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)

Myelo-cytotoxicity of extended nitrous oxide (N2O) inhalation was described almost forty years ago and then incidentally applied already with temporary success for suppressing leukemia. In 1948 the accompanying megaloblastic maturation arrest was explained by inactivation of the methylcobalamin coenzyme and subsequent folate deficiency. We studied the anti-leukemic effect of N2O on a transplantable acute leukemia in B(rown) N(orway) rats. Progression of this B,N,M(yelocytic)L(eukemia) was measured as spleen and liver weights, and leukemic blood cell counts. The deoxyuridine (dU)-suppression test provided in vitro indication of the functional folate activity of leukemic cells. Breathing of N2O-oxygen considerably reduced but did not eradicate, BNML-proliferation. Addition of anti-metabolites, interfering with some enzyme in the folate metabolism beyond the methylcobalamin co-enzyme dependent methionine synthase step, acted at least synergistically. The anti-leukemic effect of cycloleucine, which reduces S-adenosyl-methionine synthesis by inactivation of methionine adenosyltransferase, was moderate but became much stronger with N2O inhalation. Methotrexate, a potent anti-leukemic agent by inhibiting tetrahydrofolate (THF) generation through inactivation of di-HF reductase, became highly anti-BNML, even in low dosage when combined with or preceded by N2O. 5-Fluorouracil, which inhibits methylene-THF dependent thymidilate synthase, itself was surprisingly anti-BNML, but also became much more potent with previous or concomitant N2O exposure. Preliminary dU-suppression test results with human acute leukemia cells, exposed to N2O and/or folate antagonists in vitro, correlated well with the in vivo BNML-experiments. Combining the anticobalamin activity of N2O with an anti-folate therefore seems to be a promising chemotherapeutic approach.
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PMID:Anti-leukemic potential of methyl-cobalamin inactivation by nitrous oxide. 218 35

The administration of nitrous oxide rapidly inactivates the vitamin B12-dependent enzyme methionine synthase. This inactivation disrupts the normal interrelationships between vitamin B12 and folic acid, and results in altered levels of folic acid derivatives and certain amino acids and their metabolites. Attempts have been made to use the antifolate properties of nitrous oxide to treat patients with leukemia. Although transient improvements may be observed in patients with leukemia who are given nitrous oxide, prolonged administration of nitrous oxide is highly toxic and causes marked hematological and neurological abnormalities. Animal and in vitro studies suggest that the action of nitrous oxide may be tumor selective, and that nitrous oxide may interact with and enhance the therapeutic effect of other antitumor agents. However, there is a delicate balance between the possible beneficial and harmful effects of nitrous oxide, and the conditions for which nitrous oxide may prove useful as a chemotherapeutic adjuvant remain to be defined. Concern has also been raised that nitrous oxide may have carcinogenic potential, especially in operating room and dental personnel who are chronically exposed to trace concentrations of this gas. However, there is no convincing evidence to date that nitrous oxide causes cancer in either animals or humans.
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PMID:Nitrous oxide: a cause of cancer or chemotherapeutic adjuvant? 218 94

Exponentially growing human lymphoblasts (culture LS-2) were separated by cell sorting (FACS II, Becton Dickinson) according to their deoxyribonucleic acid (DNA) content, designating them at particular phases of the cell cycle. Prior to cell sorting the DNA has been fluorochrome-labeled with the Hoechst stain H 33342. Maximum cell enrichments of 94% for G0 + G1 cells, 96% for S cells and 74% for G2 + M cells could be achieved. The enzyme activities of thymidine kinase (TK), thymidylate synthase (TS), DNA polymerase (DNA-P), dihydrofolate reductase (FH2-R), methionine synthase (MS), and hexokinase (HK) were determined in the obtained cell fractions. Although incorporation of 3H-thymidine (3H-dTR) and the 3H-dTR labeling index were significantly inhibited by the dye, no evidence of cell staining's having a significant effect on the enzyme activities was found. The enzyme activities for approximately 100% pure G0 + G1, S, and G2 + M cells were computed. With exception of TK, all the enzymes under study were shown to exhibit activities--although of differing degree--in the G0 + G1, S, and G2 + M cells. No TK activity was shown in G0 and G1 cells; its activity, however, was approximately the same in S and G2 + M cells. This applies likewise for TS which, in contrast to TK, exhibits minor activity in G0 + G1 cells. DNA-P was highly active in G0 + G1 cells, but maximum activity was in S cells. FH2-R exhibited maximum activity in S cells, although the difference in activity between S and G2 + M cells was not significant. None of the observed differences in MS activity was significant, indicating equally high activity in cells of all cell cycle phases. HK activity is approximately twice as high in G2 + M cells as in G0 + G1 cells.
Leukemia 1989 May
PMID:Relation between cell cycle stage and the activity of DNA-synthesizing enzymes in cultured human lymphoblasts: investigations on cells separated according to DNA content by way of a cell sorter. 271 50

