Butyrate derivatives. New agents for stimulating fetal globin production in the beta-globin disorders.
OBJECTIVE
Stimulating expression of the normal fetal globin genes is a preferred method of ameliorating sickle cell disease and beta-thalassemia for the majority of patients in North America who do not have appropriate bone marrow donors.


METHODS
Due to increased survival of red blood cells that contain both hemoglobin S and hemoglobin F, as little as 4-8% fetal globin synthesis in the bone marrow can produce levels of hemoglobin F of approximately 20% in the peripheral circulation. Some success has been achieved in stimulating hemoglobin F using chemotherapeutic agents (such as hydroxyurea and 5-azacytidine) and growth factors (erythropoietin) that alter erythroid growth kinetics. However, there is reluctance to treat children with chemotherapeutic agents because of possible undesirable long-term side effects.


RESULTS
Butyric acid and butyrate derivatives are generally safe compounds that stimulate the promoters of individual fetal and embryonic globin genes and thus provide a more specific therapy. An initial trial with the parent compound, given as arginine butyrate, has demonstrated rapid stimulation of fetal globin expression to levels that can ameliorate these conditions. Phase I trials of an oral butyrate derivative with a long plasma half-life have begun.


CONCLUSIONS
These agents may provide a new and specific approach for ameliorating the clinical manifestations of sickle cell disease and beta-thalassemia.
Perrine
S P
SP
Children's Hospital Oakland Research Institute, California 94609.
Olivieri
N F
NF
Faller
D V
DV
Vichinsky
E P
EP
Dover
G J
GJ
Ginder
G D
GD
D000293:Adolescent; D000328:Adult; D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002087:Butyrates / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D005914:Globins / Q000235:genetics; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017086:beta-Thalassemia / Q000188:drug therapy* / Q000378:metabolism
D000577:Amides; D002087:Butyrates; C030197:isobutyramide; D005914:Globins; D005319:Fetal Hemoglobin; D001120:Arginine; C033018:arginine butyrate