Mammalian target of rapamycin (mTOR) inhibitors: Potential uses and a review of haematological adverse effects

Drug Safety

Volumn 34, Issue 2, 2011, Pages 97-115

  Sofroniadou, Sofia ^a   Goldsmith, David ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Anaemia, drug induced; Everolimus, adverse reactions; Haematological disorders, drug induced; Leucopenia; mTOR protein inhibitors, adverse reactions; Sirolimus, adverse reactions; Tacrolimus, adverse reactions; Temsirolimus, adverse reactions; Thrombocytopenia, drug induced.

Indexed keywords

AZATHIOPRINE; CORTICOSTEROID; CYCLOSPORIN A; DACLIZUMAB; ERYTHROPOIETIN; EVEROLIMUS; HEPCIDIN; INTERFERON; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; PLACEBO; PREDNISONE; RAPAMYCIN; RIDAFOROLIMUS; TACROLIMUS; TEMSIROLIMUS; ZOTAROLIMUS;

ADVANCED CANCER; ANEMIA; AUTOIMMUNE DISEASE; AUTOIMMUNE HEPATITIS; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; AUTOIMMUNE MYOCARDITIS; BONE MARROW CELL; BONE MARROW SUPPRESSION; BREAST CANCER; COLORECTAL CANCER; COWDEN SYNDROME; DIFFERENTIAL DIAGNOSIS; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG ELUTING STENT; DRUG MECHANISM; DRUG MEGADOSE; DRUG SUBSTITUTION; DRUG WITHDRAWAL; ENDOMETRIUM CANCER; GRAFT REJECTION; GRAFT VERSUS HOST REACTION; HEART LUNG TRANSPLANTATION; HEART VENTRICLE HYPERTROPHY; HEMATOLOGIC DISEASE; HEMATOLOGIC MALIGNANCY; HEMATOLOGICAL PARAMETERS; HEMOGLOBINOPATHY; HOMEOSTASIS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HUNTINGTON CHOREA; IMMUNOSUPPRESSIVE TREATMENT; IRON DEFICIENCY ANEMIA; IRON METABOLISM; KAPOSI SARCOMA; KIDNEY CARCINOMA; KIDNEY POLYCYSTIC DISEASE; KIDNEY TRANSPLANTATION; LEUKEMIA; LEUKOCYTE COUNT; LEUKOPENIA; LIVER FIBROSIS; LIVER TRANSPLANTATION; LOW DRUG DOSE; LUNG FIBROSIS; LUNG NON SMALL CELL CANCER; LYMPHOPROLIFERATIVE DISEASE; MANTLE CELL LYMPHOMA; MEAN CORPUSCULAR VOLUME; MEMBRANOUS GLOMERULONEPHRITIS; META ANALYSIS (TOPIC); METABOLIC REGULATION; METASTASIS; MICROCYTIC ANEMIA; MICROCYTOSIS; MULTICENTER STUDY (TOPIC); MYELOID LEUKEMIA; MYOCARDITIS; NEUROENDOCRINE TUMOR; NEUROFIBROMATOSIS; NEUTROPENIA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHODGKIN LYMPHOMA; NONHUMAN; OBESITY; PANCREAS TRANSPLANTATION; PEUTZ JEGHERS SYNDROME; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER; POSTTRANSPLANTATION ANEMIA; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RHEUMATOID ARTHRITIS; SARCOMA; SIDE EFFECT; SIGNAL TRANSDUCTION; SOLID TUMOR; SYSTEMIC LUPUS ERYTHEMATOSUS; THROMBOCYTE COUNT; THROMBOCYTOPENIA;

ANTINEOPLASTIC AGENTS; AUTOIMMUNE DISEASES; HEMATOLOGIC NEOPLASMS; HUMANS; IMMUNOSUPPRESSIVE AGENTS; TOR SERINE-THREONINE KINASES;

EID: 78751616780     PISSN: 01145916     EISSN: 11791942     Source Type: Journal    
DOI: 10.2165/11585040-000000000-00000     Document Type: Review

References (138)

1. Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001; 15: 807-26
2. Jacinto E, Hall MN. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 2003; 4: 117-26
3. Avruch JK, Hara Y, Lin X, et al. Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene 2006; 25 (48): 6361-72
4. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124: 471-84
5. Yang Q, Guan K-L. Expanding mTOR signaling. Cell Res 2007; 17: 666-81
6. Kim DH, Sarbassov DD, Ali SM, et al. MTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110: 163-75
7. Loewith R, Jacinto E, Wullschleger S, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 2002; 10: 457-68
8. Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulin-regulated inhibitor of themTORC1 protein kinase. Mol Cell 2007; 25: 903-15
9. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14: 1296-302
10. Pearce LR, Huang X, Boudeau J, et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 2007; 405: 513-22
11. Sarbassov DD, Ali SM, Sabatini DM. Growing roles for themTORpathway. Curr Opin Cell Biol 2005; 17: 596-603
12. Morelon E, Mamzer-Breneel MF, Peraldi MN, et al. Sirolimus: a new promising immunosuppressive drug. Towards a rationale for its use in renal transplantation. Nephrol Dial Transplant 2001; 16: 18-20
13. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22: 159-68
14. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006; 5: 671-88
15. Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 2000; 27: 6680-6
16. Rowinsky EK. Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol 2004; 16: 564-75
17. Kahan BD, Podbielski J, Napoli KL, et al. Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. Transplantation 1998; 66: 1040-6
18. Groth CG, Bä ckman L, Morales JM, et al. Sirolimus (rapamycin)- based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Transplantation 1999; 67: 1036-42
19. Kreis H, Cisterne JM, Land W, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000; 69: 1252-60
20. Chapman TM, Perry CM. Everolimus. Drugs 2004; 64: 861-73
21. Vincenti F, Stock P. De novo use of sirolimus in immunosuppression regimens in kidney and kidney-pancreas transplantation at the University of California, San Francisco. Transplant Proc 2003; 35 (3 Suppl.): 18-6S
22. Rogers J, Ashcraft EE, Emovon OE, et al. Long-term outcome of sirolimus rescue in kidney-pancreas transplantation. Transplantation 2004; 78: 619-22
23. McAlister VC, Peltekian KM, Malatjalian DA, et al. Orthotopic liver transplantation using low-dose tacrolimus and sirolimus. Liver Transpl 2001; 7: 701-8
24. Trotter JF, Wachs M, Bak T, et al. Liver transplantation using sirolimus and minimal corticosteroids (3-day taper). Liver Transpl 2001; 7: 343-51
25. Keogh AM, the Sirolimus Cardiac Transplant Trial Group. Sirolimus immunotherapy reduces the rates of cardiac allograft rejection: 6-month results froma phase 2, open-label study [abstract]. Am J Transplant 2002; 2 Suppl. 3: S246
26. Groetzner J, Meiser B, Landehr P, et al. Mycophenolate mofetil and sirolimus as calcineurin inhibitor-free immunosuppression for late cardiac-transplant recipients with chronic renal failure. Transplantation 2004; 77: 568-74
27. Villanueva J, Boukhamseen A, Bhorade SM. Successful use in lung transplantation of an immunosuppressive regimen aimed at reducing target blood levels of sirolimus and tacrolimus. Heart Lung Transplant 2005; 24: 421-5
28. Venuta F, De Giacomo T, Rendina EA, et al. Recovery of renal impairment with sirolimus after lung transplantation. Ann Thorac Surg 2004; 78: 1940-3
29. Benito AI, Furlong T, Martin PJ, et al. Sirolimus (rapamycin) for the treatment of steroid-refractory acute graftversus- host disease. Transplantation 2001; 72: 1924-9
30. Stallone G, Schena A, Infante B, et al. Sirolimus forKaposi's sarcoma in renal transplant recipients. N Engl J Med 2005; 352: 1317-23
31. Campistol JM, Eris J, Oberbauer R, et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol 2006; 17: 581-9
32. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008; 358: 140-51
33. Reardon DA, Quinn JA, Vredenburgh JJ, et al. Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 2006; 12: 860-8
34. Ratain MJ, Napoli KL, Moshier KK, et al. A phase 1b study of oral rapamycin (sirolimus) in patients with advanced malignancies. ASCO Annu Meet Proc 2007; 25 Suppl. 18 (Pt I): 3510
35. Chen W, Grammatikakis I, Li J, et al. Inhibition of Akt/mTOR signaling pathway induces cell cycle arrest and apoptosis in acute myelogenous leukaemia [abstract]. Blood (ASH Annual Meeting Abstracts) 2005; 106: 2355
36. Milton DT, Riely GJ, Azzoli CG, et al. Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall- cell lung cancer. Cancer 2007; 110: 599-605
37. Bendell JC, George D, Nixon A, et al. Results of a phase I study of bevacizumab (BV), everolimus (EV), and erlotinib (E) in patients with advanced solid tumors. ASCO Annu Meet Proc 2007; 25 Suppl. 18 (Pt 1): 3548
38. Speca JC, Mears AL, Creel PA, et al. Phase I study of PTK787/ZK222584 (PTK/ZK) and RAD001 for patients with advanced solid tumors and dose expansion in renal cell carcinoma patients. ASCO Annu Meet Proc 2007; 25 Suppl. 18 (Pt I): 5039
