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

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    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.
    Original languageEnglish
    Pages (from-to)499-505
    JournalBRITISH JOURNAL OF CANCER
    Volume73
    Issue number4
    Publication statusPublished - Feb 1996

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    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.