolyzed with 1 N sodium hydroxide to give 1; the glycine analogue 16 was prepared in a similar manner. The N-methyl analogue 2 and N-formyl analogue 3 were prepared from 11 and 1, respectively. Compounds 1-3 inhibited growth of Detroit 98 and L cells in cell culture, with IC50s ranging from 2 to 0.018 microM. Cell culture toxicity reversal studies and enzyme inhibition tests showed that 1 was cytotoxic but not by the mechanism of the dihydrofolate reductase inhibitor aminopterin. Compound 1 and its polyglutamylated homologues inhibited glycinamide ribonucleotide transformylase (GAR-TFase) and aminoimidazole ribonucleotide transformylase (AICAR-TFase), the folate-dependent enzymes in de novo purine biosynthesis; and 1 was an effective substrate for mammalian folyl-polyglutamate synthetase. The compound inhibited (IC50 = 20 nM) the conversion of [14C]formate to [14C]-formylglycinamide ribonucleotide by MOLT-4 cells in culture. These data suggest that the site of action of 1 is inhibition of purine de novo biosynthesis. Moderate activity was observed against P388 leukemia in vivo.
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PMID:Synthesis and biological activity of an acyclic analogue of 5,6,7,8-tetrahydrofolic acid, N-[4-[[3-(2,4-diamino-1,6-dihydro-6-oxo-5- pyrimidinyl)propyl]amino]-benzoyl]-L-glutamic acid. 229 24

A glutamine analogue, L-glutamic acid gamma-monohydroxamate (GAH) demonstrated complete cytotoxicity against L1210 cells in culture and marked anti-tumoral activity in vivo against L1210 leukemia and B16 melanoma. In vitro, GAH caused concentration-dependent inhibition of L1210 cell growth, with complete cell death being reached at 72 hr and at a 500 microM concentration. A minimal incubation time of 38 hr with 500 microM GAH was necessary to obtain complete cell death at 72 hr. During incubation, GAH is metabolized to hydroxylamine. Hydroxylamine acts as the active form of GAH, since the concentration-dependent inhibition of cell growth caused by hydroxylamine is the same as that observed with GAH. The cytotoxic effects of GAH and hydroxylamine on L1210 cells were not reversed or prevented by L-glutamine or L-glutamic acid and purine nucleosides but were prevented or reversed by pyruvate, 2-oxaloacetate and 2-oxoglutarate. In vivo, GAH considerably increased survival of mice bearing L1210 leukemia or a solid tumor, the B16 melanoma. Antitumor activity of GAH against L1210 leukemia and B16 melanoma was schedule-dependent. The administration of GAH 3 times daily was more effective than a twice daily treatment and the maximum ILS was observed using split-dose schedules on days 1 through 3 and 7 through 9 without noticeable toxicity. Under these conditions hydroxylamine is highly toxic, suggesting that in vivo GAH might act as an hydroxylamine releaser in the tumor cells and is not significantly metabolized in the body.
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PMID:In vitro and in vivo anti-tumor activity of L-glutamic acid gamma-monohydroxamate against L1210 leukemia and B16 melanoma. 232 50

We performed analyses of electrolytes, amino acids, albumin, alpha 2-macroglobulin, gamma-globulin and LDH in the lumbar cerebrospinal fluid of children undergoing treatment for acute lymphoblastic leukemia, non-Hodgkin-lymphoma or acute myeloid leukemia. At the time of diagnosis signs of a disturbance of the blood-brain barrier were found in some patients. During induction treatment with L-asparaginase a rise of glutamic acid and a decrease of glutamine occurred. This finding correlated with slowing of the EEG. Treatment with vincristine was associated with a slight drop of sodium and chloride concentration in serum, but not in the cerebrospinal fluid. Central nervous system prophylaxis with cranial irradiation, and to a lesser degree with intravenous medium-dose methotrexate, gave rise to a further deterioration of the blood-brain barrier function as indicated by an increase in albumin, alpha 2-macroglobulin and LDH levels. During radiotherapy the concentration of several amino acids rose, probably due to a disturbance of active carrier mechanisms. Patients with elevated albumin at the end of radiotherapy more often suffered an early leukemia relapse while still on treatment. No other clinical or electroencephalographic correlations of altered barrier function could be found.
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PMID:Electrolytes, amino acids and proteins in lumbar CSF during the treatment of acute leukemia in childhood. 233 48