39. Yao JC, Phan A, Chang DZ, et al. Phase II study of RAD001 (everolimus) and depot octreotide (sandostatin LAR) in advanced low grade neuroendocrine carcinoma (LGNET). ASCO Ann Meet Proc 2007; 25 Suppl. 18 (Pt 1): 4503
40. Majewski M, Korecka M, Kossev P, et al. The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo: a potential approach to prevention and treatment of posttransplant lymphoproliferative disorders. Proc Natl Acad Sci USA 2000; 97: 4285-90
41. Yee KWL, Wierda W, O'Brien S, et al. A phase I/II study of the oral mTOR inhibitor RAD001 in patients with advanced hematologic malignancies [abstract]. Blood (ASH Annual Meeting Abstracts) 2004; 104: 4818
42. Hidalgo M, Buckner JC, Erlichman C, et al. A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 2006; 12: 5755-63
43. Carpenter JT, Roche H, Campone M, et al. Randomized 3-arm, phase 2 study of temsirolimus (CCI-779) in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer. ASCO Annu Meet Proc 2005; 23 Suppl. 16 (Pt 1): 564
44. Oza AM, Elit L, Biagi J, et al. Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer-NCIC IND 160. ASCO Annu Meet Proc 2006; 24 Suppl. 18 (Pt I): 3003
45. Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005; 23: 5347-56
46. Mita MM, Mita AC, Chu QS, et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 2008; 26: 361-7
47. Desai AA, Janisch L, Berk LR, et al. A phase I trial of a novel mTOR inhibitor AP23573 administered weekly (wkly) in patients (pts) with refractory or advanced malignancies: a pharmacokinetic (PK) and pharmacodynamic (PD) analysis. ASCOAnnu Meet Proc 2004; 22 Suppl. 14: 3150
48. Chawla SP, TolcherAW, StaddonAP, et al. Updated results of a phase II trial of AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas. ASCO Annu Meet Proc 2006; 24 Suppl. 18 (Pt I): 9505
49. Lee L, Sudentas P, Donohue B, et al. Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Genes Chromosomes Cancer 2005; 42: 213-27
50. Foroncewicz B, Mucha K, Paczek L, et al. Efficacy of rapamycin in patient with juvenile rheumatoid arthritis. Transpl Int 2005; 18: 366-8
51. Bruyn GA, Tate G, Caeiro F, et al. Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3 month double-blind, randomized, placebocontrolled parallel-group, proof-of-concept study. Ann Rheum Dis 2008; 67: 1090-5
52. Fernandez D, Bonilla E, Mirza N, et al. Rapamycin reduces activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum 2006; 54: 2983-8
53. Teachey DT, Greiner R, Seif A, et al. Treatment with sirolimus results in complete response in patients with autoimmune lymphoproliferative syndrome. Br J Haematol 2009; 145: 101-6
54. Maeda K, Shioi T, Kosugi R, et al. Rapamycin ameliorates experimental autoimmune myocarditis. Int Heart J 2005; 46: 513-30
55. Kerkar N, Dugan C, Rumbo C, et al. Rapamycin successfully treats post-transplant autoimmune hepatitis. Am J Transplant 2005; 5: 1085-9
56. Bonegio RG, Fuhro R, Wang Z, et al. Rapamycin ameliorates proteinuria-associated tubulointerstitial inflammation and fibrosis in experimental membranous nephropathy. J Am Soc Nephrol 2005; 16: 2063-72
57. Heredia A, Amoroso A, Davis C, et al. Rapamycin causes down-regulation of CCR5 and accumulation of anti-HIV beta-chemokines: an approach to suppress R5 strains of HIV-1. Proc Natl Acad Sci USA 2003; 100: 10411-6
58. Sarkar S, Krishna G, Imarisio S, et al. A rationalmechanism for combination treatment of Huntington's disease using lithium and repamycin. HumMol Genet 2008; 17: 170-8
59. MoriH, Inoki K, Masutani K, et al. The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem Biophys Res Commun 2009; 384: 471-5
60. Um SH, Frigerio F, Watanabe M, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004; 431: 200-5
61. Wang C-Y, Kim H-H, Hiroi Y, et al. Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR. Sci Signal 2009; 2 (62): ra11
62. Serra AL, Kistler AD, Poster D, et al. Safety and tolerability of sirolimus treatment in patients with autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2009; 24: 3334-42
63. Simler NR, Howell DC, Marshall RP, et al. The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats. Eur Respir J 2002; 19: 1124-7
64. Biecker E, De Gottardi A, Neef M, et al. Long-term treatment of bile duct-ligated rats with rapamycin (sirolimus) significantly attenuates liver fibrosis: analysis of the underlying mechanisms. J Pharmacol Exp Ther 2005; 313: 952-61
65. Shioi T, McMullen JR, Tarnavski O, et al. Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation 2003; 107: 1664-70
66. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003; 349: 1315-23
67. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346: 1773-80
68. Sehgal SN. Immunosuppressive profile of rapamycin. Ann N Y Acad Sci 1993; 696: 1-8
69. Martel RR, Klicius J, Galet S. Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J Physiol Pharmacol 1977; 55: 48-51
70. Calne RY, Collier DS, Lim S, et al. Rapamycin for immunosuppression in organ allografting [letter]. Lancet 1989; II (8656): 227
71. Morris RE, Meiser BM. Identification of a new pharmacologic action for an old compound. Med Sci Res 1989; 17: 877-81
72. Neff GW, Montalbano M, Tzakis AG. Ten years of sirolimus therapy in orthotopic liver transplant recipients. Transplant Proc 2003; 35 (3 Suppl.): 209-16S
73. Douros J, Suffness M. New antitumor substances of natural origin. Cancer Treat Rev 1981; 8: 63-87
74. Houchens DP, Ovejera A, Riblet SM, et al. Human brain tumor xenografts in nude mice as a chemotherapy model. Eur J Cancer Clin Oncol 1983; 19: 799-805
75. Applegate RJ, Hermiller JJ, Sanz M, et al. Comparison of everolimus-eluting and paclitaxel-eluting coronary stents in patients with two treated vessels: 2-year results from the SPIRIT III randomised trial. EuroIntervention 2010; 6: 437-46
76. Park DW, Kim YH, Yun SC, et al. Comparison of zotarolimus- eluting stents with sirolimus- and paclitaxel-eluting stents for coronary revascularization: the ZEST (comparison of the efficacy and safety of zotarolimus-eluting stent with sirolimus-eluting and paclitaxel-eluting stent for coronary lesions) randomized trial. JAmColl Cardiol 2010; 56: 1187-95
77. Murgia MG, Jordan S, Kahan BD. The side effect profile of sirolimus: a phase I study in quiescent cyclosporineprednisone- treated renal transplant patients. Kidney Int 1996; 49: 209-16
78. Hong J, Kahan BD. Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients: risk factors, incidence, progression and management. Transplantation 2000; 69: 2085-90
79. Babinska A, Markell MS, Salifu MO, et al. Enhancement of human platelet aggregation and secretion induced by rapamycin. Nephrol Dial Transplant 1998; 13: 3153-9
80. MacDonald AS, for the Rapamune Global Study Group Transplant Service. A randomized trial of sirolimus, cyclosporine and prednisone vs cyclosporine-prednisone alone in recipients of mismatched first kidney grafts: results at one year [abstract]. 25th Annual Meeting of the American Society of Transplant Surgeons; 1999 May 19-21; Chicago (IL)
81. Kahan BD, for the USA Rapamune Study Group. Pivotal phase III multicenter, randomized, blinded trial of sirolimus versus azathioprine in combination with cyclosporine and prednisone in primary renal transplants [abstract]. 25th Annual Meeting of the American Society of Transplant Surgeons; 1999 May 19-21; Chicago (IL)
82. Paul SR, Bennett F, Calvetti JA, et al. Molecular cloning of a cDNA encoding interleukin 11, a stromal cell-derived lymphopoietic and hematopoietic cytokine. Proc Natl Acad Sci USA 1990; 87 (19): 7512-6
83. Quesniaux VF, Wehrli S, Steiner C, et al. The immunosuppressant rapamycin blocks in vitro responses to hematopoietic cytokines and inhibits recovering but not steady-state hematopoiesis in vivo. Blood 1994; 84: 1543-52
84. Tabernero J, Rojo F, Burris H, et al. A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and schedule of the oral mTOR-inhibitor everolimus (RAD001) in patients (pts) with advanced solid tumors [abstract]. J Clin Oncol 2005; 23 Suppl. 16: 3007
85. Vanrenterghem Y, Ponticelli C, Morales JM, et al. Prevalence and management of anaemia in renal transplant recipients: a European survey. Am J Transplant 2003; 3: 835-45
86. Shah N, Al-Khoury S, Afzali B, et al. Posttransplantation anaemia in adult renal allograft recipients: prevalence and predictors. Transplantation 2006; 81: 1112-8
87. Afzali B, Al-Khoury S, Shah N, et al. Anaemia after renal transplantation. Am J Kidney Dis 2006; 48: 519-36
88. MacDonald AS. A worldwide, phase III randomized controlled, safety and efficacy study of a SRL/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 2001; 71: 271-80
89. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomized multicentre study. The Rapamune US Study Group. Lancet 2000; 356: 194-202
90. Augustine JJ, Knauss TC, Schulak JA, et al. Comparative effects of sirolimus and mycophenolate mofetil on erythropoiesis in kidney transplant patients. Am J Transplant 2004; 4: 2001-6
91. Larson TS, Dean PG, Stegall MD, et al. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant 2006; 6: 514-22
92. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357: 2562-75
93. Toso Ch, Meeberg GA, Bigam DL, et al. De novo sirolimus- based immunosuppression after liver transplantation for hepatocellular carcinoma: long-term outcomes and side effects. Transplantation 2007; 83: 1162-8
94. Demirjian S, Stephany B, Abu Romeh IS, et al. Conversion to sirolimus with calcineurin inhibitor elimination vs. dose minimization and renal outcome in heart and lung transplant recipients. Clin Transplant 2009; 23: 351-60
95. Vitko S, Margreiterb R, Weimarc W, et al. Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2005; 5: 2521-30
96. Webster AC, Lee VWS, Chapman JP, et al. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. Transplantation 2006; 81: 1234-48
97. Bellmunt J, Szczylik C, Feingold J, et al. Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features . Ann Oncol 2008; 19 (8): 1387-92
98. Cahill BC, Troy K, Crompton JA, et al. Early experience with sirolimus in lung transplant recipients with chronic allograft rejection. J Heart Lung Transplant 2003; 22: 169-76
99. Friend P, Russ G, Oberbauer R, et al. Incidence of anaemia in sirolimus-treated renal transplant recipients: the importance of preserving renal function. Transplant Int 2007; 20: 754-60
100. Russ G, Schena FP, Oberbauer R, et al. Incidence and treatment of anaemia after conversion to sirolimus vs continuation of calcineurin inhibitors in renal allograft recipients: 2-year results from the CONVERT trial. American Society of Nephrology Annual Meeting: Renal Week 2006; 2006 Nov 14-19; San Diego (CA). J Am Soc Nephrol 2006; 17: 18A
101. Sanchez Fructuoso A, Calvo N, Moreno MA, et al. Study of anaemia after late introduction of everolimus in the immunosuppressive treatment of renal transplant patients. Transpl Proc 2007; 39: 2242-4
102. Masetti M, Rompianesi G, Montalt R, et al. Effects of everolimus monotherapy on haematological parameters and iron homeostasis in de novo liver transplant recipients: preliminary results. Transplant Proc 2008; 40: 1947-9
103. Bouscary D, Pene F, Claessens YE. Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation. Blood 2003; 101: 3436-43
104. Cruz R, Hedden L, Boyer D, et al. S6 kinase 2 potentiates interleukin-3-driven cell proliferation. J Leukoc Biol 2005; 78: 1378-85
105. Jaster R, Bittorf T, Klinken SP, et al. Inhibition of proliferation but not erythroid differentiation of J2E cells by rapamycin. Biochem Pharmacol 1996; 51: 1181-5
106. Kim MJ, Mayr M, Pechula M, et al. Marked erythrocyte microcytosis under primary immunosuppression with sirolimus. Transplant Int 2006; 19: 12-8
107. Maiorano A, Stallone G, Schema A, et al. Sirolimus interferes with iron homoestasis in renal transplant recipients. Transplantation 2006; 82: 908-12
108. Thaunat O, Beaumont C, Chatenoud L, et al. Anaemia after late introduction of sirolimus may correlate with biochemical evidence of a chronic inflammatory state. Transplantation 2005; 80: 1212-9
109. Augustine JJ, Rodriguez V, Padiyar A, et al. Reduction in erythropoietin resistance after conversion from sirolimus to enteric coated mycophenolate sodium. Transplantation 2008; 86: 548-53
110. Fishbane S, Cohen DJ, Coyne DW, et al. Posttransplant anaemia: the role of sirolimus.Kidney Int 2009; 76: 376-82
111. Fibach E, Bianchi N, Borgatti M, et al. Effects of rapamycin on accumulation of a-, b- and c-globin mRNAs in erythroid precursor cells from b-thalassaemia patients. Eur J Haematol 2006; 77: 437-41
112. Mischiati C, Sereni A, Lampronti I, et al. Rapamycinmediated induction of c-globin mRNA accumulation in human erythroid cells. Br J Haematol 2004; 126: 612-21
113. Zuccato C, Bianchi N, Borgatti M, et al. Everolimus is a potent inducer of erythroid differentiation and gammaglobin gene expression in human erythroid cells. Acta Haematol 2007; 117: 168-76
114. Sofroniadou S, Kassimatis T, Goldsmith D. Anaemia, microcytosis and sirolimus: is iron the missing link? Nephrol Dial Transplant 2010; 25: 1667-75
115. Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 2001; 98: 8780-5
116. Ganz T, Nemeth E. Iron imports: IV. Hepcidin and regulation of body iron metabolism. Am J Physiol Gastrointest Liver Physiol 2006; 290: G199-203
117. Donovan A, Lima CA, Pinkus GS, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005; 1: 191-200
118. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306: 2090-3
119. Ganz T. Molecular control of iron transport. J Am Soc Nephrol 2007; 18: 394-400
120. Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liverspecific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001; 276: 7811-9
121. Pak M, Lopez MA, Gabayan V, et al. Suppression of hepcidin during anemia requires erythropoietic activity. Blood 2006; 108: 3730-5
122. Nemeth E, Valore EV, Territo M, et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003; 101: 2461-3
123. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002; 110: 1037-44
124. Means Jr RT, Krantz SB. Inhibition of human erythroid colony-forming units by interferons alpha and beta: differing mechanisms despite shared receptor. Exp Hematol 1996; 24: 204-8
125. Theurl I, Mattle V, Seifert M, et al. Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease. Blood 2006; 107: 4142-8
126. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001; 276: 7806-10
127. Kulaksiz H, Gehrke SG, Janetzko A, et al. Pro-hepcidin: expression and cell specific localisation in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anaemia. Gut 2004; 53: 735-43
128. Taes YE, Wuyts B, Boelaert JR, et al. Prohepcidin accumulates in renal insufficiency. Clin Chem Lab Med 2004; 42: 387-9
129. Thaunat O, Beaumont C, Lechaton S, et al. Late introduction of sirolimus induces anaemia in renal transplant recipients [letter]. Transplantation 2007; 15: 1283
130. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003; 102: 783-8
131. Kemna E, Tjalsma H, Laarakkers C, et al. Novel urine hepcidin assay by mass spectrometry. Blood 2005; 106: 3268-70
132. Tomosugi N, Kawabata H, Wakatabe R, et al. Detection of serum hepcidin in renal failure and inflammation by using protein chip system. Blood 2006; 108: 1381-7
133. Murphy AT, Witcher DR, Luan P, et al. Quantitation of hepcidin from human and mouse serum using liquid chromatography tandem mass spectrometry. Blood 2007; 110: 1048-54
134. Kobold U, Dulffer T, Dangl M, et al. Quantification of hepcidin-25 in human serum by isotope dilution micro- HPLC-tandem mass spectrometry. Clin Chem 2008; 54: 1584-6
135. Li H, RoseMJ, Tran L, et al. Development of a method for the sensitive and quantitative determination of hepcidin in human serum using LC-MS/MS. J Pharmacol Toxicol Methods 2009; 59: 171-80
136. Ganz T, Olbina G, Girelli D, et al. Immunoassay for human serum hepcidin. Blood 2008; 112: 4292-7
137. Zaritsky J, Young B, Wang HJ, et al. Hepcidin: a potential novel biomarker of iron status in chronic kidney disease. Clin J Am Soc Nephrol 2009; 4: 1051-6
138. Koliaraki V, Marinou M, Vassilakopoulos TP, et al. A novel immunological assay for hepcidin quantification in human serum. PLoS ONE 2009; 4: e4581