Pharmacologic induction of fetal hemoglobin: raising the therapeutic bar in sickle cell disease

The favorable effects of high levels of fetal hemoglobin (Hb F) in sickle c ell disease have been recognized for several decades. This has been an impo rtant incentive for the development of therapeutic agents that increase Hb F production. 5-Azacytidine, the first such agent in clinical use, was prop osed based on a molecular understanding of the role of DNA methylation in g lobin gene regulation. Controversy over the mechanism of Hb F induction by 5-azacytidine led to the identification of hydroxyurea as another agent tha t can increase Hb F production. Although the clinical benefit of hydroxyure a has been demonstrated in a randomized clinical trial, greater increases i n Hb F are clearly needed for optimal therapeutic effect. Butyrates also in crease Hb F levels, and their use in combination with hydroxyurea appears t o be synergistic. Now that multiple therapeutic agents are available for Hb F induction, the use of combination therapy to increase Hb F levels suffic iently to prevent all the complications of sickle cell disease has become a realistic goal. (C) 2001 Lippincott Williams & Wilkins, Inc.