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Cellular and Molecular Effects of a Pulse Butyrate Regimen and New Inducers of Globin Gene Expression and Hematopoiesis
Author(s) -
IKUTA TOHRU,
ATWEH GEORGE,
BOOSALIS VASSILIKI,
WHITE GARY L.,
DA FONSECA SILVANA,
BOOSALIS MICHAEL,
FALLER DOUGLAS V.,
PERRINE SUSAN P.
Publication year - 1998
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1998.tb10466.x
Subject(s) - haematopoiesis , inducer , butyrate , globin , gene expression , regimen , gene , biology , chemistry , microbiology and biotechnology , medicine , genetics , stem cell , biochemistry , fermentation
A bstract : Cooley's anemia is characterized by a deficiency of β‐globin chains, a relative excess of α‐globin chains, and consequent accelerated programmed death of developing erythroid cells in the bone marrow. Increasing expression of the γ‐globin genes to adequately balance excess α‐globin chains can ameliorate this disorder. Butyrates induce γ‐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 γ‐globin mRNA and protein synthesis, total hemoglobin increased in β‐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 γ‐ and β‐globin gene promoters to which new binding of transcription factors, including αCP2 (an activator of γ globin) occur during therapy solely in the butyrate‐responsive patients. Other compounds which induce γ globin, derivatives of acetic, phenoxyacetic, propionic, and cinnamic acids, and dimethylbutyrate, are under investigation. Some of these newer γ‐globin inducers (designated hemokines) provide better potential as therapeutics by also acting to increase hematopoietic cell viability and proliferation. Pharmacologic induction of expression of the endogenous γ‐globin genes is a realistic approach to therapy of the β‐globin disorders for many patients, with some effective agents available now and new therapeutics, with enhanced activities, under development.