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Titolo:
Etoposide metabolites enhance DNA topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints
Autore:
Lovett, BD; Strumberg, D; Blair, IA; Pang, SK; Burden, DA; Megonigal, MD; Rappaport, EF; Rebbeck, TR; Osheroff, N; Pommier, YG; Felix, CA;
Indirizzi:
Childrens Hosp Philadelphia, Joseph Stokes Jr Res Inst, Dept Pediat, Div Oncol, Philadelphia, PA 19104 USA Childrens Hosp Philadelphia Philadelphia PA USA 19104 lphia, PA 19104 USA Univ Penn, Sch Med, Ctr Canc Pharmacol, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 Pharmacol, Philadelphia, PA 19104 USA Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 Epidemiol, Philadelphia, PA 19104 USA Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 & Biostat, Philadelphia, PA 19104 USA Univ Penn, Sch Med, Ctr Canc, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 Ctr Canc, Philadelphia, PA 19104 USA NCI, Div Canc Treatment, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892 Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA VanderbiltUniv Nashville TN USA 37232 t Biochem, Nashville, TN 37232 USA
Titolo Testata:
BIOCHEMISTRY
fascicolo: 5, volume: 40, anno: 2001,
pagine: 1159 - 1170
SICI:
0006-2960(20010206)40:5<1159:EMEDTI>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACUTE MYELOID-LEUKEMIA; ANTITUMOR DRUG ETOPOSIDE; EUKARYOTIC TOPOISOMERASE; CLUSTER REGION; CHROMOSOMAL BREAKPOINTS; RECIPROCAL EXCHANGE; CYTOCHROME-P450 3A4; RELIGATION REACTION; SEQUENCE-ANALYSIS; CHO CELLS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
65
Recensione:
Indirizzi per estratti:
Indirizzo: Felix, CA Childrens Hosp Philadelphia, Joseph Stokes Jr Res Inst, Dept Pediat, Div Oncol, Philadelphia, PA 19104 USA Childrens Hosp Philadelphia Philadelphia PA USA 19104 19104 USA
Citazione:
B.D. Lovett et al., "Etoposide metabolites enhance DNA topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints", BIOCHEM, 40(5), 2001, pp. 1159-1170

Abstract

Chromosomal breakage resulting from stabilization of DNA topoisomerase II covalent complexes by epipodophyllotoxins may play a role in the genesis ofleukemia-associated MLL gene translocations. We investigated whether etoposide catechol and quinone metabolites can damage the MLL breakpoint clusterregion in a DNA topoisomerase II-dependent manner Like the parent drug andthe nature of the damage. Cleavage of two DNA substrates containing the normal homologues of five MLL intron 6 translocation breakpoints was examinedin vitro upon incubation with human DNA topoisomerase Bo, ATP, and either etoposide, etoposide catechol, or etoposide quinone. Many of the same cleavage sites were induced by etoposide and by its metabolites, but several unique sites were induced by the metabolites. There was a preference for G(-1)among the unique sites, which differs from the parent drug. Cleavage at most:sites was greater and more heat-stable in the presence of the metabolites compared to etoposide. The MLL translocation breakpoints contained withinthe substrates were near strong and/or stable cleavage sites. The metabolites induced more cleavage than etoposide at the same sites within a 40 bp double-stranded oligonucleotide containing two of the translocation breakpoints, confirming the results at a subset of the sites. Cleavage assays usingthe same oligonucleotide substrate in which guanines at several positions were replaced with N7-deaza guanines indicated that the N7 position of guanine is important in metabolite-induced cleavage, possibly suggesting N7-guanine alkylation by etoposide quinone. Not only etoposide, but also its metabolites, enhance DNA topoisomerase II cleavage near MLL translocation breakpoints in in vitro assays. It is possible that etoposide metabolites may berelevant to translocations.

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Documento generato il 19/01/20 alle ore 09:05:51