title: Oxidation-mediated DNA cross-linking contributes to the toxicity of 6-thioguanine in human cells.
abstract: The thiopurines azathioprine and 6-mercaptopurine have been extensively prescribed as immunosuppressant and anticancer agents for several decades. A third member of the thiopurine family, 6-thioguanine (6-TG), has been used less widely. Although known to be partly dependent on DNA mismatch repair (MMR), the cytotoxicity of 6-TG remains incompletely understood. Here, we describe a novel MMR-independent pathway of 6-TG toxicity. Cell killing depended on two properties of 6-TG: its incorporation into DNA and its ability to act as a source of reactive oxygen species (ROS). ROS targeted DNA 6-TG to generate potentially lethal replication-arresting DNA lesions including interstrand cross-links. These triggered processing by the Fanconi anemia and homologous recombination DNA repair pathways. Allopurinol protected against 6-TG toxicity by acting as a ROS scavenger and preventing DNA damage. Together, our findings provide mechanistic evidence to support the proposed use of thiopurines to treat HR-defective tumors and for the coadministration of 6-TG and allopurinol as an immunomodulation strategy in inflammatory disorders.
authors: Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts, United Kingdom.
authors: Reto
authors: R
authors: Brem
authors: Peter
authors: P
authors: Karran
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D005199:Fanconi Anemia / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D010084:Oxidation-Reduction / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013866:Thioguanine / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D003432:Cross-Linking Reagents; D017382:Reactive Oxygen Species; D004247:DNA; D013866:Thioguanine