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Cited by 412Bioactive Compounds and Antitumor AgentsDNA and Nucleic Acid ChemistrySynthesis and pharmacology of benzodiazepine derivatives

Bleomycin‐induced strand‐scission of DNA. Mechanism of deoxyribose cleavage

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Giloni, L., Takeshita, M., Johnson, F., Iden, C., Grollman, A.P.·1981·Journal of Biological Chemistry
DOI 10.1016/s0021-9258(19)68888-5
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Abstract

The bleomycins, a family of glycopeptides with antineoplastic activity, bind to DNA and cause strand-scission in a reaction requiring Fe(I1) and oxygen.Strandscission is accompanied by the simultaneous release of free bases and four low molecular weight compounds that react with 2-thiobarbituric acid to form chromophores absorbing maximally at 532 nm.The structure of these four products was elucidated as follows: formic acid hydrolysis released thymine, cytosine, adenine, and guanine, respectively; treatment of each compound with phenylhydrazine yielded 1-phenylpyrazole.The adenine-containing compound was reduced with sodium borohydride and the trimethylsilyl derivative was prepared.High resolution mass spectrometry of this derivative revealed silylated 3-(adenin-B'-y1)-2-propen-1-01, consistent with formulation of the original compound as 3-(adenin-9'-~1)-2-propenal.The reaction product containing thymine was similarly shown to be 3-(thymin-l'-yl)-2-propenal.The 3-substituted propenal structures proposed were confirmed by chemical synthesis.Oligonucleotides, produced by bleomycin-induced strand-scission, were found to contain glycolic acid residues esterified through the hydroxyl group to the 3'-phosphate termini.We conclude that the primary reaction products resulting from bleomycin-induced strand-scission of DNA have a common structure: Base-CH=CH-CHO.These observations are consistent with a reaction mechanism initiated by free radical abstraction of the C-4' proton of deoxyribose and leading to oxidative cleavage of the (C-3')-(C-43 bond.DNA, isolated from bleomycin-treated cells, is known to be degraded (1-7), an effect which is presumed to be responsible for the chemotherapeutic properties of this family of antibiotics.Bleomycin creates single-and double-stranded breaks in purified preparations of DNA (1, 3-6, 8-19), strand-scission occurring preferentially at guanine-pyrimidine (5' + 3') base sequences (20,21).Products of the reaction between bleomycin and DNA include free bases, oligonucleotides, and several compounds which form chromophores with TBA' (9-11, 18,

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  • ROS radicals compromise the DNA backbone causing an estimated 2300 single-strand breaks per cell per hour in mammalian cells.

    “Other than attacking DNA bases, ROS radicals can also compromise the DNA backbone causing an estimated 2300 single strand breaks per cell per hour in mammalian cells [Giloni et al., 1981; R, 1981; Henner et al., 1983a; Henner et al., 1983b].”

    From Mechanisms of DNA damage, repair, and mutagenesis (2017) · cites this paper as Giloni et al., 1981

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Authors
Giloni, L., Takeshita, M., Johnson, F., Iden, C., & Grollman, A. P.
Affiliations
State University of New York (US)
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1981-08
Volume
256
Issue
16
Pages
8608-8615
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/s0021-9258(19)68888-5
OpenAlex
W28829384
Cited by
412
References
48
Citations by year
2026: 1 · 2024: 1 · 2023: 3 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 1 · 2014: 5 · 2013: 2 · 2012: 10
FWCI
30.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and pharmacology of benzodiazepine derivatives
Keywords
bleomycin, DNA strand scission, oxidative DNA damage, 1-phenylpyrazole, oligonucleotide degradation, antitumor antibiotics
MeSH terms
Bleomycin, Chemistry, DNA, DNA, Neoplasm, HeLa Cells, Humans, Iron, Gas Chromatography-Mass Spectrometry, Molecular Weight, Magnetic Resonance Spectroscopy, Chemical Phenomena

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