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Evidence for a pathway independent from 2'-deoxyguanosine and reversible by IL-2 by which purine nucleoside phosphorylase inhibitors block T-cell proliferation.

Abstract
Patients with homozygous deficiency of purine nucleoside phosphorylase (PNP) present with a T-cell selective immune deficiency. To elucidate the potential use of PNP inhibitors in the therapy of cutaneous T-cell lymphomas (CTCLs) the authors studied the effects of CI-1000 (formerly PD141955-2) and CI-972 on a T-cell line MyLa established from a patient with mycosis fungoides. Both PNP inhibitors had significant, dose-dependent, inhibitory effects on the proliferation of the T-cell line. CI-1000 (ED50: 3.7 microM) was approximately six-fold more potent in blocking 3H-thymidine uptake than CI-972 (ED50: 22.5 microM). The inhibitory effect of either substance could not be increased by addition of deoxyguanosine. Flow cytometric analysis revealed that both PNP inhibitors caused a block in the S-phase of the cell cycle. The inhibitory effect on proliferation was reversible partially by addition of IL-2. When testing proliferation inhibition of both substances on an IL-2-dependent T-cell line (SeAx), their inhibitory effects were reduced significantly. These data document a mechanism of action of the PNP inhibitors independent of deoxyguanosine and partially reversible by IL-2. The authors' observations suggest the potential use of PNP inhibitors in the therapy of cutaneous T-cell lymphomas and provide evidence for a pathway independent from deoxyguanosine by which PNP inhibitors might function in T cells.
AuthorsW H Boehncke, R B Gilbertsen, J Hemmer, W Sterry
JournalScandinavian journal of immunology (Scand J Immunol) Vol. 39 Issue 3 Pg. 327-32 (Mar 1994) ISSN: 0300-9475 [Print] ENGLAND
PMID8128192 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Interleukin-2
  • Interleukin-7
  • Pyrimidines
  • Thiophenes
  • CI 972
  • 9-deaza-9-(3-thienylmethyl)guanine
  • Guanine
  • Purine-Nucleoside Phosphorylase
  • Deoxyguanosine
Topics
  • Cell Cycle
  • Cell Line
  • Deoxyguanosine (pharmacology)
  • Flow Cytometry
  • Guanine (analogs & derivatives, pharmacology)
  • Humans
  • Interleukin-2 (pharmacology)
  • Interleukin-7 (pharmacology)
  • Lymphocyte Activation
  • Mycosis Fungoides
  • Purine-Nucleoside Phosphorylase (antagonists & inhibitors)
  • Pyrimidines (pharmacology)
  • S Phase
  • Sezary Syndrome
  • T-Lymphocytes (immunology)
  • Thiophenes (pharmacology)
  • Time Factors

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