cyclic-gmp and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Platelet aggregation profiles were studied in chronic myelogenous leukemia patients who were undergoing hydroxyurea therapy. Nitric oxide (NO) generation induced by hydroxyurea was measured from the altered aggregatory response, in which the platelet suspension exhibits a de-aggregatory behaviour. NO caused platelet de-aggregation by generation of cyclic guanidine monophosphate through the activation of soluble guanylate cyclase (SGC). The fact that the observed response is specific to NO was confirmed by the reversal of the de-aggregatory behaviour in the presence of (1)H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of SGC. Among the subjects studied, one subset showed an hydroxyurea-induced de-aggregatory effect that was inhibited by ODQ, whereas another subset did not show any such effect. The observed inter-individual variability in platelet aggregometric response after the ingestion of drugs may be an indicator for NO generation from hydroxyurea, and this may help to explain the drug efficacy encountered in such cases.

Topics: Adult; Biological Availability; Blood Platelets; Cyclic GMP; Enzyme Inhibitors; Female; Humans; Hydroxyurea; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Nitric Oxide; Oxadiazoles; Platelet Aggregation; Quinoxalines; Time Factors

This study was performed to investigate whether measurement of cyclic GMP (cGMP), a marker for nitric oxide production, before and after allogeneic bone marrow transplantation (BMT) with total body irradiation (TBI) conditioning was of prognostic value. cGMP levels were monitored in 23 consecutive patients who received TBI as conditioning for BMT, and were compared with the outcome. cGMP became positive during the aplastic phase after BMT in 12 patients. In nine of these 12 patients, cGMP level decreased during the recovery phase. Eight of the nine patients survived, one dying after relapse. In three other patients, the cGMP level continued to increase even during the recovery phase and they died of severe complications. cGMP became positive on day 0 of BMT and during the leukocyte recovery phase after BMT in two and seven of the 23 patients, respectively. Subsequently, all patients died of severe complications. The two patients who were negative for cGMP both before and after BMT survived without complications. These results suggest that monitoring cGMP from early after BMT may be useful for predicting outcome and that it may be a useful prognostic marker.

Topics: Adolescent; Adult; Biomarkers; Blast Crisis; Bone Marrow Transplantation; Cyclic GMP; Cyclosporine; Drug Therapy, Combination; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Methotrexate; Methylprednisolone; Monitoring, Physiologic; Myelodysplastic Syndromes; Neoplasm Staging; Nitric Oxide; Prognosis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

The presence and functional role of the cyclic nucleotide signal transduction system was investigated in platelets from patients with myeloproliferative disorders. Platelets from certain patients with chronic myelocytic leukemia showed decreased expression of cGMP-dependent protein kinase, and platelets from two such patients were studied in some detail. These platelets had very little if any cGMP-dependent protein kinase but a normal level of cAMP-dependent protein kinase. They also contained a normal level of VASP (vasodilator-stimulated phosphoprotein, a specific substrate of both cAMP- and cGMP-dependent protein kinase), as well as a functionally intact prostaglandin E1-stimulated cAMP-mediated VASP phosphorylation. In contrast, sodium nitroprusside-stimulated VASP phosphorylation was severely impaired in these cGMP-dependent protein kinase-deficient platelets, despite an exaggerated cGMP response to sodium nitroprusside. Furthermore, whereas selective activation of the cGMP-dependent protein kinase by 8-(4-chlorophenylthio)-cGMP strongly inhibited the ADP- or thrombin-evoked calcium mobilization from intracellular stores in normal platelets, this agonist-evoked calcium response was not inhibited by the cGMP analog in cGMP-dependent protein kinase-deficient platelets. The results demonstrate a defect in the nitrovasodilator-/cGMP-regulated signal transduction system in human platelets from some patients with myeloproliferative disorders, and underscore that a cGMP-dependent protein kinase regulatory system, distinct from that of cAMP-dependent protein kinase or other cGMP-dependent effectors is operative in normal human platelets.

Topics: Blood Platelets; Blood Proteins; Blotting, Western; Calcium; Catalysis; Cells, Cultured; Cyclic GMP; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Nitric Oxide; Nitroprusside; Phosphoproteins; Protein Kinases; Signal Transduction; Vasodilation