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)

Longitudinal studies for the detection of circulating immune complexes (CIC-s) were performed in leukaemic patients using three methods in parallel. Results of these studies indicated that immune complexes in leukaemia are heterogeneous and their composition changes in the course of the disease. These results were supported by the changes in the concentration of a complement component (C1) and in the IgG subclasses in the immune complex-enriched fraction prepared by polyethylene glycol precipitation from different serum samples of individual patients with leukaemia. CIC-s from leukaemic patients are normally engulfed by granulocytes of healthy donors. The phagocytic capacity of leukaemic blast cells is hampered. The phagocytic activity through Fc and C3 receptors of peripheral mononuclear cells of leukaemic patients did not run parallel. On the basis of these studies it may be surmised that the total phagocytic capacity of the leukaemic patients cannot keep pace with the increased rate of immune complex formation.
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PMID:Studies on the composition and elimination of circulating immune complexes in leukaemia. 725 Aug 13

Rat peritoneal mast cells and 6-thioguanine-resistant rat basophilic leukemia cells, representative of connective tissue-type (CTMC) and mucosal (MMC) mast cells, respectively, were fused using polyethylene glycol. Four out of 14 primary hybrid mast cell lines contained more than 50% of CTMC as demonstrated by histochemical staining. Two cell lines, one predominantly of the CTMC and the other of the MMC phenotype, were selected for further study. Among these, the phenotype was also confirmed by analysis for rat mast cell protease I and by mediator release triggered by compound 48/80 and ionophore A23187. The CTMC phenotype disappeared after culturing cells for 2 weeks. The change in phenotype did not significantly alter the mediator release due to calcium ionophore A23187. Repeated cloning of cells bearing the CTMC phenotype did not yield a cloned line of cells expressing the CTMC phenotype only, although it prolonged the persistence of this phenotype. During the period of CTMC phenotype loss, a drop in cellular DNA content occurred, suggesting that chromosome instability may, at least partially, have been responsible for the phenotypic changes.
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PMID:Phenotypic changes among hybrid rat mast cells. 758 Feb 87

The PU.1 transcription factor is a member of the ets gene family of regulatory proteins. These molecules play a role in normal development and also have been implicated in malignant processes such as the development of erythroid leukemia. The Ets proteins share a conserved DNA-binding domain (the ETS domain) that recognizes a purine-rich sequence with the core sequence: 5'-C/AGGAA/T-3'. This domain binds to DNA as a monomer, unlike many other DNA-binding proteins. The ETS domain of the PU.1 transcription factor has been crystallized in complex with a 16-base pair oligonucleotide that contains the recognition sequence. The crystals formed in the space group C2 with a = 89.1, b = 101.9, c = 55.6 A, and beta = 111.2 degrees and diffract to at least 2.3 A. There are two complexes in the asymmetric unit. Production of large usable crystals was dependent on the length of both protein and DNA components, the use of oligonucleotides with unpaired A and T bases at the termini, and the presence of polyethylene glycol and zinc acetate in the crystallization solutions. This is the first ETS domain to be crystallized, and the strategy used to crystallize this complex may be useful for other members of the ets family.
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PMID:Co-crystallization of an ETS domain (PU.1) in complex with DNA. Engineering the length of both protein and oligonucleotide. 759 33

Twenty-five patients with acute lymphoblastic leukaemia (ALL) aged 10 months to 43 years and twenty-five age and sex matched healthy control subjects were investigated in this study. Serum immunoglobulins A, G and M levels were measured by single radial immunodiffusion method and immune complex levels estimated by polyethylene glycol precipitation technique. Significant increase in immune complexes and decrease in immunoglobulin G were observed in the patients. Although not statistically significant, the patients had a lower mean level of immunoglobulin A, and a higher mean immunoglobulin M concentration than the controls. Hypoimmunoglubulinaemia observed in this study may contribute to the aetiology of ALL or be an effect of the disease. Raised immune complexes could result from specific antibodies combining with tumour associated or microbial antigens. Immunoglobulin G levels showed a significant positive correlation with survival in the patients. The adverse effect of reduced immunoglobulin G on the prognosis of ALL is probably due to compromised immunity in the patients.
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PMID:Immunoglobulin and immune complex levels in Nigerians with acute lymphoblastic leukaemia. 762 7

