Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CN-Cbl) bound to transcobalamin II (transcobalamin, TC). The intracellular pool of free [57Co]Cbl increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound [57Co]Cbl fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme.
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PMID:The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. 759 60

Using electron microscopy, confocal laser scanning microscopy and measurements of intact DNA we have studied the morphology and DNA degradation of human leukaemia HL-60 cells undergoing drug initiated apoptosis. Apoptosis was initiated by 100 microM 3-deazaadenosine (c3Ado), 25 microM c3Ado plus 1 mM homocysteine thiolactone (Hcy) and 100 microM c3Ado plus 5 micrograms/ml cytochalasin B (CB). Two different phenotypes of apoptotic cells (APC), blebbed and non-blebbed, were present in the cultures. Blebbed APC dominated in cultures exposed to c3Ado, whereas most APC in cultures treated with c3Ado plus Hcy and all the APC in cultures treated with c3Ado plus CB displayed a non-blebbed phenotype. A more pronounced reduction of the chromatin/cytoplasm ratio, lower volume fractions of uncondensed chromatin and higher volume fractions of highly condensed chromatin (micronuclei) were found in cultures exposed to c3Ado and c3Ado plus Hcy when compared with cultures exposed to c3Ado plus CB. A partial inhibition of c3Ado apoptosis by CB was confirmed by measurements of intact DNA. The inhibitory effect of CB was not reproducible by CE, indicating that CB exerts its effect by an actin independent mechanism. Both blebbed and non-blebbed APC displayed nuclear fragmentation, segregation of organelles and cytoplasmic vesiculation, suggesting that the differences between the phenotypes were restricted to the cytoplasmic membrane. We were not able to demonstrate the presence of F-actin by fluorescein isothiocyanate-phalloidin staining in blebbed APC nor in non-blebbed APC in cultures treated with c3Ado plus Hcy. Non-blebbed APC in cultures treated with c3Ado plus CB displayed foci of F-actin at the internal part of the cytoplasmic membrane. This suggests that F-actin is preserved by the mechanism by which CB inhibits blebbing, and may indicate that blebbing of the cytoplasmic membrane during apoptosis is associated with F-actin deficiency rather than a result of actin-myosin interactions.
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PMID:Morphological modifications of apoptosis in HL-60 cells: effects of homocysteine and cytochalasins on apoptosis initiated by 3-deazaadenosine. 777 5

The effect of exogenous homocysteine thiolactone (Hcy) on apoptosis initiated by 3-deazaadenosine (c3Ado) was studied in human leukemia HL-60 cells. Flow cytometric analysis allowed evaluation of the relative number of apoptotic cells (APC) to apoptotic bodies (APB) with a sub G0/G1 DNA content. Addition of 1 mM Hcy to HL-60 cells exposed to 5 to 100 microM c3Ado was followed by a large increase in the number of APC and a simultaneous decrease in the number of APB. The effects of Hcy on both the formation of APC and APB was dose-dependent; however, Hcy concentrations above 250 microM were required for inhibition of APB formation to take place. Fluorescence microscopic examination of unfixed cells stained with acridine orange demonstrated different morphology of APC between cultures treated with c3Ado or c3Ado plus Hcy. Whereas APC in cultures treated with 100 microM c3Ado displayed pronounced cytoplasmic membrane blebbing, only minor blebbing was displayed by APC in cultures treated with 25 microM c3Ado and 1 mM Hcy. Extensive nuclear fragmentation was observed in APC regardless of Hcy addition. By cell sorting we demonstrate the presence of APC with the same DNA content as viable G0/G1 and S-phase cells in cultures treated with 25 microM c3Ado and 1 mM Hcy, indicating that cells in all cell cycle phases undergo apoptosis in these cultures. Neither the formation of APC nor APB in apoptosis initiated by cycloheximide or dactinomycin were influenced by 1 mM Hcy. The Hcy effects on c3Ado apoptosis were abrogated in part by 3-deaza-(+/-)-aristeromycin, a more specific and potent inhibitor of S-adenosylhomocysteine hydrolase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Homocysteine increases the relative number of apoptotic cells and reduces the relative number of apoptotic bodies in HL-60 cells treated with 3-deazaadenosine. 801 68

