Rapamune® (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression

Vezina, 1975, Rapamycin (AY-22,989), a new antifungal antibiotic. I. toxonomy of the producing streptomycete and isolation of the active principle, J Antibiot, 28, 721, 10.7164/antibiotics.28.721 Sehgal, 1975, Rapamycin (AY-22,989) a new antifungal antibiotic. II. Fermentation, isolation and characterization, J Antibiot, 28, 727, 10.7164/antibiotics.28.727 Douros, 1981, New antitumor substances of natural origin, Cancer Treatment Reviews, 8, 63, 10.1016/S0305-7372(81)80006-0 Eng, 1984, Activity of rapamycin (AY-22,989) against transplanted tumors, J Antibiot, 37, 1231, 10.7164/antibiotics.37.1231 Martel, 1977, Inhibition of the immune response by rapamycin, a new antifungal antibiotic, Can J Physiol Pharmacol, 55, 48, 10.1139/y77-007 Sehgal, 1994, Rapamycin, Medicinal Research Reviews, 14, 1, 10.1002/med.2610140102 Kahan, 1996, Multi-center Phase II Trails of Sirolimus (SRL) in Renal Transplantation, Abstracts of XVI International Congress of the Transplantation Society, Abstract #86, 75 Sehgal, 1993, An in vitro immunological profile of rapamycin, Annal NY Acadm Sci, 685, 58, 10.1111/j.1749-6632.1993.tb35852.x Bertagnolli, 1994, Evidence that rapamycin inhibits interleukin-12-induced proliferation of activated T lymphocytes, Transplantation, 58, 1091, 10.1097/00007890-199411000-00006 Terada, 1993, Rapamycin blocks cell cycle progression of activated T cells prior to events characteristic of the middle to late G1 phase of the cycle, J Cell Physiol, 154, 7, 10.1002/jcp.1041540103 Dumont, 1990, Distinct mechanisms of suppression of murine T-cell activation by the related macrolides FK-506 and rapamycin, J Immunology, 144, 251, 10.4049/jimmunol.144.1.251 Aaguaard-Tillery, 1994, Inhibition of human B lymphocyte cell cycle progression and differentiation by rapamycin, Cell Immunol, 152, 493, 10.1006/cimm.1994.1193 Kim, 1994, Effects of cyclosporine and rapamycin on immunoglobulin production by preactivated human B cells, Clin Exp Immunol, 96, 508, 10.1111/j.1365-2249.1994.tb06058.x Ferraresso, 1994, Rapamycin inhibits production of cytotoxic but not noncytotoxic antibodies and preferentially activates T helper 2 cells that mediate long-term survival of heart allografts in rats, J Immunol, 153, 3307, 10.4049/jimmunol.153.7.3307 Schmidbauer, 1994, Abrogation by rapamycin of accelerated rejection in sensitized rats by inhibition of alloantibody responses and selective suppression of intragraft mononuclear and endothelial cell activation, cytokine production, and cell adhesion, Transplantation, 57, 933, 10.1097/00007890-199403270-00028 Molnar-Kimber, 1994, Evidence that the anti-tumor and immunosuppressive effects of rapamycin are mediated via similar mechanisms, Cold Spring Harbor Symposium, 141 Cao, 1995, Effect of rapamycin on growth factor-stimulated vascular smooth muscle cell DNA synthesis, Transplantation, 59, 390, 10.1097/00007890-199502150-00014 Marx, 1995, Rapamycin-FKBP inhibit cell cycle regulators of proliferation in vascular smooth muscle cell, Circ Res, 76, 412, 10.1161/01.RES.76.3.412 Francavilla, 1992, Effects of rapamycin on cultured hepatocyte proliferation and gene expression, Hepatology, 15, 871, 10.1002/hep.1840150520 Nair, 1997, Antiproliferative effect of rapamycin on growth factor-stimulated human adult lung fibroblasts in vitro may explain its superior efficacy for prevention and treatment of allograft obliterative airway disease in vivo, Transplant Proc, 