Whole-cell patch-clamp recordings of membrane currents were performed in combination with measurements of mediator secretion from mucosal-type mast cells (rat basophilic leukemia cells, subline 2H3), to determine the involvement of membrane conductances induced upon depletion of intracellular Ca2+ stores. In patch-clamp experiments, ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid-induced depletion of internal Ca2+ stores led to activation of two distinct membrane conductances, a Ca2+ current and a Cl- current. The Ca2+ current was blocked by 100 microM La3+, which did not affect the Cl- current. In contrast, 500 microM 4,4'-diisothiocyanato-2,2'-disulfonic acid produced selective blocked of the Cl- current. Remarkably, the Cl- channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), niflumic acid, and N-phenylanthranilic acid (NPAA) inhibited not only the Cl- current but also the Ca2+ current. IC50 values for the blockade of the Ca2+ inward current by NPPB, niflumic acid, and NPAA were determined to be 23, 150, and 190 microM, respectively. In secretion experiments, thapsigargin-induced depletion of internal Ca2+ stores stimulated serotonin release, which was found to be strictly dependent on extracellular Ca2+. In the presence of 100 microM La3+ secretion was almost completely inhibited. In contrast, only 50% of secretion was suppressed by 500 microM 4,4'-diisothiocyanato-2,2'-disulfonic acid, which fully blocked the Cl- current without affecting Ca2+ influx, as monitored by electrophysiological experiments. The other Cl- channel blockers produced a very different pattern for the inhibitory dose dependence of secretion, with IC50 values for NPPB, niflumic acid, and NPAA of 23, 60, and 180 microM, respectively. Taken together, these findings suggest that Ca2+ store depletion leads to concomitant activation of Cl- and Ca2+ currents. Blockade of the latter is apparently an additional mode of action for diarylaminocarboxylate-type Cl- channel blockers inhibiting mast cell secretory responses.
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PMID:Blockade of capacitive Ca2+ influx by Cl- channel blockers inhibits secretion from rat mucosal-type mast cells. 774 67

The effect of the topoisomerase II inhibitor doxorubicin and its non-cross-resistant analogue annamycin on DNA degradation and programmed cell death was examined in murine leukemia P388 cells. P388 parental cells exposed to various concentrations of doxorubicin and annamycin for 24 h displayed dose-dependent DNA cleavage: at 1 microM, both doxorubicin and annamycin were effective in inducing DNA breakdown, but at 10 microM, the effect was markedly decreased or totally absent. In multidrug-resistant P388/Dox cells, doxorubicin did not cause DNA cleavage, while 10 microM annamycin had a significant effect. By agarose gel analysis, drug-induced DNA fragmentation showed the characteristic pattern of internucleosomal ladder. Morphologically, P388 cells treated with 1 microM doxorubicin or annamycin for 24 h showed a reduction in cell volume and condensation of nuclear structures. Similar changes were observed in P388/Dox cells exposed to 10 microM annamycin for 24 h but not in cells exposed to 10 microM doxorubicin. Time course studies demonstrated that DNA fragmentation was detected 12 h after incubation with 1 microM doxorubicin or annamycin, while loss of membrane integrity appeared at 24 h, thus indicating that DNA degradation was a preceding event. DNA fragmentation caused by doxorubicin and annamycin was inhibited by the RNA synthesis inhibitor actinomycin D, the protein synthesis inhibitor cycloheximide, and the endonuclease inhibitor aurintricarboxylic acid. Drug-induced cell death was partially prevented by cycloheximide and aurintricarboxylic acid, thus suggesting that the apoptotic process caused by these drugs requires gene expression, synthesis of new proteins, and activation of endogenous nucleases. In contrast, DNA cleavage was not affected by incubating cells with 1 mM ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid, thus indicating that intracellular calcium depletion does not affect anthracycline-induced apoptosis. The results obtained demonstrate that the cell killing effect of anthracyclines is mediated, at least in part, by the induction of apoptosis.
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PMID:Apoptosis induced by anthracycline antibiotics in P388 parent and multidrug-resistant cells. 846 4

L-asparaginase is an enzyme which hydrolyses asparagine. Since the 1960s it has been known that some leukemic cells are deficient in asparagine synthetase and therefore cannot manufacture sufficient quantities of this essential amino acid to maintain cell viability. L-asparaginase is predominantly useful in acute lymphocytic leukemia (ALL) although responses have been noted in patients with acute myeloid leukemia, lymphoma, and rarely other tumors. L-asparaginase has been used in conjunction with methotrexate and ara-C in combination programs in leukemia. The major side-effect limiting the usefulness of L-asparaginase is allergic reactions. In addition, it is probable that neutralizing antibodies develop which shorten the half life of the drug so that the goal of depletion of plasma levels of asparagine cannot be attained or maintained. Polyethylene glycol (M.W. 5000) can be conjugated to L-asparaginase at sites not involving the active site of the enzyme. This enables free access of a small molecule, asparagine, to the active site of the enzyme but prevents uptake by the reticuloendothelial system, greatly decreasing the probability of developing antibodies against the asparaginase and prolongs the circulating half life of the drug. In a phase I/II study conducted at the M.D. Anderson Cancer Center, 37 heavily pretreated patients with refractory hematologic malignancy were treated. The age range from 15 to 73 years, median 49 years. Nineteen patients had ALL, 15 lymphoma, two myeloma, and one Hodgkin's disease. The dose levels of PEG L-asparaginase varied from 250 IU/m2 up to 8000 IU/m2. The pharmacokinetic profile demonstrated a monophasic half life consistent with a one compartment model with a single elimination phase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:L-asparaginase and PEG asparaginase--past, present, and future. 848 65