To investigate the role of transmethylation metabolites in initiation of apoptosis in human leukemia HL-60 cells exposed to 3-deazaadenosine (c3 Ado) as single agent and c3Ado plus homocysteine thiolactone (Hcy), S-adenosylmethionine (AdoMet), S-adenosylhomocysteine (AdoHcy) and 3-deazaadenosylhomocysteine (c3AdoHcy), were measured by HPLC in HL-60 cells exposed to 1-100 microM c3Ado as single agent and 1 to 100 microM c3Ado plus 1 mM Hcy. 3-deaza-(+/-)-aristeromycin (c3Ari), a more specific and potent S-adenosylhomocysteine hydrolase inhibitor compared with c3Ado, was used to inhibit synthesis of c3AdoHcy. AdoMet increased to maximum values 1.5- and 2.3-fold control in cultures treated with c3Ado as single agent and c3Ado plus Hcy, respectively. AdoHcy did not change in cultures treated with c3Ado as single agent, but increased to maximum values 2.0-fold control when Hcy was added. The synthesis of c3AdoHcy was favored by Hcy, and 35- to 70-fold higher levels of c3AdoHcy were found in cultures treated with c3Ado plus Hcy vs. c3Ado as single agent. The amounts of c3AdoHcy in cultures treated with c3Ado at concentrations initiating apoptosis did not exceed c3AdoHcy levels in cultures treated with c3Ado plus Hcy at concentrations not initiating apoptosis. Pretreatment of c3Ado plus Hcy cultures with c3Ari diminished c3AdoHcy and almost completely abrogated apoptosis. Exposure of cells to 100 microM c3Ari as single agent resulted in an increase in AdoHcy to 8.4-fold control but no changes in AdoMet and no initiation of apoptosis. Our findings indicate that c3Ado as single agent exerts its apoptosis-initiating effect through a nontransmethylase-related bio-chemical action. c3AdoHcy seems to be related to biochemical events initiating apoptotic cell death of HL-60 cells when c3Ado and Hcy are combined.
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PMID:Apoptosis and transmethylation metabolites in HL-60 cells. 881 18

The vitamin B12 antagonist cyanocobalamin [c-lactam] was cytotoxic to cultured human leukemia cells, grown in methylfolate, homocysteine, and vitamin B12, but not in the presence of methionine. Small concentrations of methionine were effective in restoring the growth rate in a dose-dependent fashion, confirming methionine deficiency as the cytotoxic principle. Cyanocobalamin [c-lactam] prevented utilization of the methyl group of methylfolate, but no evidence of folate deficiency developed in long-term culture. High concentrations of non-methylated folate were unable to reverse the cytotoxicity, excluding a methylfolate 'trap' as the cause. Low concentrations of serine in the medium induced transient biochemical megaloblastosis. Cyanocobalamin [c-lactam] caused this to occur earlier, and persist. In high concentrations of serine, the inhibitor caused only transient changes in deoxyuridine suppression. Homocysteine cannot be remethylated without vitamin B12, and condensation with serine is the only other excretory pathway for this toxic amino acid. We hypothesize that impaired DNA synthesis in vitamin B12 deficiency is the result of diverting serine away from thymidylate synthesis, into homocysteine metabolism.
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PMID:The cytotoxic effect of the vitamin B12 inhibitor cyanocobalamin [c-lactam], and a review of other vitamin B12 antagonists. 972 Jul 12

Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional and/or genetic disruptions in homocysteine metabolism. The most common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. This variant, with mild enzymatic deficiency, is associated with an increased risk for neural tube defects and pregnancy complications and with a decreased risk for colon cancer and leukemia. Although many studies have reported that this variant is also a risk factor for vascular disease, this area of investigation is still controversial. Severe MTHFR deficiency results in homocystinuria, an inborn error of metabolism with neurological and vascular complications. To investigate the in vivo pathogenetic mechanisms of MTHFR deficiency, we generated mice with a knockout of MTHFR: Plasma total homocysteine levels in heterozygous and homozygous knockout mice are 1.6- and 10-fold higher than those in wild-type littermates, respectively. Both heterozygous and homozygous knockouts have either significantly decreased S-adenosylmethionine levels or significantly increased S-adenosylhomocysteine levels, or both, with global DNA hypomethylation. The heterozygous knockout mice appear normal, whereas the homozygotes are smaller and show developmental retardation with cerebellar pathology. Abnormal lipid deposition in the proximal portion of the aorta was observed in older heterozygotes and homozygotes, alluding to an atherogenic effect of hyperhomocysteinemia in these mice.
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PMID:Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. 1118 67

Homocysteine is considered to be an important risk factor for cancer as well as cardiovascular diseases. To clarify whether homocysteine has potential carcinogenicity, we investigated formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), which is known to be correlated with the incidence of cancer, induced by homocysteine in human cultured cell lines. Homocysteine increased the amount of 8-oxodG in human leukemia cell line HL-60, whereas the amount of 8-oxodG in its hydrogen peroxide (H(2)O(2))-resistant clone HP100 was not increased. We investigated the mechanism for oxidative DNA damage by homocysteine using (32)P-labeled DNA fragments obtained from human tumor suppressor genes and a proto-oncogene. There were two mechanisms by which homocysteine caused DNA damage in the presence of Cu(II). A low concentration of homocysteine (20 microM) frequently induced piperidine-labile sites at thymine residues, whereas a high concentration of homocysteine (100 microM) resulted in damage principally to guanine residues. Catalase inhibited DNA damage by 20 microM homocysteine, indicating the participation of H(2)O(2), but was ineffective in preventing DNA damage by 100 microM homocysteine. Experiments using a singlet oxygen probe showed that 100 microM homocysteine enhanced chemiluminescence intensity in deuterium oxide more than that in H(2)O. These results indicated that the metal-dependent DNA damage through H(2)O(2) is likely to be a more relevant mechanism for homocysteine carcinogenicity.
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PMID:Oxidative damage to cellular and isolated DNA by homocysteine: implications for carcinogenesis. 1278 61

