Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukemia in the first year of life is extremely rare world-wide. However, unlike leukemias in older children, nearly 75% of infant leukemias demonstrate a specific abnormality involving a gene, MLL, on chromosome band 11q23. Molecular studies suggest strongly that these leukemias occur in utero. Treatment-related acute myeloid leukemias (AML), associated with specific chemotherapeutic agents that inhibit DNA topoisomerase II (topo 2), also manifest identical abnormalities involving the MLL gene. This led us to speculate that maternal exposure during pregnancy to environmental agents that inhibit DNA topo 2 may be associated with the development of leukemia in infants. DNA topo 2 inhibitors have been found in specific fruits and vegetables, and in soy, coffee, wine, tea and cocoa, as well as in certain pesticides, solvents and medications. In a preliminary study, we reinterviewed mothers of infant cases and their matched controls who had participated previously in 1 of 3 epidemiologic studies of childhood leukemia conducted by the Children's Cancer Group over a 10-year period. We evaluated potential DNA topo 2 inhibitor exposure through maternal diet and medications. Of the 84 original matched sets who were reinterviewed, there was no positive association with increasing maternal consumption of DNA topo 2 inhibitor-containing foods either for the overall group or for infants in the acute lymphoblastic leukemia stratum. However, there was an approximately 10-fold higher risk of infant AML with increasing maternal consumption of DNA topo 2 inhibitor-containing foods. The assay to screen environmental agents that inhibit DNA topo 2 has been established and new inhibitors are being identified routinely.
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PMID:Maternal diet and infant leukemia: a role for DNA topoisomerase II inhibitors? 987 73

We performed a functional genomic analysis to study the effect of epicatechin and polyphenolic cocoa extract in the human colon adenocarcinoma cell line Caco-2. The specific Human Hematology/Immunology cDNA arrays by Clontech, containing 406 genes in duplicate, were used. The differentially expressed genes were classified according to their level of expression, calculated as the ratio of the value obtained after each treatment relative to control cells, with a statistical significance of P < 0.05 (upregulated: ratio > 1.5; downregulated: ratio < 0.6). Treatment with epicatechin decreased the expression of 21 genes and upregulated 24 genes. Upon incubation with the cocoa polyphenolic extract, 24 genes were underexpressed and 28 were overexpressed. The changes in expression for ferritin heavy polypeptide 1 (FTH1), mitogen-activated protein kinase kinase 1 (MAPKK1), signal transducer and activator of transcription 1 (STAT1), and topoisomerase 1 upon incubation with epicatechin, and for myeloid leukemia factor 2 (MLF2), CCAAT/enhancer binding protein gamma (C/EBPG), MAPKK1, ATP-binding cassette, subfamily c member 1 (MRP1), STAT1, topoisomerase 1, and x-ray repair complementing defective repair 1 (XRCC1) upon incubation with the cocoa polyphenolic extract were validated by RT-PCR. Changes in the messenger RNA levels for MAPKK1, STAT1, MRP1, and topoisomerase 1 upon incubation with either epicatechin or cocoa extract were further confirmed at the protein level by Western blotting. The changes in the expression of STAT1, MAPKK1, MRP1, and FTH1 genes, which are involved in the cellular response to oxidative stress, are in agreement with the antioxidant properties of cocoa flavonoids. In addition, the changes in the expression of C/EBPG, topoisomerase 1, MLF2, and XRCC1 suggest novel mechanisms of action of flavonoids at the molecular level.
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PMID:Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. 1546 39

There is cumulative strong evidence that diets rich in flavanols can provide certain positive health benefits, particularly with respect to the cardiovascular system. Consequently, it has been suggested that increasing one's dietary intake of flavanols may be of benefit. Complicating this idea, there are reports that high intakes of certain flavonoids during pregnancy are associated with an increased risk for acute infant leukemia due to a poison effect of select polyphenolic compounds on DNA topoisomerase (topo) II activity that promotes aberrant chromosomal translocations. In the current study, we characterized the effects of select flavanols (epicatechin and catechin monomers), and select flavanol dimers and longer oligomers, on topo II activity, and on cellular toxicity in vitro. In contrast to the chemotherapeutic drug etoposide (VP16) and the flavonol quercetin, which strongly inhibited topo II activity and increased the formation of cleavage complexes demonstrating a poison effect, the flavanols epicatechin and catechin had little effect on topo II enzyme activity. Accordingly, several fold greater concentrations of the flavanols were required to achieve cellular toxicity similar to that of quercetin and VP16 in cultures of myeloid and lymphoid cells. Low cellular toxicity and limited topo II inhibition were also observed with a procyanidin-rich cocoa extract. Of all the flavanols tested, the dimers (B2, B5 and a mix of both) exerted the greatest inhibition of topo II and inhibited cellular proliferation rates at concentrations similar to quercetin. However, in contrast to quercetin, the dimers did not function as topo II poisons. Collectively, our in vitro data show that cocoa-derived flavanols have limited effects on topo II activity and cellular proliferation in cancer cell lines. We predict that these compounds are likely to have limited leukemogenic potential at physiological concentrations.
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PMID:Dietary factors and the risk for acute infant leukemia: evaluating the effects of cocoa-derived flavanols on DNA topoisomerase activity. 2040 22