title: A novel mouse model of veno-occlusive disease provides strategies to prevent thioguanine-induced hepatic toxicity.
abstract: OBJECTIVE
  The anti-leukemic drugs, azathioprine and 6-mercaptopurine (6MP), are important in the treatment of inflammatory bowel disease but an alternative faster-acting, less-allergenic thiopurine, 6-thioguanine (6TG), can cause hepatic veno-occlusive disease/sinusoidal obstructive syndrome (SOS). Understanding of SOS has been hindered by inability to ethically perform serial liver biopsies on patients and the lack of an animal model.
  
  
  METHODS
  Normal and C57Bl/6 mice with specific genes altered to elucidate mechanisms responsible for 6TG-SOS, were gavaged daily for upto 28d with 6TG, 6MP or methylated metabolites. Animal survival was monitored and at sacrifice a histological score of SOS, haematology and liver biochemistry were measured.
  
  
  RESULTS
  Only 6TG caused SOS, which was dose related. 6TG and to a lesser extent 6MP but not methylated metabolites were associated with dose-dependent haematopoietic toxicity. SOS was not detected with non-lethal doses of 6TG. SOS did not occur in hypoxanthine-phosphoribosyl transferase-deficient C57Bl/6 mice, demonstrating that 6TG-SOS requires thioguanine nucleotides. Hepatic inflammation was characteristic of SOS, and C57Bl/6 mice deficient in P- and E-selectins on the surface of vascular endothelial cells showed markedly reduced SOS, demonstrating a major role for leukocytes recruited from blood. Split dosing of 6TG markedly attenuated SOS but still effected immunosuppression and prevented spontaneous colitis in Winnie mice, which have a single nucleotide polymorphism mutation in Muc2.
  
  
  CONCLUSIONS
  This novel model provides clinically relevant insights into how 6TG induces SOS, and how this dangerous adverse drug reaction may be avoided by either inhibition of endothelial activation or simple changes to dosing regimens of 6TG, while still being effective treatment for colitis.
authors: IBD Team, Immunology Infection Inflammation Program, Mater Medical Research Institute, South Brisbane, Queensland, Australia.
authors: Iulia
authors: I
authors: Oancea
authors: Chin Wen
authors: CW
authors: Png
authors: Indrajit
authors: I
authors: Das
authors: Rohan
authors: R
authors: Lourie
authors: Ingrid G
authors: IG
authors: Winkler
authors: Rajaraman
authors: R
authors: Eri
authors: Nathan
authors: N
authors: Subramaniam
authors: H A
authors: HA
authors: Jinnah
authors: Brett C
authors: BC
authors: McWhinney
authors: Jean-Pierre
authors: JP
authors: Levesque
authors: Michael A
authors: MA
authors: McGuckin
authors: John A
authors: JA
authors: Duley
authors: Timothy H J
authors: TH
authors: Florin
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced* / Q000517:prevention & control; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D013866:Thioguanine / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D013866:Thioguanine