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

Br J Cancer. 1996 Feb;73(4):499-505. doi: 10.1038/bjc.1996.87.

Abstract

AQ4N (1,4-bis-([2-(dimethylamino-N- oxide)ethyl]amino)5,8-dihydroxyanthracene-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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aerobiosis
  • Animals
  • Anthraquinones / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Cell Hypoxia
  • Cell Line
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • DNA Damage*
  • DNA, Neoplasm / drug effects*
  • DNA, Neoplasm / radiation effects*
  • Female
  • Humans
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Tumor Cells, Cultured

Substances

  • Anthraquinones
  • Antineoplastic Agents
  • DNA, Neoplasm
  • AQ4N