Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In continuation of efforts to improve the antitumor selectivity of the 2,2-dimethylaziridine class of alkylating agents, a series of N-substituted bis(2,2-dimethyl-1-aziridinyl)phosphinic amides has been synthesized and evaluated. All of these compounds (3-15) were tested in vivo against leukemia P-388 in mice, where most of them caused significant increase of survival time at nontoxic dose levels. Some of the most active compounds were also tested against leukemia L1210, B16 melanoma, and colon 26 carcinoma; in the latter tests, the parent unsubstituted amide 3 appeared to show the highest antitumor activity. Since the dose-limiting toxicity of the clinically tested prototypes of this class of anticancer agents AB-132 (1) and AB-163 (2) had been found to be CNS toxicity attributable mainly to the inhibition of cholinesterase, the compounds were tested in vitro against the cholinesterases from horse serum, electric eel, and bovine erythrocytes, as well as in vivo for the inhibition of the cholinesterase present in the whole blood of mice. In all of these assays, the various members of the present series showed a wide range of anticholinesterase activities, ranging from almost zero (for 3) to even higher potency than that of the prototype 2. A similarly wide range of stability was observed toward hydrolytic ring opening of the 2,2-dimethylaziridine moieties. Several of the compounds, particularly 3, deserve further study.
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PMID:Synthesis and properties of bis(2,2-dimethylaziridinyl)phosphinic amides: a series of new antineoplastic agents. 406 95

Fifty-two cultured leukemia/lymphoma cell lines were studied for their acetylcholinesterase activity. There was a striking effect of maturity on enzyme activity, only the most mature cells showing significant activity. Mature T cells exhibited far more enzyme activity than mature B cells, paralleling results on normal T and B cells.
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PMID:Acetylcholinesterase in cultured human leukemia/lymphoma cell lines. 633 44

Two sublines of the human leukemia cell line K562 including the original cell line and three clones have been investigated for their erythroid features. All of them produce embryonic and fetal hemoglobins, glycophorin A, spectrin and true acetylcholinesterase, but to a varying extent among the cell lines. The Hb and glycophorin contents were correlated in the different K562 cell lines, whereas acetylcholinesterase was independently expressed from these two other erythroid markers. Hb accumulation is enhanced by exposure of the cells to 100 microM hemin without a significant modification of the expression of the other erythroid markers. Butyrate greatly increased the activity of acetylcholinesterase, slightly enhanced the production of hemoglobin, but did not modify the expression of glycophorin and spectrin. 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced an almost complete disappearance of glycophorin, reduced the synthesis of Hb by K562 cells and also abolished the action of hemin on Hb accumulation. Therefore, all the different K562 cell lines exhibit clear erythroid features including acetylcholinesterase. Butyrate or hemin did not induce terminal differentiation of K562 cells, whereas TPA significantly diminished the erythroid phenotype.
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PMID:Erythroid properties of K562 cells. Effect of hemin, butyrate and TPA induction. 657 18

Differentiation-dependent expression of enzyme loci was evaluated in two human leukemic cell lines, the pluripotent leukemia cell line K-562 and the promyelocytic-like cell line HL-60. Acetylcholinesterase, a marker of erythroid differentiation, was present in K-562 cells and absent in HL-60 cells. This difference between the two lines was apparently unrelated to dosage effect; other enzymes carried on trisomic chromosomes in K-562 cells did not show dosage effect. Acetylcholinesterase activity was higher in subclone K-562 (S), which shows higher expression of hemoglobin. Electrophoretic mobility of acetylcholinesterase from K-562 (S) was of fetal type.
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PMID:Expression of erythroid acetylcholinesterase in the K-562 leukemia cell line. 657 51

Reaction of 3'-acetylthymidine with phosphorus oxychloride in trimethyl phosphate yielded the phosphorodichloridate 5, which was subsequently reacted with aziridine, or 2,2-dimethylaziridine to give compounds 6 and 7, respectively. The 2,2-dimethylaziridine derivative 7 was considerably more active than 6 against leukemia L1210 and P-388 in mice but less active than the previously synthesized, simpler phosphinate derivatives 2 and 3. It appears that the thymidine moiety did not enable these compounds to use the nucleoside transport mechanism of the cells and also failed to increase the selectivity of the 2,2-dimethylaziridine analogues by interference with their binding to cholinesterase. Compound 7 strongly inhibited horse serum cholinesterase, while 6 was inactive.
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PMID:Synthesis of 5'-thymidinyl bis(1-aziridinyl)phosphinates as antineoplastic agents. 727

