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1.
Int Immunopharmacol ; 3(6): 879-87, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12781704

RESUMEN

Purine nucleoside phosphorylase (PNP) deficiency in humans produces a relatively selective depletion of T cells. BCX-1777 is a potent inhibitor of PNP. BCX-1777 in the presence of deoxyguanosine (dGuo) inhibits the proliferation of CEM-SS [T-acute lymphoblastic leukemia (T-ALL)] cells with an IC(50)=0.015 microM. This inhibition by BCX-1777 and dGuo is accompanied by elevation of dGTP (154-fold) and dATP (8-fold). Deoxycytidine (dCyt) completely and lamivudine (3TC) partially reverse this inhibition caused by BCX-1777 and dGuo. dNTP analysis of these samples indicates that, in the presence of dCyt, where complete reversal of inhibition is observed, dGTP and dATP pools revert back to the control levels. In samples containing 3TC, where partial reversal of inhibition was observed, dGTP decreased from 154-fold to 38-fold and dATP levels further increased from 8-fold to 30-fold compared to the control sample. In CEM-SS cells, inhibition of proliferation by BCX-1777 and dGuo is not due to accumulation of dATP because in the presence of 3TC, where reversal of inhibition is observed, dATP levels are further increased. These studies clearly indicate that inhibition of T cells is due to accumulation of dGTP resulting in cell death with characteristics of apoptosis. The half-life of dGTP in CEM-SS cells is 18 h, which is longer than that observed in human lymphocytes (4 h), suggesting that the nucleotidase level in CEM-SS cells is lower than in human lymphocytes. A 154-fold accumulation of dGTP in CEM-SS cells in the presence of BCX-1777 and dGuo compared to a 15-fold accumulation of dGTP in human lymphocytes suggests that kinase level is higher in CEM-SS cells compared to human lymphocytes. High kinase and low nucleotidase levels make CEM-SS cells more sensitive to inhibition by BCX-1777 and dGuo than human lymphocytes. Currently, BCX-1777 is in phase I/II clinical trial for the treatment of T cell malignancies.


Asunto(s)
Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Pirimidinonas/farmacología , Pirroles/farmacología , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular , Medios de Cultivo , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Semivida , Humanos , Lamivudine/farmacología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Nucleósidos de Purina , Inhibidores de la Transcriptasa Inversa/farmacología , Estavudina/farmacología
2.
Int Immunopharmacol ; 2(7): 913-23, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12188033

RESUMEN

Purine nucleoside phosphorylase (PNP) deficiency in humans produces a relatively selective depletion of T-cells. Inhibitors of PNP are therefore of interest as potential T-cell selective immunosuppressive agents. BCX-1777 is a potent inhibitor of PNP and in vitro T-cell proliferation. Inhibition of human T-cells by BCX-1777 and deoxyguanosine (dGuo) is accompanied by deoxyguanosine triphosphate (dGTP) accumulation. Unlike human T-cells, mouse, rat, dog and monkey T-cells are neither inhibited (IC50>100 microM) nor accumulate dGTP in the presence of BCX-1777 and dGuo. Cells pretreated with BCX-1777 and dGuo for 24 h (to elevate dGTP levels) prior to stimulation demonstrated 80% inhibition similar to the inhibition observed with cells treated with BCX-1777 and dGuo during the stimulation and proliferation process. This further confirms that inhibition of T-cells is due to the accumulation of dGTP in these cells. Deoxynucleotide (dNTP) analysis of the cells treated with BCX-1777 and dGuo for 48 h showed no significant change in deoxycytidine triphosphate (dCTP) and deoxyadenosine triphosphate (dATP) pools. However, a decrease (2-fold) in thymidine triphosphate (dTTP) pools, and a large increase in dGTP pools (15-fold) were observed. Results from various groups have shown that alteration in the dNTP supply results in DNA fragmentation and cell death with characteristics of apoptosis. Indeed, apoptosis is observed in human T-lymphocytes treated with BCX-1777 and dGuo. To compare the in vivo efficacy of BCX-1777 with another potent T-cell inhibitor, cyclosporin, these drugs were tested in a xenogeneic graft-vs.-host disease model (XGVHD). In this model, human lymphocytes are engrafted into severe combined immunodeficient mice (SCID) mice inducing severe XGVHD. The efficacy of BCX-1777 in the XGVHD model was comparable to cyclosporin and a combination of BCX-1777 and cyclosporin treatment showed a trend towards increased efficacy compared to cyclosporin alone. These results suggest that BCX-1777 may be useful for the treatment of disease characterized by activated T-cell responses.


Asunto(s)
Ciclosporina/uso terapéutico , Nucleótidos de Desoxiguanina/metabolismo , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Inhibidores de Crecimiento/uso terapéutico , Inmunosupresores/uso terapéutico , Pirimidinonas/uso terapéutico , Pirroles/uso terapéutico , Trasplante Heterólogo/inmunología , Animales , Ciclosporina/farmacología , Perros , Quimioterapia Combinada , Enfermedad Injerto contra Huésped/inducido químicamente , Enfermedad Injerto contra Huésped/metabolismo , Inhibidores de Crecimiento/farmacología , Humanos , Inmunosupresores/química , Inmunosupresores/farmacología , Linfocitos/citología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Macaca fascicularis , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Nucleósidos de Purina , Pirimidinonas/farmacología , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Tasa de Supervivencia
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