Differences in O2 reduction by the iron complexes of adriamycin and daunomycin: the importance of the sidechain hydroxyl group

Jay L. Zweier, Luca Gianni, Josephia Muindi, Charles E. Myers

Research output: Contribution to journalArticle

Abstract

Both adriamycin and daunomycin chelate Fe3+, forming complexes with similar spectroscopic properties but very different redox chemistry. Anaerobic Fe3+-adriamycin and Fe3+-daunomycin complexes of identical stoichiometry give rise to identical optical absorbance and EPR spectra with maxima at 600 nm and signals at g = 4.2 and g = 2.01. In anaerobic preparations, however, the 600 nm absorption band and the EPR signals of the Fe3+-adriamycin complexes decrease as Fe3+ is reduced to Fe2+, with the appearance of an adriamycin free-radical signal at g = 2.0035, while the spectra of Fe3+-daunomycin complexes remain unchanged, with no free-radical signal appearing. Polarographic measurements demonstrate that the Fe3+-adriamycin complexes consume O2 while the Fe3+-daunomycin complexes do not. Measurements in the presence of catalase and superoxide dismutase suggest that 75% of the O2 consumed by Fe3+-adriamycin is reduced to H2O2 or .O2-. Spin-trapping experiments demonstrate that the Fe3+-adriamycin complexes generate .OH, while the daunomycin complexes do not. Qunatitation of .OH generation by Fe3+-adriamycin demonstrates that the initital rate of .OH generation approaches the rate of total O2 consumption. DNA cleavage studies show that only the Fe3+-adriamycin complexes cleave DNA in the absence of exogenous added H2O2. This DNA cleavage can be blocked by catalasa or .OH radical scavengers. These results indicate that the side-chain hydroxyl group is essential for Fe3+ reduction, subsequent O2 reduction, as well as for the generation of the drug free radical, since adriamycin and daunomycin are structurally identical except for this hydroxyl. The difference in redox chemistry of the iron complexes of adriamycin and daunomycin is the only known mechanism which can explain the difference in anti-tumor potency and cardiotoxicity of these two structurally similar drugs.

Original languageEnglish (US)
Pages (from-to)326-336
Number of pages11
JournalBiochimica et Biophysica Acta - General Subjects
Volume884
Issue number2
DOIs
StatePublished - Nov 19 1986
Externally publishedYes

Fingerprint

Daunorubicin
Hydroxyl Radical
Doxorubicin
Free Radicals
DNA Cleavage
Oxidation-Reduction
Paramagnetic resonance
Spin Trapping
doxorubicin-iron complex
DNA
Stoichiometry
Pharmaceutical Preparations
Catalase
Superoxide Dismutase
Tumors
Absorption spectra

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology
  • Medicine(all)

Cite this

Differences in O2 reduction by the iron complexes of adriamycin and daunomycin : the importance of the sidechain hydroxyl group. / Zweier, Jay L.; Gianni, Luca; Muindi, Josephia; Myers, Charles E.

In: Biochimica et Biophysica Acta - General Subjects, Vol. 884, No. 2, 19.11.1986, p. 326-336.

Research output: Contribution to journalArticle

@article{45fa2bd9ba28439db2b9b048767bf49a,
title = "Differences in O2 reduction by the iron complexes of adriamycin and daunomycin: the importance of the sidechain hydroxyl group",
abstract = "Both adriamycin and daunomycin chelate Fe3+, forming complexes with similar spectroscopic properties but very different redox chemistry. Anaerobic Fe3+-adriamycin and Fe3+-daunomycin complexes of identical stoichiometry give rise to identical optical absorbance and EPR spectra with maxima at 600 nm and signals at g = 4.2 and g = 2.01. In anaerobic preparations, however, the 600 nm absorption band and the EPR signals of the Fe3+-adriamycin complexes decrease as Fe3+ is reduced to Fe2+, with the appearance of an adriamycin free-radical signal at g = 2.0035, while the spectra of Fe3+-daunomycin complexes remain unchanged, with no free-radical signal appearing. Polarographic measurements demonstrate that the Fe3+-adriamycin complexes consume O2 while the Fe3+-daunomycin complexes do not. Measurements in the presence of catalase and superoxide dismutase suggest that 75{\%} of the O2 consumed by Fe3+-adriamycin is reduced to H2O2 or .O2-. Spin-trapping experiments demonstrate that the Fe3+-adriamycin complexes generate .OH, while the daunomycin complexes do not. Qunatitation of .OH generation by Fe3+-adriamycin demonstrates that the initital rate of .OH generation approaches the rate of total O2 consumption. DNA cleavage studies show that only the Fe3+-adriamycin complexes cleave DNA in the absence of exogenous added H2O2. This DNA cleavage can be blocked by catalasa or .OH radical scavengers. These results indicate that the side-chain hydroxyl group is essential for Fe3+ reduction, subsequent O2 reduction, as well as for the generation of the drug free radical, since adriamycin and daunomycin are structurally identical except for this hydroxyl. The difference in redox chemistry of the iron complexes of adriamycin and daunomycin is the only known mechanism which can explain the difference in anti-tumor potency and cardiotoxicity of these two structurally similar drugs.",
author = "Zweier, {Jay L.} and Luca Gianni and Josephia Muindi and Myers, {Charles E.}",
year = "1986",
month = "11",
day = "19",
doi = "10.1016/0304-4165(86)90181-9",
language = "English (US)",
volume = "884",
pages = "326--336",
journal = "Biochimica et Biophysica Acta - General Subjects",
issn = "0304-4165",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - Differences in O2 reduction by the iron complexes of adriamycin and daunomycin

T2 - the importance of the sidechain hydroxyl group

AU - Zweier, Jay L.

