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)

2-Chloroethyl-N-nitrosoureas are highly active anti-neoplastic drugs in clinical use for many years. Therapy with these DNA cross-linking agents is limited by their toxic side effects, cumulative and delayed bone marrow toxicity being the main dose-limiting one. Since the intrinsic anti-tumour activity of the nitrosourea group is very high, coupling to appropriate carrier molecules represents a challenge for target-orientated chemotherapy. Many human tumours contain receptors for steroid hormones. Therefore, 2-chloroethyl-N-nitroso-carbamoyl(CNC)-amino acid derivatives have been developed that are linked to steroid hormones. In the series of oestradiol (E2)-linked analogues CNC-L-alanine-E2-17-ester was significantly superior to other E2-linked congeners and to the unlinked equimolar mixture when tested against hormone-dependent N-methyl-N-nitrosourea-induced mammary carcinoma of the rat. Relevance of E2 receptor contents for therapy with E2-linked drugs is evidenced by loss of superiority of this analogue in hormone-independent mammary carcinomas. Some androgen-linked CNC-amino acids showed substantial affinity to the androgen receptor and in part also to the progesterone receptor. A preliminary study in rat leukaemia L5222 revealed the CNC-L-alanine-dihydrotestosterone-17-ester to be highly active. Studies with hormone-dependent tumour models are under way.
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PMID:Development of more selective anti-cancer nitrosoureas. 336 4

Two tyrosine protein kinase activities have been identified previously to be present in HL-60 leukemia cells during induction of granulocytic and monocytic differentiation with a variety of differentiating agents. We have copurified a membrane-associated tyrosine kinase (p93) and an activity associated with both the cytosol and membrane fractions (p60). Triton X-100 extracts from HL-60 cells treated with dimethyl sulfoxide were subjected to tyrosine-agarose chromatography, polypropyl aspartamide high performance liquid chromatography (HPLC), and HPLC using an antiphosphotyrosine IgG-derivatized column. Overall purification was 2700-fold for p93 and 1800-fold for p60. p60 and p93 are phosphorylated exclusively on tyrosine residues and can use poly(Glu,Tyr)4:1, histone H1 and vasoactive intestinal peptide as substrates. Poly(Glu,Tyr)1:1 and poly(Glu,Ala,Tyr)6:3:1 were less effective substrates for p60 and p93. The activity of p93 was dependent on Mg2+ or Mn2+, whereas p60 was dependent on Mg2+; however, the activity of p60 was stimulated in a synergistic manner by the presence of both Mg2+ and Mn2+, whereas the activity of p93 was not enhanced further by the combination of divalent ions. Both p60 and p93 were immunoprecipitated by an anti-v-src monoclonal antibody but only p93 was immunoprecipitated by an anti-v-fps/fes antibody. V8 protease digestion of p60 revealed one major proteolytic fragment containing phosphotyrosine, whereas V8 protease digestion of p93 produced two major peptides that were phosphorylated on tyrosine residues. These results suggest that, although p93 and p60 may possess some epitopic similarities, they have distinguishing phosphorylation sites. Moreover, p93, in contrast to p60, appears to be strictly associated with granulocytic/monocytic differentiation and related to the cellular fps/fes protooncogene.
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PMID:Purification and characterization of p93fes- and p60src-related tyrosine protein kinase activities in differentiated HL-60 leukemia cells. 348 Feb 86

It was previously reported that the gag proteins of mammalian type C retroviruses are modified by the addition of myristate to the N-terminal glycine residue. We have performed oligonucleotide-directed mutagenesis to change this glycine codon in the Moloney murine leukemia virus genome to an alanine codon and also to specifically delete the glycine codon. Upon transfection into mammalian cells, these mutant genomes direct the synthesis of gag proteins, but these proteins are not myristylated. The mutants do not form virus particles or any recognizable virus-specific structures visible in thin sections with the electron microscope. Further, the mutant gag proteins appear to remain in the cytosol, whereas the wild type is found principally in particulate fractions of the cell. The results are consistent with the theory that myristate is required for the association of the gag protein with the plasma membrane and that this association is necessary for virus assembly.
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PMID:Myristylation site in Pr65gag is essential for virus particle formation by Moloney murine leukemia virus. 348 36

