Abstract 3498: Synergistic effects of sinomenine combined with low dose cyclosporine A on acute graft-versus-host disease in a murine model

Abstract

Abstract Hematopoietic stem cell transplantation (HSCT) is now routinely used to treat patients with cancers and other disorders of the blood and immune systems. Allogeneic HSCT (allo-HSCT) is limited by acute graft-versus-host disease (aGVHD), a significant cause of post-transplant morbidity and mortality. Cyclosporine A (CsA) is used as the basis of most immuno-suppressive regimens for the prevention of aGVHD, but is limited by side effects at high doses. High plasma concentrations are normally needed to ensure allograft survival in episodes of acute rejection. Therefore, new drugs or treatment strategies are needed. Our objective was to investigate the effect of sinomenine (SIN), a pure alkaloid from the plant Sinomenium acutum Rehd.et Wils, in combination with subtherapeutic dose of CsA on aGVHD in a murine model of allogeneic bone marrow transplantation (allo-BMT). We used a MHC-mismatched allo-BMT mouse model (H-2banti H-2d). Injection of lethally irradiated BALB/C (H-2d) mice with C57BL/6(H-2b) spleen and bone marrow cells induces severe aGVHD resulting in death within 2-3 weeks. To prevent aGVHD, recipients were randomly divided into 5 groups and given CsA and SIN alone or in combination. Subtherapeutic SIN (25 mg/kg, group A) or CsA (5 mg/kg, group B) alone could not prolong the mean survival time (MST) of recipients after transplantation (MST 15.9 days for SIN and 16.0 days for CsA, P>0.05). By contrast, combined therapy (SIN 25 mg/kg with CsA 5 mg/kg, group C) demonstrated synergistic effect resulting in significant prolongation of MST (44.4 days, P<0.01). This effect was similar to the therapeutic dose of CsA (20 mg/kg, group D) treatment (MST 41.0 days). Interestingly, we found that high dose SIN (50 mg/kg, group E) alone could also significantly increase MST (33.4 days, P<0.01). Body weight and peripheral white blood cell count significantly improved under combined therapy. On the 14th day post-transplantation, serum IL-2 level was significantly reduced with the combined treatment. On the 25th day post-transplantation, FACS analysis of the recipient peripheral blood showed high percentage H-2 Kb positive white blood cells (group B 38.92%, group C 83.50%, and group E 78.85%). Histopathology examination of liver, gut, and skin from the recipients on day 14 after BMT showed decreased aGVHD induced tissue damage in treated groups which have longer MST.These data suggested a potential value of sinomenine in the prevention of aGVHD with low dose CsA after allo-BMT. Sinomenine has markedly reduced side effects and improved safety in this allo-BMT mouse model. The potential application of sinomenine in transplantation and its mechanisms should be further investigated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3498. doi:1538-7445.AM2012-3498