Undifferentiated human lymphoblasts (culture LS-2) were separated according to cell size during their exponential growth phase by way of centrifugal elutriation. The cell fractions thus obtained were characterized in terms of different cell cycle stages by flow cytometric measurement of their deoxyribonucleic acid (DNA histogram), the [3H]thymidine labeling index, and by determining the rate of [3H]thymidine incorporation. In these cell fractions the activities of thymidine kinase, thymidylate synthase, DNA polymerase, dihydrofolate reductase, methionine synthase, and hexokinase were determined. The results showed that all the enzymes investigated exhibited activities in all cell fractions. With the exception of DNA polymerase, all of the enzymes exhibited the lowest level of activity in the fraction containing the highest proportion of G0 + G1 phase cells (fraction 2); the activity of thymidine kinase was particularly low. This would suggest that thymidine kinase is not active in G0 + G1 phase cells and that the activity measured in fraction 2 is perhaps attributable to contamination of this fraction by S and G2 + M phase cells.
Leukemia 1987 Mar
PMID:Relation between cell cycle stage and the activity of DNA-synthesizing enzymes in cultured human lymphoblasts: investigations on cell fractions enriched according to cell cycle stages by way of centrifugal elutriation. 366 41

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

Studies of childhood leukemia and the potential etiologic role of genetic variation in folate metabolism have produced conflicting findings and have often been based on small numbers. We investigated the association between polymorphisms in key folate metabolism enzymes (MTHFR 677 C>T, MTHFR 1298 A>C, SHMT1 1420 C>T, MTR 2756 A>G, TS 1494del6, and TS 28bp repeat) in 939 cases of childhood acute lymphoblastic leukemia (ALL) and 89 cases of acute myeloid leukemia (AML) recruited into the United Kingdom Childhood Cancer Study. We also examined the maternal genotypes of 752 of these cases. Data from 824 noncancer controls recruited were used for comparison. No evidence of an association with MTHFR 677 was observed for ALL or AML, either in children or their mothers. However, in children an increased risk of ALL (odds ratio [OR] = 1.88; 95% confidence interval [CI], 1.16-3.07; P = .010) and AML (OR = 2.74; 95% CI, 1.07-7.01; P = .036) was observed with the MTR 2756 GG genotype; the association was most pronounced for cases with the MLL translocation (OR = 4.90; 95% CI, 1.30-18.45; P = .019). These data suggest that genetic variation in methionine synthase could mediate risk of childhood leukemia, either via effects on DNA methylation or via effects on fetal growth and development.
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PMID:Genetic variation in the folate metabolic pathway and risk of childhood leukemia. 2010 Oct 25

Methionine synthase reductase (MTRR) is required for the reductive methylation of cobalamin, which is the functional cofactorial form of methionine synthase (MS) in the remethylation of homocysteine to methionine. The MTRR A66G (rs1801394) polymorphism is found to be associated with decreased enzyme affinity for MTR, the gene that encodes MS, and has been widely investigated for cancer risk, including leukemia. However, the conclusions of epidemiological studies have always been contradictory. To further clarify the association of MTRR A66G polymorphism with the risk of leukemia, this meta-analysis was performed for 2913 cases and 4764 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Pooled ORs were determined for the co-dominant model (GG vs. AA, AG vs. AA), dominant model (GG + AG vs. AA) and recessive model (GG vs. AA+ AG), respectively. No significant associations were found for all comparisons in the overall pooled analysis. However, the results of stratified analyses revealed that MTRR A66G GG genotype was associated with decreased leukemia risk in the Caucasian population, in children and for acute lymphoblastic leukemia (ALL). In contrast, increased risk was observed in the Asian population and for acute myeloid leukemia (AML). This meta-analysis suggests that MTRR A66G GG is associated with decreased risk of leukemia in a Caucasian population and in children, especially for ALL.
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PMID:Methionine synthase reductase A66G polymorphism and leukemia risk: evidence from published studies. 2426 78

Folate-dependent one-carbon metabolism is present in every cell of the body. It represents a central systems biology hub that reverberates into countless other pathways with more specialized roles in specialized cell types throughout the body. I have spent 25 years of research on this core biochemical pathway with several unanticipated iterations that led me from Down syndrome to congenital heart defects to leukemia and finally to autism about 12 years ago. Figure 1 provides an overview of the three interdependent pathways involved in folate-dependent methionine "transmethylation" and "transsulfuration." Methionine is necessary for the synthesis of S-adenosylmethionine (SAM), the major methyl donor for all cellular methylation reactions. It is also the major precursor for cysteine, the rate-limiting amino acid for glutathione synthesis linking transmethylation and transsulfuration pathways. Methionine levels can be negatively affected by genetic and environmental factors that reduce folate availability and/or oxidative inhibition of the methionine synthase enzyme. Because these three metabolic pathways are mutually interdependent, genetic or environmental perturbation of folate or methionine metabolism will indirectly impact glutathione synthesis, and conversely, alterations in glutathione synthesis will alter flux through pathways of folate and methionine metabolism. This interdependency translates into broader impact on essential cellular functions.
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PMID:Autism and Folate-dependent One-carbon Metabolism: Serendipity and Critical Branch-point Decisions in Science. 2441 8