Enhancement of intercalator-induced deoxyribonucleic acid scission and cytotoxicity in murine leukemia cells treated with 5-azacytidine

Zwelling, L. A.; Minford, Jon; Nichols, Margaret; Glazier, Robert I.; Shackney, Stanley E.

doi:10.1016/0006-2952(84)90059-5

Cited by 12 publications

(4 citation statements)

References 24 publications

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“…The second observation involves the antineoplastic agent m-AMSA, whose mechanism of action is believed to involve topoisomerase II mediated DNA interaction (Nelson et al, 1984). In a recent report, Zwelling et al (1984) have provided evidence that undermethylated DNA may also be a better substrate for this agent in vivo.…”

Section: Resultsmentioning

confidence: 99%

DNA methylation diminishes bleomycin-mediated strand scission

Hertzberg¹,

Caranfa²,

Hecht³

1985

Biochemistry

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Three DNA duplexes differing substantially in sequence were derived from pBR322 plasmid DNA and supercoiled SV40 DNA by digestion with appropriate restriction endonucleases. Following treatment with the restriction methylase HhaI (recognition sequence: GCGC) or HhaI and HpaII (CCGG), the unmethylated and methylated DNAs were compared as substrates for the antitumor agent bleomycin. Bleomycin-mediated strand scission was shown to diminish substantially at a number of sites in proximity to the methylated cytidine moieties, especially where multiple sites had been methylated within a DNA segment of limited size. Detailed analysis of the DNA substrates revealed that both strands of DNA within a methylated region became more refractory to cleavage by bleomycin and that the protective effect could extend as many as 14 base pairs in proximity to the 5-methylcytidine moieties. Among the methylated DNA segments that became more resistant to bleomycin cleavage was a HpaII site of SV40 DNA, methylation of which has previously been shown to diminish the synthesis of the major late viral capsid protein following microinjection into Xenopus laevis oocytes. Study of the cleavage reaction at varying salt levels suggested that diminished bleomycin strand scission may be due, at least in part, to local conformational changes of the DNA to Z form (or other non-B-form structures). The results are generally consistent with the hypothesis that one mechanism for the expression of selective therapeutic action by certain DNA damaging agents could involve the recognition of specific methylation patterns.

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Section: Resultsmentioning

confidence: 99%

DNA methylation diminishes bleomycin-mediated strand scission

Hertzberg¹,

Caranfa²,

Hecht³

1985

Biochemistry

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“…Data also suggested that later incorporation into DNA could not only inhibit DNA synthesis but also sensitize cells to the effects of other DNA-damaging drugs. 40 More recently it has been shown that 5-aza-2'-deoxycytidine (decitabine) cell killing is dependent on the p53 DNA-damage response pathway and is related to enzyme-DNA adduct formation. 41 Our data, showing a rapid onset of cell killing and activity against both p53-wild type and p53-null human myeloma cell lines (data not shown) excludes the latter pathway as a dominant mechanism in AZA-induced MM cell killing.…”

Section: Discussionmentioning

confidence: 99%

The effect of azacitidine on interleukin-6 signaling and nuclear factor- B activation and its in vitro and in vivo activity against multiple myeloma

Khong

Sharkey²,

Spencer³

2008

Haematologica

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“…It remains possible that cell cycle stage dependent alterations in chromatin structure per se account for the hypersensitivity of mitotic DNA to topoisomerase II reactive compounds. Changes in chromatin structure have been proposed to underlie the enhanced m-AMSA-stimulated DNA cleavage seen following pretreatment of LI210 cells with antimetabolites such as cytosine arabinoside, hydroxyurea, and 5-azacytidine (Zwelling et al, 1984;Minford et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

Cell cycle stage-dependent variations in drug-induced topoisomerase II mediated DNA cleavage and cytotoxicity

Estey¹,

Adlakha²,

Hittelman³

et al. 1987

Biochemistry

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The DNA cleavage produced by 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) in mammalian cells is putatively mediated by topoisomerase II. We found that in synchronized HeLa cells the frequency of such cleavage was 4-15-fold greater in mitosis than in S while the DNA of G1 and G2 cells exhibited an intermediate susceptibility to cleavage. The hypersensitivity of mitotic DNA to m-AMSA-induced cleavage was acquired relatively abruptly in late G2 and was lost similarly abruptly in early G1. The susceptibility of mitotic cells to m-AMSA-induced DNA cleavage was not clearly paralleled by an increase in topoisomerase II activity (decatenation of kinetoplast DNA) in 350 mM NaCl extracts from mitotic cells compared to similar extracts from cells in G1, S, or G2. Furthermore, equal amounts of decatenating activity from cells in mitosis and S produced equal amounts of m-AMSA-induced cleavage of simian virus 40 (SV40) DNA; i.e., the interaction between m-AMSA and extractable enzyme was similar in mitosis and S. The DNA of mitotic cells was also hypersensitive to cleavage by 4'-demethylepipodophyllotoxin 4-(4,6-O-ethylidene-beta-D-glucopyranoside) (etoposide), a drug that produces topoisomerase II mediated DNA cleavage without binding to DNA. Thus, alterations in the drug-chromatin interaction during the cell cycle seem an unlikely explanation for results in whole cells. Cell cycle stage dependent fluctuations in m-AMSA-induced DNA cleavage may result from fluctuations in the structure of chromatin per se that occur during the cell cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

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Enhancement of intercalator-induced deoxyribonucleic acid scission and cytotoxicity in murine leukemia cells treated with 5-azacytidine

Cited by 12 publications

References 24 publications

DNA methylation diminishes bleomycin-mediated strand scission

DNA methylation diminishes bleomycin-mediated strand scission

The effect of azacitidine on interleukin-6 signaling and nuclear factor- B activation and its in vitro and in vivo activity against multiple myeloma

Cell cycle stage-dependent variations in drug-induced topoisomerase II mediated DNA cleavage and cytotoxicity

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