29, 614, 10.1016/S0041-1345(96)00325-9 Harding, 1989, A receptor for the immunosuppressant FK-506 is a cis-trans peptidyl prolyl isomerase, Nature, 341, 758, 10.1038/341758a0 Fretz, 1991, Rapamycin and FK506 binding proteins, J Am Chem Soc, 113, 1409, 10.1021/ja00004a051 Wood, 1994, Rapamycin, Perspec Drug Discovery Design, 2, 163, 10.1007/BF02171742 Wiederrecht, 1994, Immunophilins, Perspec Drug Discovery Design, 2, 57, 10.1007/BF02171737 Koltin, 1991, Rapamycin sensitivity in Sacharomyces cerevisiae is mediated by a peptidyl-prolyl cis-trans isomerase related to human FKBP, Mol Cell Biol, 11, 1718, 10.1128/MCB.11.3.1718 Liu, 1991, Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes, Cell, 66, 807, 10.1016/0092-8674(91)90124-H Liu, 1992, Inhibition of T cell signaling by immunophilin.ligand complexes correlates with loss of calcineurin phosphatase activity, Biochemistry, 31, 3896, 10.1021/bi00131a002 Flanagan, 1992, Nuclear association of a T-cell transcription factor blocked by FK506 and Cyclosporin A, Nature, 352, 803, 10.1038/352803a0 McCaffrey, 1993, NF-ATp, a T lymphocyte DNA-binding protein that is a target for calcineurin and immunosuppressive drugs, J Biol Chem, 268, 3747, 10.1016/S0021-9258(18)53757-1 Albers, 1993, FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line, J Biol Chem, 268, 22825, 10.1016/S0021-9258(18)41602-X Jayaraman, 1993, Rapamycin-FKBP12 blocks proliferation, induces differentiation, and inhibits cdc2 kinase activity in a myogenic cell line, J Biol Chem, 268, 25385, 10.1016/S0021-9258(19)74403-2 Heitman, 1991, Target for cell cycle arrest by the immunosuppressant rapamycin in yeast, Science, 253, 905, 10.1126/science.1715094 Cafferkey, 1994, Yeast TOR (DRR) proteins, Gene, 141, 133, 10.1016/0378-1119(94)90141-4 Helliwell, 1994, TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast, Mol Biol Cell, 5, 105, 10.1091/mbc.5.1.105 Chen, 1994, A putative sirolimus (rapamycin) effector protein, Biochem Biophys Res Commun, 203, 1, 10.1006/bbrc.1994.2140 Brown, 1994, Purification and molecular cloning of FRAP, a direct target of G1 arrest complex FKBP12-rapamycin, Nature, 369, 756, 10.1038/369756a0 Sabers, 1994, Isolation of protein target of FKBP12-rapamycin complex in mammalian cells, J Biol Chem, 270, 815, 10.1074/jbc.270.2.815 Sabatini, 1995, Characterization of the RAFT-1 protein, the mammalian target of the G1-arrest complex, FKBP12-rapamycin, Soc Neurosci Abstr, 21, 1128 Chiu, 1994, RAPT1, a mammalian homolog of Yeast TOR, interacts with the FKBP12/Rapamycin Complex, Proc Natl Acad Sci USA, 91, 12574, 10.1073/pnas.91.26.12574 Kunz, 1993, Targer of Rapamycin in Yeast, TOR2, is an essential Phosphatidylinossitol kinase Homolog Required for G1 Progression, Cell, 73, 585, 10.1016/0092-8674(93)90144-F Sabatini, 1995, The rapamycin and FKBP12 target (RAFT) displays phosphatidylinositol 4-kinase activity, J Biol Chem, 270, 20875, 10.1074/jbc.270.36.20875 Alarcon, 1996, Mammalian RAFT1 kinase domain provides rapamycin-sensitive TOR function in yeast, Genes Develop, 10, 279, 10.1101/gad.10.3.279 Chen, 1995, Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue, Proceed Natl Acad Sci USA, 92, 4947, 10.1073/pnas.92.11.4947 Lorenz, 1995, TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin, J Biol Chem, 270, 27531, 10.1074/jbc.270.46.27531 Choi, 1996, Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP, Science, 273, 239, 10.1126/science.273.5272.239 Brown, 1995, Control of p70 S6 kinase by kinase activity of FRAP in vivo, Science, 377, 441 Chung, 1992, Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 Kd S6 protein kinases, Cell, 69, 1227, 10.1016/0092-8674(92)90643-Q Kuo, 1992, Rapamycin Selectively Inhibits Interleukin-2 Activation of p70 S6 Kinase, Nature, 358, 70, 10.1038/358070a0 Price, 1992, Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase, Science, 257, 973, 10.1126/science.1380182 Dumont, 1994, Relationship between multiple biologic effects of rapamycin and the inhibition of pp70S6 protein kinase activity. Analysis in mutant clones of a T cell lymphoma, J Immunol, 152, 992, 10.4049/jimmunol.152.3.992 Jefferies, 1997, Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70(s6k), EMBO J, 16, 3693, 10.1093/emboj/16.12.3693 Jefferies, 1994, Rapamycin selectively represses translation of the “polypyrimidine tract” mRNA family, Proc Natl Acad Sci USA, 91, 441, 10.1073/pnas.91.10.4441 Terada, 1994, Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins, Proc Natl Acad Sci USA, 91, 11477, 10.1073/pnas.91.24.11477 Terada, 1995, Rapamycin inhibits ribosomal protein synthesis and induces G1 prolongation in mitogen-activated T lymphocytes, J Immunology, 155, 3418, 10.4049/jimmunol.155.7.3418 Beretta, 1996, Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent intiation of translation, EMBO J, 15, 658, 10.1002/j.1460-2075.1996.tb00398.x Brunn, 1997, Phosphorylation of the translational repressor phase-I by the mammalian target of rapamycin, Science, 277, 99, 10.1126/science.277.5322.99 Brown, 1996, A signaling pathway to translational control, Cell, 86, 517, 10.1016/S0092-8674(00)80125-7 de Groot, 1994, Positive regulation of the cAMP-Responsive Activator CREM by the p70 S6 Kinase, Cell, 79, 81, 10.1016/0092-8674(94)90402-2 Feuerstein N, Huang D, Prystowsky MB. Rapamycin selectively blocks IL-2 induced PCNA gene expression in T lymphocytes: evidence for the role of CREB-ATF binding activities. 9th International Congress of Immunology-July 23–29, San Francisco 1995. Javier, 1997, Rapamycin (sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells, J Clin Invest, 99, 2094, 10.1172/JCI119382 Feuerstein, 1996, Late Induction of CREB/AFT Binding and a concomitant Increase in cAMP levels in T and B Lymphocytes Stimulated via the Antigen Receptor, J Immunol, 156, 4582, 10.4049/jimmunol.156.12.4582 Lai, 1994, CD28 signalling causes a sustained down-regulation of 1 kappa B alpha which can be prevented by the immunosuppressant rapamycin, J Biol Chem, 269, 30077, 10.1016/S0021-9258(18)43774-X Sherr, 1994, G1 Phase progression, Cell, 79, 551, 10.1016/0092-8674(94)90540-1 Nourse, 1994, Interleukin 2 mediated elimination of the p27kip1 cyclin dependent kinase inhibitor prevented by rapamycin, Nature, 372, 570, 10.1038/372570a0 Flanagan, 1993, Rapamycin inhibits p34cdc2 expression and arrests T lymphocyte proliferation at the G1/S transition, Ann NY Acad Sci, 696, 31, 10.1111/j.1749-6632.1993.tb17139.x Schmandt, 1994, IL-2-induced expression of TTK, a serine, threonine, tyrosine kinase, correlates with cell cycle progression, J Immunol, 152, 96, 10.4049/jimmunol.152.1.96 Adachi, 1996, Interleukin-2 (IL-2) upregulates BAG-1 gene expression through serine-rich region within IL-2 receptor beta c chain, Blood, 88, 4118, 10.1182/blood.V88.11.4118.4118 Shi, 1995, Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro, Cancer Res, 55, 1982 Miyazaki, 1995, Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation, Cell, 81, 223, 10.1016/0092-8674(95)90332-1