A series of 3- and 5-alkylamino derivatives, as well as other structurally modified analogues of pyridine-2-carboxaldehyde thiosemicarbazone, have been synthesized and evaluated as inhibitors of CDP reductase activity and for their cytotoxicity in vitro and antineoplastic activity in vivo against the L1210 leukemia. Alkylation of 3- and 5-amino-2-(1,3-dioxolan-2-yl)pyridines (1, 2) resulted in corresponding 3-methylamino, 5-methylamino, 3-allylamino, 5-ethylamino, 5-allylamino, 5-propylamino, and 5-butylamino derivatives (5, 6, and 11-15), which were then condensed with thiosemicarbazide to yield the respective thiosemicarbazones (7, 8, and 16-20). Oxidation of 3,5-dinitro-2-methylpyridine (21) with selenium dioxide, followed by treatment with ethylene glycol and p-toluenesulfonic acid, produced the cyclic ethylene acetal, 23. Oxidation of 2-(1,3-dioxolan-2-yl)-4-methyl-5-nitropyridine (26) with selenium dioxide, followed by sequential treatment with sodium borohydride, methanesulfonyl chloride, and morpholine afforded the morpholinomethyl derivative 30. Catalytic hydrogenation of 23 and 30 with Pd/C yielded the corresponding amino derivatives 24 and 31. Catalytic hydrogenation of 5-cyano-2-methylpyridine (33) with Raney nickel, followed by treatment with acetic anhydride, gave the amide derivative 35. N-Oxidation of 35, followed by rearrangement with acetic anhydride, produced the acetate derivative, 5-[(acetylamino)methyl]-2-(acetoxymethyl)pyridine (37). Repetition of the N-oxidation and rearrangement procedures with compound 37 yielded the diacetate derivative 39. Condensation of compounds 24, 31, and 39 with thiosemicarbazide afforded the respective 3,5-diaminopyridine-, 4-(4-morpholinylmethyl)-5-aminopyridine-, and 5-(aminomethyl)pyridine-2-carboxaldehyde thiosemicarbazones (25, 32, and 40). The most biologically active compounds synthesized were the 5-(methylamino)-, 5-(ethylamino)-, and 5-(allylamino)pyridine-2-carboxaldehyde thiosemicarbazones (8, 17, and 18), which were potent inhibitors of ribonucleotide reductase activity with corresponding IC50 values of 1.3, 1.0, and 1.4 microM and which produced significant prolongation of the survival time of L1210 leukemia-bearing mice, with corresponding optimum % T/C values of 223, 204, and 215 being obtained when administered twice daily for six consecutive days at dosages of 60, 80, and 80 mg/kg, respectively.
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PMID:Synthesis and biological activity of 3- and 5-amino derivatives of pyridine-2-carboxaldehyde thiosemicarbazone. 869 57

L-asparaginase from Escherichia coli, an antitumor enzyme, was chemically modified with a comb-shaped copolymer of poly(ethylene glycol) derivative and maleic anhydride (activated PM). The PM-modified asparaginase lost the immunoreactivity with retaining high enzymic activity and also prolonged the clearance time in blood. Intraperitoneal administration of PM-asparaginase markedly increased the mean survival-time of lymphoma L5178Y-bearing mice in comparison with that of unmodified asparaginase. Pretreatment of mice with PM-asparaginase before immunizing with unmodified asparaginase extremely suppressed the anti-asparaginase antibody production.
Leukemia 1997 Apr
PMID:Chemical modification of L-asparaginase with comb-shaped copolymer of poly(ethylene glycol) derivative and maleic anhydride. 920 7

In recent years there has been a growing interest in the therapeutic application of L-ascorbic acid (AA) and its derivatives as anticancer agents. AA is a gamma-crotonolactone derivative with reactive hydroxyl groups at the 2- and 3-positions and an ethylene glycol substitution at the 4-position. Despite the various reports on AA toxicity, no work has been reported underlying the critical chemical structural features for its activity. The present study addresses this question. We tested in vivo, using malignant leukemia cell line P388D1, (i) L-AA and its isomers, (ii) substitution at the 2-position: -PO4, -SO4, O-Me, O-octadecyl, (iii) substitution at the 6-position: -PO4, -SO4, -palmitate, -stearate, (iv) substitution at the 2,6-position: dipalmitate, (v) 6-deoxy derivative: -Cl, -Br, -NH2 and (vi) dihydroxy gamma-crotonolactone with substitutions at the 4-position: -H, -CH3, -CH2-CH3 and -CH=CH2. L-AA and its isomers were very cytotoxic even at very low concentration. All 6-substituted and 6-deoxy derivatives were as toxic as AA. However, 2-substituted and 2,6-disubstituted AA derivatives were non-toxic. Interestingly, dihydroxy gamma-crotonolactone with or without substitution at the 5-position also exhibited toxicity. These results suggest that the underlying criterion for AA toxicity resides in dihydroxy gamma-crotonolactone moiety. Either substitution in the hydroxy groups or saturating the double bond render the molecule inactive.
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PMID:Growth suppression of malignant leukemia cell line in vitro by ascorbic acid (vitamin C) and its derivatives. 946 96


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