The Specific Monocarboxylate Transporter (MCT1) Inhibitor, AR-C117977, a Novel Immunosuppressant, Prolongs Allograft Survival in the Mouse.
Bueno, Valquiria 1; Binet, Isabelle 1; Steger, Ulrich 1; Bundick, Robert 2; Ferguson, Douglas 3; Murray, Clare 2; Donald, David 4; Wood, Kathryn 1,5
84(9):1204-1207, November 15, 2007.
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Novel small molecular weight compounds that act by inhibiting the monocarboxylate transporter (MCT1) receptor have been found to cause profound inhibition of T-cell responses to alloantigen in vitro. Here, we have investigated the ability of one compound in this series, AR-C117977, a potent MCT1 inhibitor, to prevent the acute and chronic rejection of vascularized and nonvascularized allografts in the mouse. Treatment with AR-C117977 or cyclosporin A (CsA) administered at a dose of 30 mg/kg subcutaneously for 15 days to adult CBA. Ca (H2k) mice, commencing either 3 days or 1 day before transplantation, was found to prolong the survival of an allogeneic (C57BL/10 H2b; NZW H2z; or BALB/c H2d) heart, aorta, or skin allograft significantly compared with treatment with vehicle alone (median survival time [MST] AR-C117977 treated 15; 19 and 18 days [skin] and 73; 66 and 67 days ([heart] vs. vehicle treated 8, 8 and 9 days [skin] and 9, 8, 10 days [heart] for B10, NZW and BALB grafts, respectively). AR-C117977 also inhibited the development of transplant arteriosclerosis in aortic allografts partially, but was unable to inhibit alloantibody production after transplantation. The specific MCT1 inhibitor AR-C117977 has potent immunosuppressive properties in vivo effectively preventing acute but not chronic allograft rejection in the mouse.
(C) 2007 Lippincott Williams & Wilkins, Inc.