You recall reading in the medical literature about a dramatic new drug treatment

Question

You recall reading in the medical literature about a dramatic new drug treatment for sickle cell anemia, and you?d like to try it on this patient. The drug is hydroxyurea, and is thought to function by stimulating the afflicted person?s synthesis of fetal hemoglobin. Exactly how hydroxyurea stimulated fetal hemoglobin synthesis is unclear, but it is believed that hydroxyurea is metabolized to NO, which binds to a soluble guanylate cyclase enzyme which then catalyzes the synthesis of a second messenger, cyclic GMP (cGMP). The cGMP interacts with transcription factors in a manner that is not completely understood to induce the transcription (and then translation) of the fetal hemoglobin gene.

a. In a clinical study, patients who took hydroxyurea showed a 50% reduction in frequency of hospital admissions for severe pain, and there was also a decrease in the frequency of fever and abnormal chest x-rays. Why would increasing the synthesis of fetal hemoglobin result in alleviating the symptoms of sickle cell anemia?

b. Medical practioners who used hydroxyurea as a treatment for sickle cell anemia noted that their patients seemed to benefit from the administration of the drug long before the synthesis of fetal hemoglobin had time to take effect. It has recently been determined that hydroxyurea can react directly with the iron ion of oxy- and deoxyHb to form iron nitrosyl hemoglobin (HbNO). Why would this be of benefit to the sickle-cell anemic patient?

c. And finally, hydroxyurea has been shown to produce NO directly, in less than an hour after hydroxyurea administration. It?s also possible that HbNO could produce NO, either directly or indirectly. NO is an important second messenger which, even in nanomolar amounts, stimulates vasodilation. How could NO production help the sickle-cell anemic patient?

Explanation / Answer

a)

The efficacy of hydroxyurea in the treatment of sickle cell disease is generally attributed to its ability to boost the levels of fetal hemoglobin (Hb F,?2?2). This lowers the concentration of Hb S (sickle cell hemoglobin) within a cell resulting in less polymerization of the abnormal hemoglobin. However, the mechanisms by which it increases Hb F are unclear. Early studies suggested that hydroxyurea is cytotoxic to the more rapidly dividing late erythroid precursors, an effect that leads to the recruitment of early erythroid precursors with an increased capacity to produce Hb F.

b)

Hydroxyurea represents an approved treatment for sickle cell anemia and acts as a nitric oxide donor under oxidative conditions in vitro. Hydroxyurea reacts with oxy-, deoxy-, and methemoglobin to produce 2?6% of iron nitrosyl hemoglobin. No S-nitrosohemoglobin forms during these reactions. Cyanide and carbon monoxide trapping studies reveal that hydroxyurea oxidizes deoxyhemoglobin to methemoglobin and reduces methemoglobin to deoxyhemoglobin. Similar experiments reveal that iron nitrosyl hemoglobin formation specifically occurs during the reaction of hydroxyurea and methemoglobin. Experiments with hydroxyurea analogues indicate that nitric oxide transfer requires an unsubstituted acylhydroxylamine group and that the reactions of hydroxyurea and deoxy- and methemoglobin likely proceed by inner-sphere mechanisms. The formation of nitrate during the reaction of hydroxyurea and oxyhemoglobin and the lack of nitrous oxide production in these reactions suggest the intermediacy of nitric oxide as opposed to its redox form nitroxyl. These direct nitric oxide producing reactions of hydroxyurea and hemoglobin may contribute to the overall pathophysiological properties of this drug.

c)

NO is a soluble gas with a half-life of seconds, continuously synthesized in endothelial cells from the amino acid L-arginine by isoforms of the NO synthase enzyme. NO released from the endothelium activates soluble guanylyl cyclase in smooth muscle after binding to its heme group, resulting in increased intracellular cyclic GMP. Cyclic GMP activates cGMP-dependent kinases that decrease intracellular calcium concentration in smooth muscle, producing relaxation, vasodilation, and increased regional blood flow. In addition, NO induces a coordinated program of cellular events that promote blood flow, primarily by suppressing platelet aggregation, expression of cell adhesion molecules on endothelial cells, and secretion of procoagulant proteins.

Hydroxyurea induces expression of fetal hemoglobin, which reduces hemoglobin S polymerization in patients with sickle cell disease reducing mortality and vaso-occclusive crises. In vitro and animal studies have demonstrated that hydroxyurea may play an additional role as an NO donor . Activation of fetal hemoglobin expression by hydroxyurea appears to occur through this NO pathway . Hydroxyurea is a proven treatment for sickle cell disease that may exert part of its therapeutic effect through the NO pathway.

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