oxadiazoles 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