Murine L1210 leukemia cells resistant to the antineoplastic agent L-phenylalanine mustard have a 1.5-2.0-fold elevation in their cellular GSH and GSSG content as compared to drug-sensitive cells. Cellular uptake of L-[U-14C]cystine and its incorporation into GSH of the resistant tumor are correspondingly elevated. Synthesis of gamma-glutamylcysteine, GSH, and GSSG is elevated 1.5-2.0-fold in cell-free preparations of the resistant tumor. This increased synthesis of GSH is attributed to increased cellular content (1.6-fold) of gamma-glutamylcysteine synthetase. GSH synthetase activity is equivalent in both drug-sensitive and -resistant cells. Investigation into the hydrolysis of selected peptides by cell-free preparations of both sensitive and resistant tumors suggest that aminopeptidase M participates in the formation of L-cysteine from L-Cys-Gly. This is supported by the observation that these preparations readily degrade L-Leu-p-nitroanilide and L-Ala-L-Ala-L-Ala, known substrates for aminopeptidase M, but not dipeptidase. The failure of the tumors to degrade Gly-D-Ala, a dipeptidase substrate, and the marked inhibition of L-Ala-Gly, L-Cys-Gly, and L-Ala-L-Ala-L-Ala hydrolysis by Bestatin further support a role for aminopeptidase M in the generation of L-cysteine from L-Cys-Gly. These results suggest that the drug-resistant tumor cell has developed an efficient mechanism for maintenance of elevated GSH which involves both gamma-glutamyl transpeptidase-initiated catabolism of GSH to cysteine and its reutilization by gamma-glutamylcysteine synthetase.
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PMID:Elevation of glutathione in phenylalanine mustard-resistant murine L1210 leukemia cells. 366 23

The feline leukemia virus (FeLV) frequently causes death by predisposing the host to acute infections by other pathogens rather than by inducing leukemia. In a previous study, cats infected with FeLV were found to have prolonged homograft rejection responses but there was no evidence that the humoral immune response was impaired. In the present study, the humoral response to the synthetic multichain polypeptide (L-tyrosine-L-glutamic acid)-poly-DL-alanine-poly-L-lysine, denoted (T.G)AL, was found to be significantly depressed in healthy cats that were naturally infected with FeLV compared to uninfected controls. In cats with persistent FeLV viremia the major antibody response to (T.G)AL, normally seen at days 9 to 14 after immunization, was both delayed and greatly reduced.
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PMID:Suppression of the humoral antibody response in natural retrovirus infections. 630 37

Aliphatic amino acids glycine, alanine, valine, and leucine were conjugated to the antitumor drug N2-methyl-9-hydroxyellipticinium (NMHE) through a peroxidase-catalyzed oxidation reaction. NMR studies of the adducts so obtained have indicated (i) that the amino acids were linked to NMHE between the nitrogen of their primary amine and the C-10 position of the ellipticine ring and (ii) that a double bond was present between the nitrogen and the alpha-carbon of the amino acid moiety. All amino acid-NMHE adducts exhibit a higher lipophilic property than the parent compound (NMHE) directly correlated with the length of the aliphatic chain of the amino acids. The adducts interact with DNA through an intercalating process with apparent binding constant ranging from 2 X 10(5) to 5 X 10(5) M-1 at pH 7.40. The presence of the amino acid moiety linked to NMHE results (i) in a slight decrease of the cytotoxicity on L1210 cells in vitro (ID50 ranged from 0.20 to 0.50 microM) as compared to NMHE (ID50 = 0.05 microM), (ii) in a decrease of the antitumor efficiency in vivo against L1210 leukemia for leucine-NMHE and valine-NMHE (ILS at LD0/2 = 35% and 31%, respectively), (iii) in a suppression of the antitumor activity for alanine-NMHE and glycine-NMHE (ILS less than 25%), (iv) in a strong increase in the bacteriostatic activity on the quaternary ammonium sensitive Escherichia coli BL101 strain and on Salmonella typhimurium TA98 strain. The bacteriostatic effect is directly correlated with the lipophilic property of the drugs. These findings are discussed in terms of a structure-activity relationship.
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PMID:Potential antitumor agents: synthesis and biological properties of aliphatic amino acid 9-hydroxyellipticinium derivatives. 647 Oct 70

