Potent orally bioavailable purine nucleoside phosphorylase inhibitor BCX-4208 induces apoptosis in B- and T-lymphocytes-A novel treatment approach for autoimmune diseases, organ transplantation and hematologic malignancies

International Immunopharmacology

Volumn 10, Issue 7, 2010, Pages 784-790

  Bantia, Shanta ^a   Parker, Cynthia ^a   Upshaw, Ramanda ^a   Cunningham, Amanda ^a   Kotian, Pravin ^a   Kilpatrick, J Michael ^a   Morris, Philip ^a   Chand, Pooran ^a   Babu, Yarlagadda S ^a  

^a BIOCRYST PHARMACEUTICALS INC   (United States)

Author keywords

Autoimmune diseases; Immunosuppression; PNP; Transplantation

Indexed keywords

BCX 4208; CONCANAVALIN A; DEOXYGUANOSINE; DEOXYGUANOSINE TRIPHOSPHATE; LIPOCORTIN 5; PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITOR; RECOMBINANT INTERLEUKIN 2; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; APOPTOSIS; AREA UNDER THE CURVE; ARTICLE; B LYMPHOCYTE; CD19+ B CELL; CD20+ B CELL; CD3+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CONTROLLED STUDY; DOSE RESPONSE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DOSE COMPARISON; DRUG DOSE INCREASE; DRUG HALF LIFE; DRUG POTENCY; DRUG STRUCTURE; ENZYME INHIBITION; FEMALE; FLOW CYTOMETRY; HUMAN; HUMAN CELL; IC 50; LYMPHOCYTE ACTIVATION; LYMPHOCYTE PROLIFERATION; LYMPHOCYTE SUBPOPULATION; MAXIMUM PLASMA CONCENTRATION; MIXED LYMPHOCYTE REACTION; MOUSE; NATURAL KILLER CELL; NONHUMAN; PRIORITY JOURNAL; RAT; SINGLE DRUG DOSE; T LYMPHOCYTE; T LYMPHOCYTE SUBPOPULATION; TIME TO MAXIMUM PLASMA CONCENTRATION;

ADMINISTRATION, ORAL; APOPTOSIS; B-LYMPHOCYTES; CELL PROLIFERATION; CELLS, CULTURED; DEOXYGUANOSINE; ENZYME INHIBITORS; GRAFT REJECTION; HEMATOLOGIC NEOPLASMS; HUMANS; LYMPHOCYTE CULTURE TEST, MIXED; ORGAN TRANSPLANTATION; PSORIASIS; PURINE-NUCLEOSIDE PHOSPHORYLASE; T-LYMPHOCYTES;

EID: 77953024322     PISSN: 15675769     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.intimp.2010.04.009     Document Type: Article

References (27)

1. Markert M.L. Purine nucleoside phosphorylase deficiency. Immunodefic Rev 3 (1991) 45-81
2. Cohen A., Doyle D., Martin D.W., and Ammann A.J. Abnormal purine metabolism and purine overproduction in a patient deficient of purine nucleoside phosphorylase. N Engl J Med 295 (1976) 1449-1454
3. Dong M.K., and Gilbertsen R.B. PD 141955 and CI-972:9-deazaguanine analog purine nucleoside phosphorylase inhibitors. II. Effects on nucleoside catabolism in human and rat blood in vitro. Agents Actions 39 (1993) C-99-C101 (special conference issue)
4. Krenitsky T.A., Tuttle J.V., Koszalka G.W., Chen I.S., Beacham L.M., Rideout J.L., et al. Deoxycytidine kinase from calf thymus: substrate and inhibitor specificity. J Biol Chem 251 (1976) 4055-4061
5. Bantia S., Montgomery J.A., Johnson H.G., and Walsh G.M. In vivo and in vitro pharmacological activity of the purine nucleoside phosphorylase inhibitor BCX-34: the role of GTP and dGTP. Immunopharmacology 35 (1996) 53-63
6. Osborne W.R. Nucleoside kinases in T and B lymphoblasts distinguished by autoradiography. Proc Natl Acad Sci 83 (1986) 4030-4034
7. Carson D.A., Kaye J., and Seegmiller J.E. Lymphospecific toxicity in adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency: possible role of nucleoside kinase(s). Proc Natl Acad Sci 74 (1977) 5677-5681
8. Eriksson S., Arnér E., Spasokoukotskaja T., Wang L., Karlsson A., Brosjö O., et al. Properties and levels of deoxynucleoside kinases in normal and tumor cells; implications for chemotherapy. Adv Enzyme Regul 34 (1994) 13-25
9. Henderson J.F., Scott F.W., and Lowe J.K. Toxicity of naturally occurring purine deoxyribonucleosides. Pharmacol Ther 8 (1980) 573-604
10. Kazmers I.S., Mitchell B.S., Dadonna P.E., Wotring L.L., Townsend L.B., and Kelley W.N. Inhibition of purine nucleoside phosphorylase by 8-aminoguanosine: selective toxicity for T-lymphocytes. Science 214 (1981) 1137-1139
11. Scharenberg J.G., Rijkers G.T., Spaapen L.J., Toebes E.A., Rijksen G., Duran M., et al. Different pathways for deoxyguanosine toxicity in T-lymphocytes of various developmental stages. Int J Imunopharmacol 10 (1988) 675-686
12. Bantia S., Miller P.J., Parker C.D., Ananth S.L., Horn L.L., Babu Y.S., et al. Comparison of in vivo efficacy of BCX-1777 and cyclosporin in xenogeneic graft- vs. -host disease: the role of dGTP in antiproliferative action of BCX-1777. Int Immunopharmacol 2 (2002) 913-923
13. Oliver F.J., Collins M.K., and Lopez-Rivas A. dNTP pools imbalance as a signal to initiate apoptosis. Experientia 52 (1996) 995-1000
14. Hirota Y., Yoshioka A., Tanaka S., Watanabe K., Otani T., Minowada J., et al. Imbalance of deoxyribonucleoside triphosphates, DNA double-strand breaks, and cell death caused by 2-chlorodeoxyadenosine in mouse FM3A cells. Cancer Res 49 (1989) 915-919
15. Oliver F.J., Collins M.K., and Lopez-Rivas A. Regulation of the salvage pathway of deoxynucleotides synthesis in apoptosis induced by growth factor deprivation. Biochem J 316 (1996) 421-425
16. Lewandowicz A., Tyler P.C., Evans G.B., Furneaux R.H., and Schramm V.L. Achieving the ultimate physiological goal in transition state analogue inhibitors for purine nucleoside phosphorylase. J. Biol Chem 278 (2003) 31465-31468
17. Gomes J., Georgy A., Passe S., Farid A., Bantia S., and Wolff G. A phase II study of the purine nucleoside phosphorylase (PNP) inhibitor R05092888 (BCX-4208) in patients with moderate to severe chronic plaque psoriasis: safety, tolerability, and lymphocyte effects. Blood (ASH Annual Meeting Abstracts) (2008) 112 [Abstract 2583]
18. Sherman P.A., and Fyfe J.A. Enzymatic assay for deoxyribonucleoside triphosphates using synthetic oligonucleotides as template primers. Anal Biochem 180 (1989) 222-226
19. Siegenbeek van Heukelom L.H., Staal G.E., Stoop J.W., and Zegers B.J. An abnormal form of a purine nucleoside phosphorylase in a family with a child with severe defective T-cell and normal B-cell immunity. Clin Chim Acta 72 (1976) 117-124
20. Giblett E.R., Ammann A.J., Wara D.W., Sandman R., and Diamond L.K. Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity. Lancet 1 (1975) 1010-1013
21. Arpaia E., Benveniste P., Di Cristofano A., Gu Y., Dalal I., Kelly S., et al. Mitochondrial basis for immune deficiency: evidence from purine nucleoside phosphorylase-deficient mice. J Exp Med 191 (2000) 2197-2208
22. Simmonds H.A., Fairbanks L.D., Morris G.S., Morgan G., Watson A., Timms P., et al. Central nervous system dysfunction and erythrocyte guanosine triphosphate depletion in purine nucleoside phosphorylase deficiency. Arch Dis Child 62 (1987) 385-391
23. Kicska G.A., Long L., Horig H., Fairchild C., Tyler P.C., Furneaux R.H., et al. Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes. Proc Natl Acad Sci 98 (2001) 4593-4598
24. Gandhi V., Kilpatrick J.M., Plunkett W., Ayres M., Harman L., Du M., et al. A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor Immucillin H (BCX-1777, forodesine). Blood 106 (2005) 4253-4260
25. Pifer J., Stephan R.P., Lill-Elghanian D.A., Le P.T., and Witte P.L. Role of stromal cells and their products in protecting young and aged B-lineage precursors from dexamethasone-induced apoptosis. Mech Ageing Dev 124 (2003) 207-218
26. Lu L., and Osmond D.G. Apoptosis and its modulation during B lymphopoiesis in mouse bone marrow. Immunol Rev 175 (2000) 158-174
27. Burger J.A., Tsukada N., Burger M., Zvaifler N.J., Dell'Aquila M., and Kipps T.J. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood 96 (2000) 2655-2663