Evidence for a Pathway Independent from 2′‐Deoxyguanosine and Reversible by IL‐2 by which Purine Nucleoside Phosphorylase Inhibitors Block T‐Cell Proliferation

  title={Evidence for a Pathway Independent from 2′‐Deoxyguanosine and Reversible by IL‐2 by which Purine Nucleoside Phosphorylase Inhibitors Block T‐Cell Proliferation},
  author={W. Boehncke and R. Gilbertsen and J. Hemmer and W. Sterry},
  journal={Scandinavian Journal of Immunology},
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 PD 141955‐2) and CI‐972 on a T‐cell line My La 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… Expand
8 Citations
A purine nucleoside phosphorylase (PNP) inhibitor induces apoptosis via caspase-3-like protease activity in MOLT-4 T cells.
Several lines of evidence are provided for the role of apoptosis and the contribution of caspase-3-like proteases in T-cell death following PNP inhibition. Expand
Effects of a novel purine nucleoside phosphorylase inhibitor, BCX-34, on activation and proliferation of normal human lymphoid cells.
BCX-34 in normal human T-cells has a deoxyguanosine-independent mechanism to suppress in vitro proliferation and appears to have little effect on T-cell viability, which suggests that it may be useful in the treatment of T- cell proliferative disorders. Expand
Blockade of nucleoside degradation in monkey whole blood in vitro by CI-1000, a purine nucleoside phosphorylase (PNP) inhibitor.
The ability of CI-1000 to retard nucleoside breakdown in blood in vitro may be a predictor of in vivo activity, and can be viewed as an early and essential biochemical consequence of PNP inhibition culminating in immunosuppression. Expand
Immunoregulatory effects of N9-benzyl- and N7-benzyl-8-bromoguanines.
It has been shown that not only 9-substituted guanines but also their 7-isomers selectively inhibit T-cell functions and both selectively inhibit Th1-related cytokines secretion. Expand
Purine nucleoside phosphorylases: properties, functions, and clinical aspects.
Detailed accounts are presented of design of potent inhibitors, largely nucleosides and acyclonucleosides, their phosphates and phosphonates, particularly of the human erythrocyte enzyme intended for induction of the immunodeficient state for clinical applications, such as prevention of host-versus-graft response in organ transplantations. Expand
In vitro lymphotoxicity and selective T cell immunotoxicity of high doses of acyclovir and its derivatives in mice.
In vitro lymphotoxicity of ACV and its acetylated derivatives was low, whereas the 7-ACV isomer enhanced the in vitro cell proliferation in PHA-stimulated cultures, and the CD4+/CD8+ ratio was affected both in vitro and in vivo by high concentrations of ACv. Expand
Antiviral Therapy Can Reverse the Development of Immune Senescence in Elderly Mice with Latent Cytomegalovirus Infection
It is demonstrated that MCMV-specific memory inflation is maintained by viral replication and that therapeutic intervention could lead to improved immune function. Expand
Uterine fluid proteome changes during diapause and resumption of embryo development in roe deer (Capreolus capreolus)
This study provides a comprehensive overview of proteins in the roe deer uterine fluid during diapause and forms a basis for studies aiming at understanding the impact of the lack of cell cycle promoters during diAPause. Expand


2'-deoxyguanosine toxicity for B and mature T lymphoid cell lines is mediated by guanine ribonucleotide accumulation.
2'-deoxyguanosine and guanosine are phosphorolyzed and actively salvaged within the cell, accounting for the accumulation of GTP, and partial inhibition of PNP activity in vivo may lead to nonselective cellular toxicity by a mechanism independent of dGTP accumulation. Expand
Selective in vitro inhibition of human MOLT-4 T lymphoblasts by the novel purine nucleoside phosphorylase inhibitor, CI-972.
Inhibition of MOLT-4 growth was associated with an increase in dGTP that was dependent on CI-972 concentration and inhibited by 2'-deoxycytidine, and growth could not be restored by hypoxanthine or adenine. Expand
B cells as well as T cells form deoxynucleotides from either deoxyadenosine or deoxyguanosine.
C cultured lymphocytes are not valid models of the toxicity to the immune system in inherited ADA or PNP deficiency and it is demonstrated that the ability to accumulate high levels of dATP or dGTP is not exclusive to T cells and that the in vitro toxicity of dAR or dGR could relate to the use of excess substrate and/or accumulation in different nucleotide, not deoxynucleotide pools. Expand
Metabolism of deoxynucleosides by lymphocytes in long-term culture deficient in different purine enzymes.
Previous studies using cell lines with intact purine pathways demonstrated that, contrary to current beliefs, some B-cell lines are capable of accumulating high levels of deoxynucleotides, confirming the existence of this route in mammalian cells of lymphoid origin. Expand
Comparative in vitro and in vivo activities of two 9-deazaguanine analog inhibitors of purine nucleoside phosphorylase, CI-972 and PD 141955.
An in-parallel comparison is presented of the in vitro and in vivo properties of two 9-deazaguanine analog inhibitors of purine nucleoside phosphorylase (PNP) and PD 141955, with PD considerably more potent and active in all systems studied. Expand
A 5-year-old girl with a history of recurrent infection and anaemia has no measurable purine nucleoside phosphorylase (N.P.) activity in her red blood-cells, and it is very likely that this patient's lack of demonstrable N.P. activity is responsible for her syndrome. Expand
Abnormal purine metabolism and purine overproduction in a patient deficient in purine nucleoside phosphorylase.
The patient's erythrocytes but not her cultured fibroblasts contained increased concentrations of phosphoribosylpyrophosphate and inosine, and the metabolic abnormalities resembled those in the ery Throcytes of patients with the Lesch-Nyhan syndrome. Expand
An abnormal form of purine nucleoside phosphorylase in a family with a child with severe defective T-cell-and normal B-cell immunity.
The nucleoside phosphorylases of the father, mother and brother of the patient were characterized by an increased KM for the substrate inosine, normal pH optimum and a decreased heat stability, and the electrophoretic patterns of NP seem to be the same as for normal NP. Expand
Interleukin-7 is a growth factor for Sézary lymphoma cells.
Results suggest that IL7 may represent an important cytokine in the physiopathology of cutaneous T cell lymphoma, and cultured normal epidermal keratinocyte supernatants could support the growth of Sézary lines. Expand
Human cutaneous T cell lymphoma and leukemia cell lines produce and respond to T cell growth factor
Three cell lines of mature T cell origin derived from patients with cutaneous T cell lymphoma-leukemias (CTCL) were found to be constitutive producers of T cell growth factor (L-TCGF). These are theExpand