Potential antitumour mitosenes: relationship between in vitro DNA interstrand cross-link formation and DNA damage in escherichia coli K-12 strains

Marc Maliepaard, Karin A.M.C. Sitters, Nico J. de Mol, Lambert H.M. Janssen, Ian J. Stratford, Miriam Stephens, Willem Verboom, David Reinhoudt

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Abstract

This investigation was aimed at determining the possible relationship between DNA interstrand cross-linking and the cytotoxic activity of potential antitumour mitosene compounds. Mitosenes, possessing two good leaving groups at C-1 and C-10, were found to be able to cross-link calf thymus DNA under hypoxic conditions following sodium dithionite (Na2S2O4) reduction at pH 7.0 and pH 5.5. DNA interstrand cross-linking was pH dependent for most of the mitosenes used, with a higher amount of cross-links formed at pH 5.5 compared to pH 7.0. Without reduction or under aerobic conditions no cross-link formation was detected. The importance of DNA damage for the toxic effect of these mitosenes was assayed by comparing the survival in a DNA repair deficient and a DNA repair proficient E. coli K-12 strain. A correlation between the number of cross-links formed in calf thymus DNA in vitro and the 50 values in the DNA repair deficient E. coli strain was found. The effect of hypoxia on toxicity of mitosenes was studied in Chinese hamster V79 cells. In these cells, mitosenes appeared to be very active. Under severe hypoxic conditions toxicity of these mitosenes increased, most likely due to the increased lifetime of the activated mitosene species as compared to aerobic conditions. The results suggest that DNA cross-linking following reductive activation is important for the eventual activity of mitosenes in a bacterial system. Increased activity of mitosenes under hypoxic conditions in the V79 cells indicates that these mitosenes may be more active in hypoxic parts of tumours.
Original languageUndefined
Pages (from-to)9320-9323
JournalBiochemical pharmacology
Volume48
Issue number48
DOIs
Publication statusPublished - 1994

Keywords

  • IR-12346
  • METIS-106617

Cite this

Maliepaard, Marc ; Sitters, Karin A.M.C. ; de Mol, Nico J. ; Janssen, Lambert H.M. ; Stratford, Ian J. ; Stephens, Miriam ; Verboom, Willem ; Reinhoudt, David. / Potential antitumour mitosenes: relationship between in vitro DNA interstrand cross-link formation and DNA damage in escherichia coli K-12 strains. In: Biochemical pharmacology. 1994 ; Vol. 48, No. 48. pp. 9320-9323.
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title = "Potential antitumour mitosenes: relationship between in vitro DNA interstrand cross-link formation and DNA damage in escherichia coli K-12 strains",
abstract = "This investigation was aimed at determining the possible relationship between DNA interstrand cross-linking and the cytotoxic activity of potential antitumour mitosene compounds. Mitosenes, possessing two good leaving groups at C-1 and C-10, were found to be able to cross-link calf thymus DNA under hypoxic conditions following sodium dithionite (Na2S2O4) reduction at pH 7.0 and pH 5.5. DNA interstrand cross-linking was pH dependent for most of the mitosenes used, with a higher amount of cross-links formed at pH 5.5 compared to pH 7.0. Without reduction or under aerobic conditions no cross-link formation was detected. The importance of DNA damage for the toxic effect of these mitosenes was assayed by comparing the survival in a DNA repair deficient and a DNA repair proficient E. coli K-12 strain. A correlation between the number of cross-links formed in calf thymus DNA in vitro and the 50 values in the DNA repair deficient E. coli strain was found. The effect of hypoxia on toxicity of mitosenes was studied in Chinese hamster V79 cells. In these cells, mitosenes appeared to be very active. Under severe hypoxic conditions toxicity of these mitosenes increased, most likely due to the increased lifetime of the activated mitosene species as compared to aerobic conditions. The results suggest that DNA cross-linking following reductive activation is important for the eventual activity of mitosenes in a bacterial system. Increased activity of mitosenes under hypoxic conditions in the V79 cells indicates that these mitosenes may be more active in hypoxic parts of tumours.",
keywords = "IR-12346, METIS-106617",
author = "Marc Maliepaard and Sitters, {Karin A.M.C.} and {de Mol}, {Nico J.} and Janssen, {Lambert H.M.} and Stratford, {Ian J.} and Miriam Stephens and Willem Verboom and David Reinhoudt",
year = "1994",
doi = "10.1016/0006-2952(94)90559-2",
language = "Undefined",
volume = "48",
pages = "9320--9323",
journal = "Biochemical pharmacology",
issn = "0006-2952",
publisher = "Elsevier",
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Potential antitumour mitosenes: relationship between in vitro DNA interstrand cross-link formation and DNA damage in escherichia coli K-12 strains. / Maliepaard, Marc; Sitters, Karin A.M.C.; de Mol, Nico J.; Janssen, Lambert H.M.; Stratford, Ian J.; Stephens, Miriam; Verboom, Willem; Reinhoudt, David.