After 30 years of experience with human exposure to dichlorvos (DDVP) in the home, workplace, and sickroom, the U.S. EPA has published its intent to revoke the food additive registration of this cholinesterase-inhibiting insecticide. The basis for the Agency action is the result of the National Toxicology Program (NTP) toxicology and carcinogenesis study of DDVP in rats and mice (NTP Technical Report No. 342, September 1989). In those experiments the NTP considered the result in the female mouse portion of the study to afford unequivocal evidence of carcinogenicity. The NTP considered the interpretations of the male and female rat and the male mouse studies to be less than clear. Despite the NTP interpretation, the EPA considers the male rat data (increased incidence of mononuclear cell leukemia) to be sufficient to warrant the regulatory change. The purpose of this report is to summarize a review of the interpretation of the NTP data and to assess the predictive validity of the results relative to potential human health impact. Critical review of experimental data indicates that the evidence for a carcinogenic effect of DDVP in animals is equivocal. Further, DDVP possess no in vivo mutagenic activity in mammalian assay systems and it bears no significant structural similarity to known carcinogens. Therefore, a weight-of-the-evidence analysis leads to the conclusion that DDVP poses neither mutagenic nor carcinogenic risks to humans exposed under normal conditions of use of foreseeable conditions of misuse.
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PMID:Dichlorvos carcinogenicity: an assessment of the weight of experimental evidence. 772 38

When irradiated with broad-band visible light in the presence of merocyanine 540 (MC540), murine leukemia L1210 cells grown under selenium-deficient conditions (Se(-) cells) accumulated lipid hydroperoxides and lost viability more rapidly than selenium-satisfied (Se(+) cells). These findings suggest that cytoprotection against photoperoxidation and photokilling is mediated at least in part by selenoperoxidase (SePX) action. Similar protection against photoinactivation of an intrinsic membrane enzyme, the Na+,K(+)-ATPase, has been observed. Thus, irradiation of MC540-sensitized Se(-) cells resulted in an immediate and progressive inactivation of ouabain-sensitive Na+,K(+)-ATPase; by contrast, activity loss in Se(+) cells was preceded by a prominent lag. Enzyme photo-inactivation in Se(-) cells was inhibited by ebselen, an SePX mimetic, confirming that SePX(s) is (are) involved in natural protection. Desferrioxamine treatment (iron sequestration/inactivation) resulted in higher hydroperoxide levels and slower Na+,K(+)-ATPase inactivation during MC540/light exposure, whereas ferric-8-hydroxyquinoline treatment (iron supplementation) had the opposite effect. Thus, iron appears to play an important role in both of these processes. In contrast, photoinactivation of another intrinsic enzyme in L1210 cells, acetylcholinesterase (AChE), was unaffected by selenium or iron manipulation. On the basis of these findings, we propose that lipid peroxidation plays an important role in the photoinactivation of Na+,K(+)-ATPase, but not AChE. This is consistent with the fact that Na+,K(+)-ATPase's active site lies within the membrane bilayer, whereas AChE's active site lies outside the bilayer.
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PMID:Cytoprotection against merocyanine 540-sensitized photoinactivation of the Na+,K(+)-adenosine triphosphatase in leukemia cells: glutathione and selenoperoxidase involvement. 801 11

To examine the role of acetylcholinesterase (EC 3.1.1.7) in hematopoietic cell proliferation and differentiation, we administered a 15-mer phosphorothioate oligonucleotide, antisense to the corresponding ACHE gene (AS-ACHE), to primary mouse bone marrow cultures. Within 2 hr of AS-ACHE addition to the culture, ACHE mRNA levels dropped by approximately 90%, as compared with those in cells treated with the "sense" oligomer, S-ACHE. Four days after AS-ACHE treatment, ACHE mRNA increased to levels 10-fold higher than in S-ACHE cultures or in fresh bone marrow. At this later time point, differential PCR display revealed significant differences between cellular mRNA transcripts in bone marrow and those in AS-ACHE- or S-ACHE-treated cultures. These oligonucleotide-triggered effects underlay considerable alterations at the cellular level: AS-ACHE but not S-ACHE increased cell counts, reflecting enhanced proliferation. In the presence of erythropoietin it also enhanced colony counts, reflecting expansion of progenitors. AS-ACHE further suppressed apoptosis-related fragmentation of cellular DNA in the progeny cells, and it diverted hematopoiesis toward production of primitive blasts and macrophages in a dose-dependent manner promoted by erythropoietin. These findings suggest that the hematopoietic role of acetylcholinesterase, anticipated to be inverse to the observed antisense effects, is to reduce proliferation of the multipotent stem cells committed to erythropoiesis and megakaryocytopoiesis and macrophage production and to promote apoptosis in their progeny. Moreover, these findings may explain the tumorigenic association of perturbations in ACHE gene expression with leukemia.
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PMID:Antisense oligonucleotide inhibition of acetylcholinesterase gene expression induces progenitor cell expansion and suppresses hematopoietic apoptosis ex vivo. 805 33

