This Volume Table of Contents Description This Article Full Text Full Text (PDF) Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by IKUTA, T. Articles by PERRINE, S. P. Search for Related Content PubMed PubMed Citation Articles by IKUTA, T. Articles by PERRINE, S. P.

Annals of the New York Academy of Sciences 850:87-99 (1998)
© 1998 New York Academy of Sciences

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 ß-globin chains, a relative excess of -globin chains, and consequent accelerated programmed death of developing erythroid cells in the bone marrow. Increasing expression of the -globin genes to adequately balance excess -globin chains can ameliorate this disorder. Butyrates induce -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 -globin mRNA and protein synthesis, total hemoglobin increased in ß-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 - and ß-globin gene promoters to which new binding of transcription factors, including CP2 (an activator of globin) occur during therapy solely in the butyrate-responsive patients. Other compounds which induce globin, derivatives of acetic, phenoxyacetic, propionic, and cinnamic acids, and dimethylbutyrate, are under investigation. Some of these newer -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 -globin genes is a realistic approach to therapy of the ß-globin disorders for many patients, with some effective agents available now and new therapeutics, with enhanced activities, under development.

This article has been cited by other articles:

				R. Mankidy, D. V. Faller, R. Mabaera, C. H. Lowrey, M. S. Boosalis, G. L. White, S. A. Castaneda, and S. P. Perrine Short-chain fatty acids induce {gamma}-globin gene expression by displacement of a HDAC3-NCoR repressor complex Blood, November 1, 2006; 108(9): 3179 - 3186. [Abstract] [Full Text] [PDF]

				E. Fibach, N. Bianchi, M. Borgatti, E. Prus, and R. Gambari Mithramycin induces fetal hemoglobin production in normal and thalassemic human erythroid precursor cells Blood, August 15, 2003; 102(4): 1276 - 1281. [Abstract] [Full Text] [PDF]

				D. W. Emery, E. Yannaki, J. Tubb, T. Nishino, Q. Li, and G. Stamatoyannopoulos Development of virus vectors for gene therapy of beta chain hemoglobinopathies: flanking with a chromatin insulator reduces gamma -globin gene silencing in vivo Blood, August 28, 2002; 100(6): 2012 - 2019. [Abstract] [Full Text] [PDF]

				M. S. Boosalis, R. Bandyopadhyay, E. H. Bresnick, B. S. Pace, K. Van DeMark, B. Zhang, D. V. Faller, and S. P. Perrine Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation Blood, May 15, 2001; 97(10): 3259 - 3267. [Abstract] [Full Text] [PDF]

				D. BOHL and J.-M. HEARD Delivering Erythropoietin through Genetically Engineered Cells J. Am. Soc. Nephrol., November 1, 2000; 11(90002): 159S - 162. [Abstract] [Full Text]

				V. Casolaro, A. M. Keane-Myers, S. L. Swendeman, C. Steindler, F. Zhong, M. Sheffery, S. N. Georas, and S. J. Ono Identification and Characterization of a Critical CP2-binding Element in the Human Interleukin-4 Promoter J. Biol. Chem., November 17, 2000; 275(47): 36605 - 36611. [Abstract] [Full Text] [PDF]