P072. A novel mouse model relates thiopurine hepatic sinusoidal obstructive syndrome to dose-exposure of 6‑thioguanosine nucleotides
I. Oancea1, C.‑W. Png2, I. Das1, R. Lourie3, I. Winkler1, M. McGuckin1, J. Duley4, T. Florin5
1Mater Medical Research Institute, Australia; 2Massachusetts General Hospital and Harvard Medical School, Australia; 3Mater Pathology Service, Australia; 4University of Queensland, Pharmacy, Australia; 5University of Queensland Mater Health Services MMRI, Australia
Background: Thiopurine drugs are a cornerstone for the maintenance treatment of IBD. 6‑thioguanine (6TG) has been proposed as an alternative faster-acting less allergenic therapy than azathioprine or mercaptopurine. However it is implicated with veno-occlusive disease/sinusoidal obstructive syndrome (SOS) [PMID20124218].
Methods: Wildtype, and Hprt ko, PE-selectin double ko or Winnie [PMID21107311] C57Bl/6 mice, were gavaged daily with 6TG (05 mg/kg/d) or 6MP, methyl-6MP or methyl-6TG (≤5 mg/kg/d). Livers were assessed blindly for SOS, using a score that comprised hepatic sinusoid, central vein and necroinflammatory subscores.
Results: Only 6TG caused SOS. SOS was dose-related for 6TG gavages ≥ 1 mg/kg/d. SOS did not occur with gavaging non-lethal doses of 6TG (≤0.5 mg/kg/d) for 28 days. Hprt ko mice do not make thioguanosine nucleotides: SOS and immunosuppression did not occur with 6TG in Hprt ko mice. PE-selectin double ko mice lack expression of both of P‑ and E‑selectins on the surface of endothelial cells and therefore the leukocyte adhesion cascade of adhesion, rolling and diapedesis is impaired: all SOS-subscores were markedly reduced when 6TG was gavaged in PE-selectin double ko mice.
Of important clinical relevance, SOS was reduced by splt-dosing, a manoeuvre that reduced portal Cmax and also improved the spontaneous colitis of Winnie.
Conclusions: We have developed a novel model of SOS due to 6TG in which it is shown that the SOS pathology is threshold dose-related, is not a thiopurine class effect, is mediated by thioguanosine nucleotides, and is amplified by inflammatory leukocytes entering the liver. There are important translational outcomes that arise from this model because there is a clinical need for an economical faster-acting, more tolerated safe immunomodulatory therapy for IBD patients.
[PMID20124218] Stork LC, Matloub Y, Broxson E, La M, Yanofsky R, Sather H, Hutchinson R, Heerema NA, Sorrell AD, Masterson M, Bleyer A, Gaynon PS (2010), Oral 6‑mercaptopurine versus oral 6‑thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial.
[PMID21107311] Eri RD, Adams RJ, Tran TV, Tong H, Das I, Roche DK, Oancea I, Png CW, Jeffery PL, Radford-Smith GL, Cook MC, Florin TH, McGuckin MA (2011), An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity.