SEARCH:   Advanced

Blood, 15 December 2005, Vol. 106, No. 13, pp. 4253-4260. Prepublished online as a Blood First Edition Paper on August 30, 2005; DOI 10.1182/blood-2005-03-1309. This Article Full Text (PDF) All Versions of this Article: 2005-03-1309v1 106/13/4253    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gandhi, V. Articles by Thomas, D. Search for Related Content PubMed PubMed Citation Articles by Gandhi, V. Articles by Thomas, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 5, 2005 Accepted June 14, 2005 A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor forodesine (BCX-1777) Varsha Gandhi*, John M Kilpatrick, William Plunkett, Mary Ayres, Leigh Harman, Min Du, Shanta Bantia, Jan Davisson, William G Wierda, Stefan Faderl, Hagop Kantarjian, and Deborah Thomas Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA BioCryst Pharmaceuticals, Inc., Birmingham, AL, USA Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA * Corresponding author; email: vgandhi{at}mdanderson.org. The discovery of purine nucleoside phosphorylase (PNP) deficiency and T-lymphocytopenia suggested that inhibition of this enzyme could serve as a therapeutic target. Inhibitors of PNP failed until structure-based synthesis of immucillin-H (BCX-1777, forodesine), a transition-state analog of PNP. The picomolar potency for PNP, T-cell-selective cytotoxicity, and animal studies provided rationale for use of forodesine in T-cell malignancies. Five patients were treated with an intravenous infusion of forodesine (40 mg/m2) on day 1; treatment continued on day 2; forodesine was administered every 12 hours for an additional 8 doses. Plasma and cellular pharmacokinetics and pharmacodynamics were investigated. Median peak level of forodesine (5.4 µM) was achieved at the end of infusion. This level was sufficient to increase plasma dGuo concentrations in all patients. Intracellular dGTP increased by 2 to 40-fold in 4 of 5 patients (8 of 9 courses), and correlated with antileukemia activity in 4 patients. However, objective responses were not observed. This was the first clinical study in humans to demonstrate the plasma pharmacokinetics of and the pharmacodynamic effectiveness of the PNP inhibitor, forodesine; however, regrowth of leukemia cells in the blood and marrow after course 1 suggested that a different therapeutic schedule should be considered for future studies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Alonso, M. Lopez-Guerra, R. Upshaw, S. Bantia, C. Smal, F. Bontemps, C. Manz, T. Mehrling, N. Villamor, E. Campo, et al. Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM Blood, August 20, 2009; 114(8): 1563 - 1575. [Abstract] [Full Text] [PDF] D. C. Madrid, L.-M. Ting, K. L. Waller, V. L. Schramm, and K. Kim Plasmodium falciparum Purine Nucleoside Phosphorylase Is Critical for Viability of Malaria Parasites J. Biol. Chem., December 19, 2008; 283(51): 35899 - 35907. [Abstract] [Full Text] [PDF] M. J. Downie, K. Kirk, and C. B. Mamoun Purine Salvage Pathways in the Intraerythrocytic Malaria Parasite Plasmodium falciparum Eukaryot. Cell, August 1, 2008; 7(8): 1231 - 1237. [Full Text] [PDF] V. Gandhi, C. Tam, S. O'Brien, R. C. Jewell, C. O. Rodriguez Jr, S. Lerner, W. Plunkett, and M. J. Keating Phase I Trial of Nelarabine in Indolent Leukemias J. Clin. Oncol., March 1, 2008; 26(7): 1098 - 1105. [Abstract] [Full Text] [PDF] J. M. Mundt, S. S. Hah, R. A. Sumbad, V. Schramm, and P. T. Henderson Incorporation of extracellular 8-oxodG into DNA and RNA requires purine nucleoside phosphorylase in MCF-7 cells Nucleic Acids Res., January 17, 2008; 36(1): 228 - 236. [Abstract] [Full Text] [PDF] V. L. Schramm Enzymatic Transition State Theory and Transition State Analogue Design J. Biol. Chem., September 28, 2007; 282(39): 28297 - 28300. [Full Text] [PDF] I. Basu, G. Cordovano, I. Das, T. J. Belbin, C. Guha, and V. L. Schramm A Transition State Analogue of 5'-Methylthioadenosine Phosphorylase Induces Apoptosis in Head and Neck Cancers J. Biol. Chem., July 20, 2007; 282(29): 21477 - 21486. [Abstract] [Full Text] [PDF] A. Reiter Diagnosis and Treatment of Childhood Non-Hodgkin Lymphoma Hematology, January 1, 2007; 2007(1): 285 - 296. [Abstract] [Full Text] [PDF] K. Balakrishnan, R. Nimmanapalli, F. Ravandi, M. J. Keating, and V. Gandhi Forodesine, an inhibitor of purine nucleoside phosphorylase, induces apoptosis in chronic lymphocytic leukemia cells Blood, October 1, 2006; 108(7): 2392 - 2398. [Abstract] [Full Text] [PDF]

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020