The octapeptide E-E-K-E-Y-H-A-E, corresponding to the amino acid sequence 841-845 of EGF receptor, whose tyrosine-845 is homologous to the main phosphorylation site of pp60v-src, has been synthesized together with seven shorter peptides encompassing variable segments around the tyrosine residue. The peptides have been employed as model substrates for inspecting the local structural determinants of three tyrosine protein kinases (TPKs), namely; TPK-IIB and TPK-III, isolated from lymphoid cells (Eur. J. Biochem. 172, 451-457 (1988] and the TPK encoded by the oncogene of Abelson murine leukemia virus. The phosphorylation order with the different peptide substrates is variable depending on the TPK used: in particular, the lysine residue at position -2 relative to tyrosine proved especially harmful with TPK-IIB, the peptides K-E-Y-H and K-E-Y-H-A-E being very poor substrates compared with their shorter derivatives devoid of the N-terminal lysine (E-Y-H and E-Y-H-A-E, respectively). Conversely, such a basic residue is well tolerated by the other two TPKs. The negative effect of the N-terminal lysine on TPK-IIB-catalyzed phosphorylation is accounted for by an increase of Km and can be overcome by the presence of additional glutamic acid(s) on that side. On the other hand, the C-terminal acidic doublet Ala-Glu specifically impairs the phosphorylation efficiency of abl-TPK, by lowering the Vmax value, the heptapeptide E-K-E-Y-H-A-E being much less readily phosphorylated than E-K-E-Y-H. Collectively, these results would indicate that the site specificity of tyrosine protein kinases results from the balance of positive and negative determinants whose influence on the catalytic activity of the individual enzymes can differ greatly.
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PMID:Synthetic peptides reproducing the EGF-receptor segment homologous to the pp60v-src phosphoacceptor site. Phosphorylation by tyrosine protein kinases. 250 Sep 78

The envelope glycoproteins of the human immunodeficiency virus (HIV) type 1 are synthesized as a precursor molecule, gp160, which is cleaved to generate the two mature envelope glycoproteins, gp120 and gp41. The cleavage reaction, which is mediated by a host protease, occurs at a sequence highly conserved in retroviral envelope glycoprotein precursors. We have investigated the sequence requirements for this cleavage reaction by introducing four single-amino-acid changes into the glutamic acid-lysine-arginine sequence immediately amino terminal to the site of cleavage. We have also examined the effects of these mutations on the syncytium formation induced by HIV envelope glycoproteins. Our results indicate that a glutamic acid to glycine change at gp120 amino acid 516, a lysine to isoleucine change at amino acid 517, and an arginine to lysine change at amino acid 518 affect neither gp160 cleavage nor syncytium formation. The results obtained with the arginine to lysine change at amino acid 518 differ significantly from the results obtained with the same mutation at the envelope precursor cleavage site of a murine leukemia virus (E. O. Freed, and R. Risser, J. Virol. 61:2852-2856, 1987). An arginine to threonine mutation at gp120 amino acid 518, the terminal residue of gp120, abolishes both gp160 cleavage and syncytium formation. These findings demonstrate that despite its highly conserved nature, the basic pair of amino acids at the site of gp160 cleavage is not absolutely required for proper envelope glycoprotein processing. This report also supports the idea that cleavage of gp160 is required for activation of the HIV envelope fusion function.
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PMID:Mutational analysis of the cleavage sequence of the human immunodeficiency virus type 1 envelope glycoprotein precursor gp160. 267

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 microtubule inhibitors on cellular accumulation of 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidine-beta-D-glu copyranoside) (VP-16) and subsequent epipodophyllotoxin-induced DNA single-strand breaks were investigated in human leukemia K562 cells. At concentrations of 0.05-20 microM, vinblastine, vincristine, and maytansine similarly increased the steady-state cell concentration of VP-16 (2.5 microM) up to 2-fold. Following removal of extracellular vinblastine, the elevation of cell VP-16 was maintained through an additional 55-min incubation period. Washing cells free of extracellular VP-16 resulted in a nonexchangeable (or bound) component comprising 15-17% of the VP-16 concentration found before removal of extracellular drug. In cells incubated with VP-16 alone, removal of extracellular drug resulted in less than 5% cell retention of drug. At vinblastine concentrations of 0.05-0.2 microM, the increase in cell VP-16 was due to a progressive increase in nonexchangeable VP-16. At greater vinblastine concentrations, up to 10 microM, there was no further increase in nonexchangeable VP-16 but there was a 1.6-fold increase in the exchangeable (or free) concentration of VP-16. Similar elevation of both nonexchangeable and exchangeable VP-16 by 10 microM vincristine and maytansine was observed; however, 50-100 microM podophyllotoxin or taxol was required for comparable elevation of exchangeable drug with no increase of nonexchangeable VP-16. Elevation of exchangeable VP-16 in the presence of vinblastine was due to inhibition of the unidirectional efflux of this epipodophyllotoxin with a 69% decline in the rate constant for efflux. There were no effects of vinblastine on VP-16 influx. There was no enhancement of DNA single-strand break frequency when cells were incubated with 2.5 microM VP-16 and 0.2 microM vinblastine, a concentration of the Vinca alkaloid that increased only nonexchangeable VP-16. VP-16-induced DNA damage was enhanced by vinblastine concentrations above 0.5 microM, concentrations that elevated exchangeable VP-16, with a maximum doubling of radiation equivalent single-strand break frequency observed with 20 microM vinblastine, consistent with the maximum elevation of cell VP-16 with 20 microM Vinca alkaloid. These results indicate that vinblastine and other microtubule inhibitors elevate cell VP-16 by inhibition of the efflux of exchangeable drug and by increasing the level of nonexchangeable drug. Potentiation of VP-16-induced DNA damage is observed only at microtubule inhibitor concentrations which elevate exchangeable VP-16.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of microtubule inhibitors on etoposide accumulation and DNA damage in human K562 cells in vitro. 287 22

