Cellular and molecular effects of a pulse butyrate regimen and new inducers of globin gene expression and hematopoiesis.
Cooley's anemia is characterized by a deficiency of beta-globin chains, a relative excess of alpha-globin chains, and consequent accelerated programmed death of developing erythroid cells in the bone marrow. Increasing expression of the gamma-globin genes to adequately balance excess alpha-globin chains can ameliorate this disorder. Butyrates induce gamma-globin experimentally, but can also cause cell growth arrest with prolonged exposure or high concentrations, which in turn can accelerate apoptosis. To determine if these potentially opposing effects can be balanced to enhance therapeutic efficacy, an intermittent "pulsed" regimen of butyrate was evaluated. Following induction of gamma-globin mRNA and protein synthesis, total hemoglobin increased in beta-thalassemia patients by more than 2 g/dl above baseline, and Hb F increased above 20% in 5/8 sickle cell patients from baseline levels of 2% Hb F. Specific regulatory regions were identified in the gamma- and beta-globin gene promoters to which new binding of transcription factors, including alpha CP2 (an activator of gamma globin) occur during therapy solely in the butyrate-responsive patients. Other compounds which induce gamma globin, derivatives of acetic, phenoxyacetic, propionic, and cinnamic acids, and dimethylbutyrate, are under investigation. Some of these newer gamma-globin inducers (designed hemokines) provide better potential as therapeutics by also acting to increase hematopoietic cell viability and proliferation. Pharmacologic induction of expression of the endogenous gamma-globin genes is a realistic approach to therapy of the beta-globin disorders for many patients, with some effective agents available now and new therapeutics, with enhanced activities, under development.
Department of Medicine, Boston University School of Medicine, MA 02118, USA.
T
T
Ikuta
G
G
Atweh
V
V
Boosalis
G L
GL
White
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S
Da Fonseca
M
M
Boosalis
D V
DV
Faller
S P
SP
Perrine
D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy; D000818:Animals; D000986:Antisickling Agents / Q000627:therapeutic use*; D002087:Butyrates / Q000627:therapeutic use*; D002648:Child; D005786:Gene Expression Regulation / Q000187:drug effects*; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects; D017086:beta-Thalassemia / Q000097:blood* / Q000188:drug therapy*
D000986:Antisickling Agents; D002087:Butyrates; D012333:RNA, Messenger; D005914:Globins