In: Biochemical pharmacology, Vol. 48, No. 48, 1994, p. 9320-9323.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Potential antitumour mitosenes: relationship between in vitro DNA interstrand cross-link formation and DNA damage in escherichia coli K-12 strains

AU - Maliepaard, Marc

AU - Sitters, Karin A.M.C.

AU - de Mol, Nico J.

AU - Janssen, Lambert H.M.

AU - Stratford, Ian J.

AU - Stephens, Miriam

AU - Verboom, Willem

AU - Reinhoudt, David

PY - 1994

Y1 - 1994

N2 - This investigation was aimed at determining the possible relationship between DNA interstrand cross-linking and the cytotoxic activity of potential antitumour mitosene compounds. Mitosenes, possessing two good leaving groups at C-1 and C-10, were found to be able to cross-link calf thymus DNA under hypoxic conditions following sodium dithionite (Na2S2O4) reduction at pH 7.0 and pH 5.5. DNA interstrand cross-linking was pH dependent for most of the mitosenes used, with a higher amount of cross-links formed at pH 5.5 compared to pH 7.0. Without reduction or under aerobic conditions no cross-link formation was detected. The importance of DNA damage for the toxic effect of these mitosenes was assayed by comparing the survival in a DNA repair deficient and a DNA repair proficient E. coli K-12 strain. A correlation between the number of cross-links formed in calf thymus DNA in vitro and the 50 values in the DNA repair deficient E. coli strain was found. The effect of hypoxia on toxicity of mitosenes was studied in Chinese hamster V79 cells. In these cells, mitosenes appeared to be very active. Under severe hypoxic conditions toxicity of these mitosenes increased, most likely due to the increased lifetime of the activated mitosene species as compared to aerobic conditions. The results suggest that DNA cross-linking following reductive activation is important for the eventual activity of mitosenes in a bacterial system. Increased activity of mitosenes under hypoxic conditions in the V79 cells indicates that these mitosenes may be more active in hypoxic parts of tumours.

AB - This investigation was aimed at determining the possible relationship between DNA interstrand cross-linking and the cytotoxic activity of potential antitumour mitosene compounds. Mitosenes, possessing two good leaving groups at C-1 and C-10, were found to be able to cross-link calf thymus DNA under hypoxic conditions following sodium dithionite (Na2S2O4) reduction at pH 7.0 and pH 5.5. DNA interstrand cross-linking was pH dependent for most of the mitosenes used, with a higher amount of cross-links formed at pH 5.5 compared to pH 7.0. Without reduction or under aerobic conditions no cross-link formation was detected. The importance of DNA damage for the toxic effect of these mitosenes was assayed by comparing the survival in a DNA repair deficient and a DNA repair proficient E. coli K-12 strain. A correlation between the number of cross-links formed in calf thymus DNA in vitro and the 50 values in the DNA repair deficient E. coli strain was found. The effect of hypoxia on toxicity of mitosenes was studied in Chinese hamster V79 cells. In these cells, mitosenes appeared to be very active. Under severe hypoxic conditions toxicity of these mitosenes increased, most likely due to the increased lifetime of the activated mitosene species as compared to aerobic conditions. The results suggest that DNA cross-linking following reductive activation is important for the eventual activity of mitosenes in a bacterial system. Increased activity of mitosenes under hypoxic conditions in the V79 cells indicates that these mitosenes may be more active in hypoxic parts of tumours.

KW - IR-12346

KW - METIS-106617

U2 - 10.1016/0006-2952(94)90559-2

DO - 10.1016/0006-2952(94)90559-2

M3 - Article

VL - 48

SP - 9320

EP - 9323

JO - Biochemical pharmacology

JF - Biochemical pharmacology

SN - 0006-2952

IS - 48

ER -