Evidence for a pathway independent from 2'-deoxyguanosine and reversible by IL-2 by which purine nucleoside phosphorylase inhibitors block T-cell proliferation.
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.
Boehncke
W H
WH
Department of Dermatology, University of Ulm, Germany.
Gilbertsen
R B
RB
Hemmer
J
J
Sterry
W
W
D002453:Cell Cycle; D002460:Cell Line; D003849:Deoxyguanosine / Q000494:pharmacology*; D005434:Flow Cytometry; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D015851:Interleukin-7 / Q000494:pharmacology; D008213:Lymphocyte Activation; D009182:Mycosis Fungoides; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology; D016196:S Phase; D012751:Sezary Syndrome; D013601:T-Lymphocytes / Q000276:immunology*; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors
D007376:Interleukin-2; D015851:Interleukin-7; D011743:Pyrimidines; D013876:Thiophenes; C070377:CI 972; C076778:9-deaza-9-(3-thienylmethyl)guanine; D006147:Guanine; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine