6-Thioguanine (6-TG), along with 6-mercaptopurine (6-MP) and azathioprine (AZA) are members of the thiopurine class of drugs. Thiopurines have immunosuppressive and antimetabolic properties and hence they have been used successfully to treat a diverse variety of disease states such as inflammatory bowel disease (IBD) and the acute leukemias [1]. 6-MP and, to a lesser extent, 6-TG, have been used extensively in the treatment of childhood acute lymphoblastic leukemia (ALL) for over half a decade with great success. However, both drugs have been implicated in the development of hepatic veno-occlusive disease or sinusoidal obstruction syndrome (SOS) of the liver in contemporary risk-based treatment protocols in children with ALL. SOS has been described in multiple clinical settings. It occurs with a frequency of 5–15% after myeloablative conditioning and stem cell transplantation (SCT) [2]. Oral thiopurine administration, in particular 6-TG therapy, is also a risk factor for the development of SOS [3,4]. The pathobiology of SOS is complex, and is not only concerned with endothelial injury and hepatocyte necrosis, but also with dysregulation of the inflammatory and coagulation pathways that modulate tissue injury and fibrosis [5]. The site of injury is zone 3 of the liver acinus [6] and is characterized by hepatic venular occlusion, sinusoidal fibrosis, and necrosis of hepatocytes [3]. Immunohistochemical staining shows deposition of fibrin(ogen), factor VIII and von Willebrand factor (vWF) in the vessel walls, indicating that at some point in the development of SOS, endothelial damage and clot formation occur [3]. Low plasma levels of Protein C and antithrombin have been observed in a number of studies of patients who develop SOS [5], while elevations in plasma vWF and thrombomodulin (TM) before and after SCT can be used to predict the occurrence of SOS [7]. Cytokines have also been implicated in the pathogenesis of SOS, as soluble Interleukin (IL)2 receptor, interferon (IFN)-g, IL-6 [3] tumor necrosis factor (TNF)-a [3,8] and IL-8 [2] have all been found at increased levels in patients who develop SOS. Biomarkers of endothelial damage, such as plasma vWF and TM are also increased in patients with SOS [5,7] as is the expression of tissue factor (TF) on the cell surface [3]. Although the pro-inflammatory and pro-coagulant nature of SOS has been reasonably well documented in clinical studies, there is still a lack of understanding of the basic mechanism(s) that trigger the development of this syndrome. The aim of this study was to examine the effects of 6-TG and 6-MP in vitro on the expression and secretion of mediators of coagulation and inflammation in an attempt to gain a better insight into the pathway(s) involved in the development of SOS. Therefore, we investigated the effect of 6-TG and 6-MP on secretion of TNF-a and IL-8 in three leukemic cell lines (THP1, acute

Pro-inflammatory and pro-coagulant properties of 6-thioguanine and 6-mercaptopurine: implications for their potential role in the development of sinusoidal obstruction syndrome.

G. Murga

Papers

Prediction of VOD Using Biomarkers of Endothelial Injury