Immune effector cells produce lethal DNA damage in cells treated with a thiopurine.
Azathioprine, a widely used immunosuppressant, is also used in the control of inflammatory disorders. These are characterized by the local accumulation of immune effector cells that produce reactive oxygen species (ROS). The DNA of azathioprine-treated patients contains 6-thioguanine (6-TG), a base analogue that is particularly susceptible to oxidation. Here, we show that 6-TG is vulnerable to ROS produced by chemical oxidants and that cells containing DNA 6-TG are hypersensitive to these oxidants. We also show that 6-TG incorporated into the DNA of macrophages sensitizes them to killing by endogenously produced ROS. ROS generated by macrophages are also a hazard for cocultured nonmacrophage cells containing DNA 6-TG. This bystander vulnerability of cells containing DNA 6-TG to oxidation by ROS generated by immune effector cells has implications for the long-term use of azathioprine in the management of inflammatory disorders.
Daehn
Ilse
I
Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Herts, United Kingdom.
Karran
Peter
P
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013866:Thioguanine / Q000378:metabolism*
D000975:Antioxidants; D004273:DNA, Neoplasm; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D013866:Thioguanine