cDNA clones, whose fusion proteins were recognised by an anti-(T3 gamma chain) serum, were isolated from a lambda gt11 expression library prepared from the human T leukaemia cell line J6. The clones encoded a unique sequence related to that of the T3 delta chain, and hybridised to two mRNA transcripts of 0.8 and 3.5 kb in size, whose expression was restricted to T lymphocytes. The 182 amino acid sequence deduced from the cDNA revealed a typical signal peptide, a predominantly hydrophilic 89 amino residue domain with two N-glycosylation sites, a hydrophobic domain with a centrally located glutamic acid residue and a 44-residue domain with at least one potential serine phosphorylation site for protein kinase C. Given this arrangement the T3 gamma polypeptide most probably has a transmembrane orientation with the N-terminal domain exposed on the cell surface. The amino acid and nucleotide sequences showed marked homology with those of the T3 delta chain, suggesting that the respective genes arose by duplication about 200 million years ago. The intracellular and membrane-proximal half of the extracellular domains were especially well conserved.
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PMID:Primary structure of the T3 gamma subunit of the T3/T cell antigen receptor complex deduced from cDNA sequences: evolution of the T3 gamma and delta subunits. 294 45

N-(all-trans-Retinoyl)amino acids were synthesized via all-trans-retinoyl chloride and an ester of the amino acid. The retinoyl derivatives of leucine, phenylalanine, alanine, tyrosine, and glutamic acid were prepared. The 13-cis-retinoyl derivatives of leucine, phenylalanine, alanine, and glycine were prepared similarly from 13-cis-retinoic acid. In assays of the retinoylamino acids for reversal of squamous metaplasia in hamster trachea organ cultures, these compounds were less active than retinoic acid, but the leucine, alanine, and phenylalanine derivatives were similar in activity to several retinamides that suppress bladder carcinogenesis in vivo. Two of the retinoylamino acids, as well as two simple retinamides, were shown to be moderately cytotoxic to murine leukemia and human epidermoid carcinoma cells in culture.
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PMID:N-(Retinoyl)amino acids. Synthesis and chemopreventive activity in vitro. 333 18

Five heretofore undescribed analogues of methotrexate (MTX) and aminopterin (AMT) were synthesized and tested as dihydrofolate reductase (DHFR) inhibitors and tumor cell growth inhibitors. The meta isomer of AMT was obtained from 2,4-diamino-6-(bromomethyl)pteridine and m-(aminobenzoyl)-L-glutamic acid, while the ortho isomer was obtained via the same route by using alpha-methyl gamma-tert-butyl o-(aminobenzoyl)-L-glutamate instead of the free acid. Analogues of MTX and AMT containing a double bond in the side chain were prepared from dimethyl D,L-2-amino-4-hexenedioate and 4-amino-4-deoxy-N10-methylpteroic acid and 4-amino-4-deoxy-N10-formylpteroic acid, respectively. Finally, a positional isomer of MTX with the CH2CH2COOH moiety moved from the alpha-carbon to the adjacent carboxamide nitrogen was synthesized from 3-[N-(carboxymethyl)amino]propanoic acid diethyl ester and 4-amino-4-deoxy-N10-methylpteroic acid. The positional isomers of AMT were weak DHFR inhibitors and showed very little growth-inhibitory activity against L1210 murine leukemia cells or the MTX-resistant L1210/R81 mutant line in culture. The MTX and AMT analogues with the CH2CH2COOH moiety replaced by a CH2CH = CHCOOH side chain showed anti-DHFR activity similar to that of the previously described saturated compound N-(4-amino-4-deoxy-N10-methylpteroyl)-L-2-aminoadipic acid, but were less potent than the parent drugs. The MTX analogue with the CH2CH2COOH side chain displaced from C to N was weakly bound to DHFR, confirming the importance of an intact CONH moiety, and showed greatly diminished cell growth inhibitory potency relative to MTX. None of the compounds was a substrate for folylpolyglutamate synthetase (FPGS) from mouse liver. Furthermore, inhibition of folic acid polyglutamylation in vitro at equimolar 500 microM concentrations of drug and substrate was negligible. The structural changes embodied in these five novel compounds are therefore too great for binding to the FPGS active site.
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PMID:Methotrexate analogues. 31. Meta and ortho isomers of aminopterin, compounds with a double bond in the side chain, and a novel analogue modified at the alpha-carbon: chemical and in vitro biological studies. 335 53


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