We have recently demonstrated that azidothymidine (AZT) elevates the levels of circulating platelets in mice made immune deficient by infection with LP-BM5 murine leukemia virus (MAIDS mice). In an attempt to elucidate the mechanisms of the AZT platelet elevating effect, we examined the number of splenic and bone marrow megakaryocyte colony-forming cells (CFU-mk) and the ploidy of megakaryocytes derived from CFU-mk using fluorescence cytophotometric methods. Two other dideoxynucleosides (ddN) 2'3'-dideoxyinosine (ddl) and 2'3'-dideoxycytidine (ddC) were assessed to determine the specificity of the effect of AZT. MAIDS mice were given ddN in drinking water for 15 days. AZT was the only ddN that significantly increased circulating platelet levels in MAIDS mice. AZT significantly increased splenic CFU-mk in MAIDS mice, but bone marrow CFU-mk were not affected. ddl and ddC failed to change either platelet levels or the numbers of splenic or bone marrow CFU-mk. The ploidy of megakaryocytes derived from splenic and bone marrow CFU-mk were examined by first identifying CFU-mk by staining for acetylcholinesterase, followed by nuclear staining with propidium iodide. The fluorescence of individual cells was then measured using a Perceptics image analysis system. Modal ploidy of CFU-mk megakaryocytes derived from spleen cells of AZT-treated immunodeficient mice was shifted upwards from 16N to 32N. Similarly, AZT treatment changed the modal ploidy number of colony megakaryocytes derived from bone marrows of immunodeficient mice from 16N to 32N. The ploidy distribution was also significantly shifted. ddl and ddC failed to significantly alter either modal ploidy number or distribution of megakaryocytes derived from splenic or bone marrow CFU-mk. These findings suggest that AZT may affect physiological processes that lead to platelet formation.
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PMID:Regulation of megakaryocyte colony forming cell numbers and ploidy by dideoxynucleosides in immunodeficient mice. 823 95

The genes for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) are located within regions subject to non-random chromosomal abnormalities in the myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Acetylcholinesterase is mapped to 7q22, within the critical deleted region presumed to contain a myeloid specific tumour suppressor gene. Butyrylcholinesterase is mapped to 3q26: abnormalities at this region are associated with sub-types of MDS and AML with thrombocytopenia, or with increased platelet counts. Both ACHE and BCHE have been implicated as playing a role in megakaryopoiesis and thrombopoiesis, and these genes have been observed to be co-amplified in acute myeloid leukaemia. Recent findings suggest a more significant role for the ACHE gene in haemopoiesis by regulating multipotent stem cell proliferation, and apoptosis in cells undergoing erythroid and myeloid differentiation. This led us to investigate gene copy-number alterations at these genes in MDS and AML. Samples were screened by slot-blot hybridization, and if changes were observed, by Southern blotting. A total of 42 samples from 31 de novo AML patients, 10 samples from eight cases of post-MDS AML and 85 samples from 67 MDS patients were analysed with probes for ACHE, BCHE, c-MYC, MDR-1 and globin control. Changes in ACHE and/or BCHE were observed in 9/31 de novo AML patients, and in 7/67 MDS patients: 1/37 cases of refractory anaemia (RA), 1/10 cases of refractory anaemia with excess blasts (RAEB) and 5/20 chronic myelomonocytic leukaemia (CMML) patients. The amplification events observed generated copy numbers no greater than 10, showed normal restriction patterns and had no clear correlation with megakaryopoiesis or thrombopoiesis. Loss of signal at the ACHE locus was observed: haploid signal intensity was seen in seven samples: one RA with thrombocytopenia, three CMML, one AML-M5a (no karyotypic abnormalities of chromosome 7), one AML-M4 (monosomy 7), and one case of AML-M7 (karyotype unknown). Homozygous deletion was observed at relapse of an additional patient with AML-M4. These data reinforce the possibility that ACHE may play a role as a myeloid tumour suppressor gene.
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PMID:Deletion of the acetylcholinesterase locus at 7q22 associated with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). 863 18


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