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Title

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

Authors
Gilbertsen, R. B.
Hemmer, J.
Sterry, Wolfram
Published in Scandinavian Journal of Immunology. 1994, vol. 39, no. 3, p. 327-332
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.
Keywords Cell CycleCell LineDeoxyguanosine/*pharmacologyFlow CytometryGuanine/analogs & derivatives/pharmacologyHumansInterleukin-2/*pharmacologyInterleukin-7/pharmacologyLymphocyte ActivationMycosis FungoidesPurine-Nucleoside Phosphorylase/*antagonists & inhibitorsPyrimidines/pharmacologyS PhaseSezary SyndromeT-Lymphocytes/*immunologyThiophenes/pharmacologyTime Factors
Identifiers
PMID: 8128192
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BOEHNCKE, Wolf-Henning et al. Evidence for a pathway independent from 2'-deoxyguanosine and reversible by IL-2 by which purine nucleoside phosphorylase inhibitors block T-cell proliferation. In: Scandinavian Journal of Immunology, 1994, vol. 39, n° 3, p. 327-332. https://archive-ouverte.unige.ch/unige:29687

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Deposited on : 2013-09-20

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