Pharmacologic Manipulation of Fetal Hemoglobin

It has long been appreciated that increases in fetal hemoglobin (Hb F) levels in patients with hemoglobinopathies such as sickle cell disease and P-thalassemia major may lead to amelioration of these diseases. In sickle cell disease, increases in H b F decrease the concentration of hemoglobin S within the red cell, thereby decrcasing the tendency for hemoglobin S to polymerize. In p-thalassemia, increases in H b F production offset the imbalance between a and p chains. With the observation of DeSimone, Heller, and co-workers that anemic animals could increase their H b F lcvels after administration of 5-azacytidine,' it became clear that the potential for elevating Hb F levels with chemotherapeutic agents was at hand. Since 1982, a variety of agents have been shown to increase H b F in animals, in humans, or in erythroid culture. These agents can be divided into two broad categories. First, there are cytotoxic agents, including 5-azacytidine,'-' hydroxyurea,h-' cytosine arabinoside,'.''' methotrexate," and myleran." Although the mechanisms by which cytotoxic agents increase Hb F rcmain unclear, two hypotheses predominate. The first suggests that these agents are toxic, if not lethal, to the more mature erythroid precursors. This toxicity leads to recruitment of earlier progenitors with greater potcntial for making H b F.'"'' The second hypothesis suggests that interruption of the cell cycle might have direct effects on differential gene expression, thereby leading to increased Hb F The second group of agents which increases H b F is the humoral growth factors."." These factors have clearly been shown by Stamatoyannopoulos and colleagues to increase recruitment of earlier crythroid precursors, thereby leading to increased Hb F production. Sodium butyrate and its analogues also increase Hb F prod~ction.*'~*~ These compounds do not fall into either of the previous catcgories but may have direct action on chromatin lcading to altered gene expression.