L-Alanosine [3-(hydroxynitrosoamino)-L-alanine] is an antitumor antibiotic that at the present is undergoing phase II clinical trials. Its mode of action as well as its metabolism has been extensively studied, and the metabolite N-[(5-amino-1-beta-D-ribofuranosyl-1H-imidazol-4-yl)carbonyl]-3- (hydroxynitrosoamino)-L-alanine ribonucleotide (L-alanosine AICOR) proved to be an extremely potent inhibitor of de novo purine biosynthesis and is thus primarily responsible for the antitumor activity of the drug. The synthesis of the corresponding ribonucleoside, i.e., N-[(5-amino-1-beta-D-ribofuranosyl-1H-imidazol-4-yl)carbonyl]-3- (hydroxynitrosamino)-L-alanine ribonucleoside (L-alanosine AICO ribonucleoside), was accomplished by condensation of a suitably protected derivative of L-alanosine with N-succinimidyl-5-amino-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-1H-im idazole-4-carboxylate followed by the removal of the protective groups. The biological activity of L-alanosine AICO ribonucleoside was tested in vitro on whole tumor cells and on the isolated enzyme adenylosuccinate synthetase and in vivo on murine experimental leukemia. The compound was found to be inactive in these tests.
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PMID:Synthesis and in vitro biological evaluation of N-[(5-amino-1-beta-D-ribofuranosyl-1H-imidazol-4-yl)carbonyl]-3- (hydroxynitrosamino)-L-alanine (L-alanosine AICO ribonucleoside). 659 59

First investigations on the therapeutic activity of a new group of steroid-linked N-(2-chloroethyl)-N-nitrosocarbamoyl-L-alanine esters (CNC-L-alanine esters) in a nitrosourea-sensitive rat leukemia (L 5222) characterized by a relatively high content of glucocorticoid binding sites are presented. Despite a considerable range of optimal and toxic doses of the different analogs, the respective therapeutic ratios do not appear to be significantly influenced by the nature of the carrier molecules to which CNC-L-alanine is attached. However several steroid-linked representatives are distinctly more active than CNC-L-alanine. The androsterone-3-ester and the dihydrotestosterone-17-ester, in particular effected high percentages of cures in contrast to CNC-L-alanine.
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PMID:Cytostatic activity of steroid linked nitrosoureas. 674 9

The region of chromosome 2 between H-13 and H-3 has been shown to contain loci coding for a variety of other alloantigens, including Ly-4 and the locus coding for beta 2-microglobulin. Herein we show that Ly-6 and Ly-11 are coded for by genes in a segment of chromosome 2 adjacent to the H-3-H-13 region and that this segment of chromosome also contains the tightly linked loci coding for antigens Ala-1, DAG, H9/25, H-30, Ly-8, and ThB. In addition, at least one locus (and probably more) affecting susceptibility to leukemia induction is found within this gene cluster.
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PMID:Evidence for a major cluster of lymphocyte differentiation antigens on murine chromosome 2. 696 23

The covalent attachment of poly-DL-alanine peptides to lysyl residues on the surface of Erwinia carotovora L-asparaginase has produced a modified enzyme which is much less immunogenic in mice and demonstrates 100-fold longer plasma half-life in the rhesus monkey. Immunogenic responses towards both the immunoglobulin G (IgG) and immunoglobulin E (IgE) antibody subclasses were evaluated in C57BL x DBA/2 F1 mice exposed to 250 rads of whole-body irradiation 4 hr prior to immunization with 5-diazo-4-oxynorvaline-inactivated native and modified L-asparaginase in complete Freund's adjuvant. Under these immunologically stressful conditions, the native enzyme evoked an IgE and IgG response which could be further amplified by a secondary immunization, whereas the modified enzyme evoked no IgE or IgG response even after a tertiary immunization. In experiments mimicking an intensive therapeutic schedule, whereby two groups of mice were given weekly injections of 5 to 10 units of either native or modified asparaginase for up to 14 weeks, neither enzyme form evoked a significant IgE response, and only the mice given injections of the native enzyme produced an IgG response. In a preliminary patient study, skin testing of a child who had shown an allergic reaction to the native enzyme resulted in a negative response after an intradermal injection of the modified enzyme, whereas a wheal and flare reaction was observed to both the native enzyme and a histamine control. All of these results suggest that the modified enzyme should show a definite reduction in immunological reactions associated with L-asparaginase treatment of childhood leukemia.
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PMID:Immunological and pharmacological characterization of poly-DL-alanyl-modified Erwinia carotovora L-asparaginase. 710 4


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