DNA damage following combination of radiation with the bioreductive drug AQ4N: Possible selective toxicity to oxic and hypoxic tumour cells

MV Hejmadi, SR McKeown, OP Friery, Irene McIntyre, LH Patterson, DG Hirst

    Research output: Contribution to journalArticle

    30 Citations (Scopus)

    Abstract

    AQ4N (1,4-bis-{[2-(dimethylamino-N-oxide)ethyl]amino}5,8-dihydroxyanthrac ene-9,10-dione) is a novel bioreductive agent that can be reduced to a stable, DNA-affinic compound, AQ4. The alkaline comet assay was used to evaluate DNA damage induced by AQ4N and radiation. Cells prepared from freshly excised T50/80 murine tumours were shown to have the ability to reduce AQ4N to a DNA-damaging agent; this had disappeared within 24 h of excision. When T50/80 tumours implanted in BDF mice were exposed to radiation in vivo a considerable amount of DNA damage was present in tumours excised immediately. Minimal levels of DNA damage were detectable in tumours excised after 2-5 h. AQ4N given 30 min before radiation had no appreciable influence on this effect and AQ4N alone caused only a small amount of damage. When AQ4N and radiation were combined an increasing number of damaged cells were seen in tumours excised 24-96 h after irradiation. This was interpreted as evidence of the continued presence of AQ4, or AQ4-induced damage, which was formed in cells hypoxic at the time of administration of AQ4N. AQ4, a potent topoisomerase II inhibitor, would be capable of damaging cells recruited into the cell cycle following radiation damage to the well-oxygenated cells of the tumour. The kinetics of the expression of the DNA damage is consistent with this hypothesis and shows that AQ4 has persistent activity in vivo.
    LanguageEnglish
    Pages499-505
    JournalBRITISH JOURNAL OF CANCER
    Volume73
    Issue number4
    Publication statusPublished - Feb 1996

    Fingerprint

    DNA Damage
    Radiation
    Pharmaceutical Preparations
    Neoplasms
    Topoisomerase II Inhibitors
    Comet Assay
    DNA
    AQ4N
    Oxides
    Cell Cycle
    Cell Count

    Keywords

    • DNA damage
    • bioreductive drug
    • AQ4N

    Cite this

    Hejmadi, MV., McKeown, SR., Friery, OP., McIntyre, I., Patterson, LH., & Hirst, DG. (1996). DNA damage following combination of radiation with the bioreductive drug AQ4N: Possible selective toxicity to oxic and hypoxic tumour cells. BRITISH JOURNAL OF CANCER, 73(4), 499-505.
    Hejmadi, MV ; McKeown, SR ; Friery, OP ; McIntyre, Irene ; Patterson, LH ; Hirst, DG. / DNA damage following combination of radiation with the bioreductive drug AQ4N: Possible selective toxicity to oxic and hypoxic tumour cells. In: BRITISH JOURNAL OF CANCER. 1996 ; Vol. 73, No. 4. pp. 499-505.
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    Hejmadi, MV, McKeown, SR, Friery, OP, McIntyre, I, Patterson, LH & Hirst, DG 1996, 'DNA damage following combination of radiation with the bioreductive drug AQ4N: Possible selective toxicity to oxic and hypoxic tumour cells', BRITISH JOURNAL OF CANCER, vol. 73, no. 4, pp. 499-505.

    DNA damage following combination of radiation with the bioreductive drug AQ4N: Possible selective toxicity to oxic and hypoxic tumour cells. / Hejmadi, MV; McKeown, SR; Friery, OP; McIntyre, Irene; Patterson, LH; Hirst, DG.

    In: BRITISH JOURNAL OF CANCER, Vol. 73, No. 4, 02.1996, p. 499-505.

    Research output: Contribution to journalArticle

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    T1 - DNA damage following combination of radiation with the bioreductive drug AQ4N: Possible selective toxicity to oxic and hypoxic tumour cells

    AU - Hejmadi, MV

    AU - McKeown, SR

    AU - Friery, OP

    AU - McIntyre, Irene

    AU - Patterson, LH

    AU - Hirst, DG

    PY - 1996/2

    Y1 - 1996/2

    N2 - AQ4N (1,4-bis-{[2-(dimethylamino-N-oxide)ethyl]amino}5,8-dihydroxyanthrac ene-9,10-dione) is a novel bioreductive agent that can be reduced to a stable, DNA-affinic compound, AQ4. The alkaline comet assay was used to evaluate DNA damage induced by AQ4N and radiation. Cells prepared from freshly excised T50/80 murine tumours were shown to have the ability to reduce AQ4N to a DNA-damaging agent; this had disappeared within 24 h of excision. When T50/80 tumours implanted in BDF mice were exposed to radiation in vivo a considerable amount of DNA damage was present in tumours excised immediately. Minimal levels of DNA damage were detectable in tumours excised after 2-5 h. AQ4N given 30 min before radiation had no appreciable influence on this effect and AQ4N alone caused only a small amount of damage. When AQ4N and radiation were combined an increasing number of damaged cells were seen in tumours excised 24-96 h after irradiation. This was interpreted as evidence of the continued presence of AQ4, or AQ4-induced damage, which was formed in cells hypoxic at the time of administration of AQ4N. AQ4, a potent topoisomerase II inhibitor, would be capable of damaging cells recruited into the cell cycle following radiation damage to the well-oxygenated cells of the tumour. The kinetics of the expression of the DNA damage is consistent with this hypothesis and shows that AQ4 has persistent activity in vivo.

    AB - AQ4N (1,4-bis-{[2-(dimethylamino-N-oxide)ethyl]amino}5,8-dihydroxyanthrac ene-9,10-dione) is a novel bioreductive agent that can be reduced to a stable, DNA-affinic compound, AQ4. The alkaline comet assay was used to evaluate DNA damage induced by AQ4N and radiation. Cells prepared from freshly excised T50/80 murine tumours were shown to have the ability to reduce AQ4N to a DNA-damaging agent; this had disappeared within 24 h of excision. When T50/80 tumours implanted in BDF mice were exposed to radiation in vivo a considerable amount of DNA damage was present in tumours excised immediately. Minimal levels of DNA damage were detectable in tumours excised after 2-5 h. AQ4N given 30 min before radiation had no appreciable influence on this effect and AQ4N alone caused only a small amount of damage. When AQ4N and radiation were combined an increasing number of damaged cells were seen in tumours excised 24-96 h after irradiation. This was interpreted as evidence of the continued presence of AQ4, or AQ4-induced damage, which was formed in cells hypoxic at the time of administration of AQ4N. AQ4, a potent topoisomerase II inhibitor, would be capable of damaging cells recruited into the cell cycle following radiation damage to the well-oxygenated cells of the tumour. The kinetics of the expression of the DNA damage is consistent with this hypothesis and shows that AQ4 has persistent activity in vivo.

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    KW - bioreductive drug

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    M3 - Article

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    EP - 505

    JO - BRITISH JOURNAL OF CANCER

    T2 - BRITISH JOURNAL OF CANCER

    JF - BRITISH JOURNAL OF CANCER

    SN - 0007-0920

    IS - 4

    ER -