The central role of methylenetetrahydrofolate reductase (MTHFR) in the folate metabolism renders MTHFR gene polymorphisms (C677T and A1298C) potential modulators of a variety of disorders whose development depends on folate/homocysteine imbalance. Here, we provide additional evidence on the protective role of these polymorphisms in acute lymphoblastic leukemia (ALL), the most common pediatric cancer. A case-control study was conducted in 270 ALL patients and 300 healthy controls of French-Canadian origin. The TT677/AA1298 and CC677/CC1298 individuals were associated with reduced risk of ALL (crude odds ratio [OR] = 0.4; 95% confidence interval [CI], 0.2-0.9; and OR = 0.3; 95% CI, 0.1-0.6; respectively). Further stratification in patients born before and after January 1996 (approximate time of Health Canada recommendation for folic acid supplement in pregnancy) revealed that the protective effect of MTHFR variants is accentuated and present only in children born before 1996. Similar results were obtained when a transmission disequilibrium test was performed on a subset of children (n = 95) in a family-based study. This finding suggests gene-environment interaction and its role in the susceptibility to childhood ALL, which is consistent with previous findings associating either folate deficiency or MTHFR polymorphisms with risk of leukemia.
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PMID:Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. 1617 54

Plasma homocysteine has recently been associated with the occurrence of methotrexate-related neurotoxicity. We observed extreme elevations of homocysteine in a 9-year-old boy presenting with leukemia treated with the ALL-BFM 95 protocol. Coma occurred at about the 71st hour from the first methotrexate administration, and lasted for 30 h but MRI and CT studies showed no intracranial pathology. The second course of high-dose methotrexate was administered with no complications. Homocysteine areas under the curve (AUC) were calculated as the sum of areas of rectangles during the 6-hour intervals from T(0) to T(72) hours (AUC(0--72)) and methotrexate AUCs were evaluated using MW/PHARM 3.3 software. The AUC of homocysteine during the first, toxic course was 5.2 times higher than AUC during the second administration, whereas AUC of methotrexate also differed by a factor of 5. Plasma concentrations of folate prior to the first and the second courses, respectively, were 4.4 versus 45 micromol/l making this difference the most striking discriminator between the two courses. Mutation analysis showed that the patient was heterozygous for the C 677 T mutation in the MTHFR gene. We suggest that plasma homocysteine, pretreatment plasma folate and possibly the presence of MTHFR mutations may be biomarkers of methotrexate toxicity and possibly its antifolate effect targeted towards the tumor as well.
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PMID:Severe encephalopathy induced by the first but not the second course of high-dose methotrexate mirrored by plasma homocysteine elevations and preceded by extreme differences in pretreatment plasma folate. 1616 15

The homozygous mutation (677TT) in the methylenetetrahydrofolate reductase (MTHFR) gene reduces enzyme activity and alters cellular folate composition. Previous epidemiological studies reported a potential protective effect of MTHFR677C --> T against acute lymphocytic leukemia and malignant lymphoma, but the mechanism remains to be determined. We investigated the biochemical impacts of MTHFR677C --> T on cellular S-adenosyl methionine (adoMet) synthesis, global DNA methylation, and de novo purine synthesis, all of which are potential regulatory pathways involved in tumorigenesis. Metabolic fluxes of homocysteine remethylation and de novo purine synthesis were compared between Epstein-Barr virus-transformed lymphoblasts expressing MTHFR 677C and MTHFR 677T using stable isotopic tracers and GCMS. MTHFR TT genotype significantly reduced folate-dependent remethylation under folate restriction, reflecting limited methylated folates under folate restriction. Data also suggested increased formylated folate pool and increased purine synthesis when folate is adequate. The impacts of MTHFR 677T polymorphism appeared closely related to folate status, and such alterations may modulate metabolic pathways involved in cancer onset/progression. The advantage of de novo purine synthesis found in the MTHFR TT genotype may account for the protective effect of MTHFR in hematological malignancies. These transformed cells are potential models for studying the consequences of human genetic variation and cancer pathogenesis.
Leukemia 2007 Apr
PMID:Folate restriction and methylenetetrahydrofolate reductase 677T polymorphism decreases adoMet synthesis via folate-dependent remethylation in human-transformed lymphoblasts. 1730 15


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