AU - Gianni, Luca

AU - Muindi, Josephia

AU - Myers, Charles E.

PY - 1986/11/19

Y1 - 1986/11/19

N2 - Both adriamycin and daunomycin chelate Fe3+, forming complexes with similar spectroscopic properties but very different redox chemistry. Anaerobic Fe3+-adriamycin and Fe3+-daunomycin complexes of identical stoichiometry give rise to identical optical absorbance and EPR spectra with maxima at 600 nm and signals at g = 4.2 and g = 2.01. In anaerobic preparations, however, the 600 nm absorption band and the EPR signals of the Fe3+-adriamycin complexes decrease as Fe3+ is reduced to Fe2+, with the appearance of an adriamycin free-radical signal at g = 2.0035, while the spectra of Fe3+-daunomycin complexes remain unchanged, with no free-radical signal appearing. Polarographic measurements demonstrate that the Fe3+-adriamycin complexes consume O2 while the Fe3+-daunomycin complexes do not. Measurements in the presence of catalase and superoxide dismutase suggest that 75% of the O2 consumed by Fe3+-adriamycin is reduced to H2O2 or .O2-. Spin-trapping experiments demonstrate that the Fe3+-adriamycin complexes generate .OH, while the daunomycin complexes do not. Qunatitation of .OH generation by Fe3+-adriamycin demonstrates that the initital rate of .OH generation approaches the rate of total O2 consumption. DNA cleavage studies show that only the Fe3+-adriamycin complexes cleave DNA in the absence of exogenous added H2O2. This DNA cleavage can be blocked by catalasa or .OH radical scavengers. These results indicate that the side-chain hydroxyl group is essential for Fe3+ reduction, subsequent O2 reduction, as well as for the generation of the drug free radical, since adriamycin and daunomycin are structurally identical except for this hydroxyl. The difference in redox chemistry of the iron complexes of adriamycin and daunomycin is the only known mechanism which can explain the difference in anti-tumor potency and cardiotoxicity of these two structurally similar drugs.

AB - Both adriamycin and daunomycin chelate Fe3+, forming complexes with similar spectroscopic properties but very different redox chemistry. Anaerobic Fe3+-adriamycin and Fe3+-daunomycin complexes of identical stoichiometry give rise to identical optical absorbance and EPR spectra with maxima at 600 nm and signals at g = 4.2 and g = 2.01. In anaerobic preparations, however, the 600 nm absorption band and the EPR signals of the Fe3+-adriamycin complexes decrease as Fe3+ is reduced to Fe2+, with the appearance of an adriamycin free-radical signal at g = 2.0035, while the spectra of Fe3+-daunomycin complexes remain unchanged, with no free-radical signal appearing. Polarographic measurements demonstrate that the Fe3+-adriamycin complexes consume O2 while the Fe3+-daunomycin complexes do not. Measurements in the presence of catalase and superoxide dismutase suggest that 75% of the O2 consumed by Fe3+-adriamycin is reduced to H2O2 or .O2-. Spin-trapping experiments demonstrate that the Fe3+-adriamycin complexes generate .OH, while the daunomycin complexes do not. Qunatitation of .OH generation by Fe3+-adriamycin demonstrates that the initital rate of .OH generation approaches the rate of total O2 consumption. DNA cleavage studies show that only the Fe3+-adriamycin complexes cleave DNA in the absence of exogenous added H2O2. This DNA cleavage can be blocked by catalasa or .OH radical scavengers. These results indicate that the side-chain hydroxyl group is essential for Fe3+ reduction, subsequent O2 reduction, as well as for the generation of the drug free radical, since adriamycin and daunomycin are structurally identical except for this hydroxyl. The difference in redox chemistry of the iron complexes of adriamycin and daunomycin is the only known mechanism which can explain the difference in anti-tumor potency and cardiotoxicity of these two structurally similar drugs.

UR - http://www.scopus.com/inward/record.url?scp=0022849760&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0022849760&partnerID=8YFLogxK

U2 - 10.1016/0304-4165(86)90181-9

DO - 10.1016/0304-4165(86)90181-9

M3 - Article

C2 - 2823890

AN - SCOPUS:0022849760

VL - 884

SP - 326

EP - 336

JO - Biochimica et Biophysica Acta - General Subjects

JF - Biochimica et Biophysica Acta - General Subjects

SN - 0304-4165

IS - 2

ER -