Nitric oxide generation from hydroxyurea: significance and implications for leukemogenesis in the management of myeloproliferative disorders

The use of myelosuppressive agents to reduce the risk of thrombosis in patients with polycythemia vera (PV) and essential thrombocythemia (ET) has been associated with an increased risk of transformation to acute myeloid leukemia (AML). Whereas chlorambucil, busulfan, and radiophosphorus (P-32) have been demonstrated to increase the risk of transformation, the leukemogenic: potential of hydroxyurea (HU) continues to be a matter of debate. Clinical studies have suggested that HU may cause a small increase in the risk of AML, but it has proven difficult to establish whether AML is actually caused by HU or arises during the natural progression of PV and ET. Reports that HU undergoes metabolic activation to species that induce mutation appear to support the notion that it is leukemogenic. Here, we suggest that the ability of HU to induce mutation in cell culture studies results from the generation of nitrogen dioxide via the autoxidation of nitric oxide, a product of HU metabolism. However, we argue that autoxidation would not occur in vivo, leading to the conclusion that generation of the mutagen nitrogen dioxide is peculiar to cell culture systems and has little relevance to the use of HU in the management of PV and ET.