(IL-1 IL-2 IL-5 IL-6 IL-8 IFN-γ) (collagenase ) T T glucocorticoid ( 1-1)[1] cortisol 90% corticosteroid binding globulin(cbg) (Alb) Alb CBG hydrocort

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1 (6 ) 1 2 cyclophosphamide ifomide melphalan etc 3 methotrexate azathioprine mercaptopurine mizoribine mycophenolate mofetil etc 4 vincristine vinblastine vindesine etoposide etc 5 mitomycin C daunorubicin doxorubicin bleomycin mitoxantrone cyclosporin FK506 etc 6 ( ) 1)monoclonal antibody 2)soluble cytokine receptor 3)IL-1receptor antagonist (1) ( glucocorticoid) cortisone( cortisol ) glucocorticoid( ) glucocorticoid receptor (GR) GR DNA GR DNA GR (cyclooxygenase 2)

mitoxantrone cyclosporin FK506 etc 6 ( ) 1)monoclonal antibody 2)soluble cytokine receptor 3)IL-1receptor antagonist

2 (IL-1 IL-2 IL-5 IL-6 IL-8 IFN-γ) (collagenase ) T T glucocorticoid ( 1-1)[1] cortisol 90% corticosteroid binding globulin(cbg) (Alb) Alb CBG hydrocortisone prednisolone ( ) [2] 1-2 Dexamethasone betamethasone [3] [3] (2)Cyclophosphamide( cyclophosphamide; CPA) 1 CPA cytochrome P-450 mixed-function oxidase system(2b6) 2 10 [4] CPA 1 phosphoramide mustard acrolein phosphoramide mustard CPA 20% (67%) CPA

Dexamethasone betamethasone [3] 1-3 1-4 [3] (2)Cyclophosphamide( cyclophosphamide; CPA) 1 CPA

3 DNA guanine γ DNA CPA CPA 7 [5] NIH CPA (5-HT3) CPA acrolein aldehyde acrolein sodium 2-mercaptoethanesulfonate [6] CPA (a) (b) (c) ( ) 1980 (3)Azathioprine( azathioprine; AZP) ( 2-1 2) AZP 6-6-mercaptopurine; 6-MP hypoxanthine-guanine phospho- ribosyltransferase AZP 6-MP DNA RNA [7]

) 1980 (3)Azathioprine( azathioprine; AZP) ( 2-1 2) AZP

4 AZP 6-MP 45 5 AZP 30% 6-MP 188% AZP 2000/µl [8] 3000/µl (4)Methotrexate( methotraxate; MTX) MTX( 3) 1 2 MTX (80%) (10 30%) MTX [9] MTX Dihydrofolic acid reductase dihydro- tetrahydrofolic acid DNA RNA S DNA

5 MTX Calcium folinate MTX (5)Mizoribine( mizoribine; MZR) MZR ( 4-1) MZR adenosine kinase (MZR-5 -P) MZR-5 -P GMP de novo IMP dehydrogenase (IMPDH) GMP synthetase IMPDH GMP synthetase 1000 de novo salvage 2 T B de novo salvage IMPDH IMPDH MZR GMP DNA RNA ( 4-2) MZR T T [10] MZR MRZ 1465% 497% 246% 242% MRZ salvage DNA MZR

synthetase IMPDH GMP synthetase 1000 de novo salvage 2 T B de novo salvage IMPDH

6 MZR AZP (6)Mycophenolate mofetil Mycophenolate mofetil T B de novo [11] cyclosporine [12 13] [12-15] (6)Mitoxantrone( ) Mitoxantrone( 5) anthraquinone doxorubicin quinone doxorubicin Mitoxantrone topoisomerase DNA [16] Mitoxantrone [17] (7)Cyclosporin A( A; cyclosporin A; CyA) Trichoderma polysporum Rifai Cylindrocarpon lucidum 2 11

doxorubicin quinone doxorubicin Mitoxantrone topoisomerase DNA [16] Mitoxantrone

7 A CyA CyA CyA bioavailability 30% CyA CyA micro-emulsion CyA bioavailability CyA 60 70% CyA CyA ( ) ( ) [18] CyA CyA CyA CyA P450 A 30 CyA 10 20% CyA l/hr/kg CyA 90% 6% 1% CyA -2(IL-2) γ (Interferon-γ; IFN-γ) (c-myc c-fos) (cyclophilin; CyP) CyA CyP cis-trans rotamase CyA CyP cis-trans CyA-CyP - T NF-AT DNA

20% CyA 038 3 l/hr/kg 19 24 CyA 90% 6% 1% CyA -2(IL-2) γ (Interferon-γ; IFN-γ)

8 AP-3 NF-κB IL-2 NF-AT phosphatase NF-AT(nuclear factor of activated T cells) CyA IL-2 IL-2 ( 6)[19] CyA CyA CyA CyA CyA T Epstein-Barr CyA bioavailability CyA 12 ( trough level) CyA ng/ml 300ng/ml ng/ml ng/ml

CyA CyA T Epstein-Barr CyA bioavailability CyA 12 (

9 CyA ng/ml CyA CyA 2 bioavailability (8) Tacrolimus hydrate (FK506) FK506 Streptomyces tsukubaensis T IL-2-3(IL-3) IFN-γ (Cyclosporin) (Cyclophilin; CyP) FK506 FKBP(FK506 binding protein) FKBP T NF-AT Jun/Fos NF-AT IL-2mRNA FK506/FKBP12 NF-AT [20] FK506 T FK506 CyA FK506 CyA CyA FK506 CYP3A4 1% FK hr ml/h/kg l/kg

FKBP(FK506 binding protein) FKBP T NF-AT Jun/Fos NF-AT IL-2mRNA FK506/FKBP12 NF-AT [20]

10 10% FK506 [21] EB ( 7) CPA AZP MTX DNA S MZR de novo MZR S B CyA FK506 IL-2 G0 G2 [1] Clark JH Schrader WT O Malley BW: Mechanism of action of steroid hormones Text of Endocrinology (ed by Wilson JD Foster DW) Saunders Philadelphia 8 th Edition pp [2] Robert C Haynes Jr: Goodman and Gilman s the pharmacological basis of therapeutics (ed by Gilman AG Rall TW Nies AS and Taylor P) Pergamon Press 8 th Edition pp [3] Meldy JC: Systemic corticosteroid therapy; pharmacology and endcrinologic considerations Ann Intern Med 81: [4] Kovarsky J: Clinical pharmacology and toxicology of cyclophosphamide: Emphasis on use in rheumatic disease Semin Arthritis Rheum 12: [5] Baltus JAM Boersma JW Hartman AP et al: The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: A controlled retrospective follow-up Ann Rheum Dis 42: [6] Hows JM Mehta A Ward L et al: Comparison of mesna with forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplantation: A prospective randamised study Br J Cancer 50:

Pergamon Press 8 th Edition pp1444-1446 1990 [3] Meldy JC: Systemic corticosteroid therapy; pharmacology and endcrinologic considerations Ann Intern Med 81: 505 1974 [4] Kovarsky J: Clinical

11 [7] Kutz P Fauci AS: Immunosuppressive and immunoadjuvants Immunological Diseases (ed by Samter M et al) 4 th Edition pp [8] Hohlfeld R Michels M Heininger K et al: Azathioprine toxicity during long-term immunosuppression of generalized myasthenia gravis Neurology 38: [9] Markham A Faulds D: Methotrexate: a view of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in rheumatoid arthritis and other immunoregulatory disorders Clin Immunother 1: [10] Kusumi T et al: Dual inhibitory effect of Bredinin Cell Biochem Funct 7: [11] Allison AC Eugui EM: Purine metabolism and immunosuppressive effects of mycophenolate mofetil(mmf) Clin Transplant 10: [12] European Mycophenolate Mofetil Cooperative Study Group Placebo-controlled study of mycophenolate mofetil combined with cyclosporine and corticosteroids for prevention of acute rejection Lancet 345: [13] Sollinger HW for the US Renal Transplantation Mycophenolate Mofetil Study Group Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients Transplantation 60: [14] Behrend M A review of clinical experience with the novel immunosuppressive drug mycophenolate mofetil in renal transplantation Clin Nephrol 45: [15] Allison AC Eugui EM: Preferential suppression of lymphocyte proliferation by mycophenolic acid and predicted long-term effects of mycophenolate mofetil in transplantation Transplant Proc 26: [16]Calabresi P Chabner BA: Goodman and Gilman s the pharmacological basis of therapeutics (ed by Gilman AG Rall TW Nies AS and Taylor P) Pergamon press 8 th Edition pp [17]Calabresi PA: Considerations in the treatment of relapsing-remitting multiple sclerosis Neurology 23;58(8 Suppl 4):S [18] : TDM

therapeutic efficacy in rheumatoid arthritis and other immunoregulatory disorders Clin Immunother 1: 217-244 1994 [10] Kusumi T et al: Dual inhibitory effect of Bredinin Cell Biochem Funct 7: 201-204

12 pp [19] : pp [20] : 117(8): [21]Wiesner RH: A long term comparison of tacrolimus(fk506) versus cyclosporine in liver transplantation Transplantion 66(4):

13 1-1 (1) (2) (3) (4) (5) 1-2 Na (h) (h)

14 ) 2) 3) 4) ST INH 1) 2) ( mg) 3) D 1) ( ) 2) H 1) ( 10mg g ) 2)

15 1) 2) (HMG-CoA ) 1 Cyclophosphamide AZP 6-MP C9H7N7O2S C5H4N4S H2O AZP 6-MP

16 2-2 AZP 3 Methotrexate 4-1 Mizoribine

17 4-2 Mizoribine 5 Mitoxantrone

18 T B Fc PLC PIP2 IP3 DG [Ca 2+ ]i PKC Ca 2+ CyA-CyP P NF-ATc NF-ATc NF-ATc NF-ATc NF-ATc NF-ATn NF-ATn 6 CyA IL-2 IL-3 IL-4 INFγ TNFα PLC: C PIP:

19 DG: PKC: C NF-AT:nuclear factor of activated T cell n:nuclear c:cytoplasmic CPA CyA FK506 AZP MZR G0 G1 S G2 M 7 CyA FK506 CPA MZR AZP

Key words: pure red cell anemia, allogeneic bone marrow transplantation.

Key words: pure red cell anemia, allogeneic bone marrow transplantation. Complete Recovery of Hemopoiesis Following Bone Marrow Transplantation in a Patient with Unresponsive Congenital Pure Red Cell Anemia Masami SHIMADA, Hideo MUGISHIMA, Mitsuhiko HARA, Masahiro MISAWA, Hideo