FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 328:81-86 January 14, 1993 Number 2 Next

	Full Text Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Fetal-globin (-globin) chains inhibit the polymerization of hemoglobin S (sickle hemoglobin) and can functionally substitute for the -globin chains that are defective or absent in patients with the -thalassemias. Identifying safe mechanisms to stimulate fetal-hemoglobin production is therefore of great interest. Previous studies have shown that administering butyrate selectively stimulates the promoter of the human fetal-globin gene and leads to increases in -globin-gene expression in the developing fetus, cultured cells, and animal models.

Methods To determine whether butyrate can stimulate fetal-globin production in humans, we treated three patients (3 to 13 years old) with sickle cell anemia and three patients (7 to 27 years old) with -thalassemia syndromes with a short course of intravenous infusions of arginine butyrate. The drug was infused continuously for either two or three weeks; the initial dose was 500 mg per kilogram of body weight per day. Globin-chain ratios, proportions of reticulocytes producing hemoglobin F (F reticulocytes), and levels of -globin messenger RNA (mRNA) were determined before and during treatment.

Results In all six patients, fetal-globin synthesis increased by 6 to 45 percent above pretreatment levels (P<0.01). The proportion of F reticulocytes increased about twofold, and the level of -globin mRNA increased twofold to sixfold. The increase in -globin synthesis led to improvement in the globin-chain ratios in the patients with thalassemia. The treatment of one patient was extended for seven weeks, and her hemoglobin level increased from 4.7 to 10.2 g per deciliter (2.9 to 6.3 mmol per liter). Side effects were minimal; one patient had a transient increase in serum aminotransferase concentrations.

Conclusions In patients with -hemoglobinopathies butyrate, a natural fatty acid, can significantly and rapidly increase fetal-globin production to levels that can ameliorate -globin disorders. Further trials of this class of compounds are warranted to determine long-term tolerance and efficacy in patients with sickle cell anemia or -thalassemia.

Source Information

From the Children's Hospital Oakland Research Institute, Oakland, Calif. (S.P.P., H.E.W., E.P.V.); the Hospital for Sick Children, Toronto (N.F.O.); the University of Minnesota School of Medicine, Minneapolis (G.D.G.); Boston University School of Medicine, Boston (D.V.F.); Howard Hughes Medical Institute, University of California, San Francisco (T.I., S.C.); and Johns Hopkins University School of Medicine, Baltimore (G.H.D.).

Address reprint requests to Dr. Perrine at Children's Hospital Oakland Research Institute, Rm. 115, 747 52nd St., Oakland, CA 94609.

Full Text of this Article

Related Letters:

Butyrate Treatment in ß-Hemoglobinopathies
Brauer M., Al-Momen A.-K., Faller D. V., Olivieri N. F.
Extract | Full Text  
N Engl J Med 1995; 333:1287-1288, Nov 9, 1995. Correspondence

This article has been cited by other articles:

• Cucciolla, V., Borriello, A., Criscuolo, M., Sinisi, A. A., Bencivenga, D., Tramontano, A., Scudieri, A. C., Oliva, A., Zappia, V., Ragione, F. D. (2008). Histone deacetylase inhibitors upregulate p57Kip2 level by enhancing its expression through Sp1 transcription factor. Carcinogenesis 29: 560-567 [Abstract] [Full Text]  
• Bianchi, N., Zuccato, C., Lampronti, I., Borgatti, M., Gambari, R. (2007). Fetal Hemoglobin Inducers from the Natural World: A Novel Approach for Identification of Drugs for the Treatment of -Thalassemia and Sickle-Cell Anemia. Evid Based Complement Alternat Med 0: nem139v1-nem139 [Abstract] [Full Text]  
• Mai, A., Jelicic, K., Rotili, D., Di Noia, A., Alfani, E., Valente, S., Altucci, L., Nebbioso, A., Massa, S., Galanello, R., Brosch, G., Migliaccio, A. R., Migliaccio, G. (2007). Identification of Two New Synthetic Histone Deacetylase Inhibitors That Modulate Globin Gene Expression in Erythroid Cells from Healthy Donors and Patients with Thalassemia. Mol. Pharmacol. 72: 1111-1123 [Abstract] [Full Text]  
• Fathallah, H., Weinberg, R. S., Galperin, Y., Sutton, M., Atweh, G. F. (2007). Role of epigenetic modifications in normal globin gene regulation and butyrate-mediated induction of fetal hemoglobin. Blood 110: 3391-3397 [Abstract] [Full Text]  
• Chui, D. H. K. (2007). THAL for THAL?. Blood 110: 2788-2789 [Full Text]  
• Camphausen, K., Tofilon, P. J. (2007). Inhibition of Histone Deacetylation: A Strategy for Tumor Radiosensitization. JCO 25: 4051-4056 [Abstract] [Full Text]  
• Yam, G. H.-F., Gaplovska-Kysela, K., Zuber, C., Roth, J. (2007). Sodium 4-Phenylbutyrate Acts as a Chemical Chaperone on Misfolded Myocilin to Rescue Cells from Endoplasmic Reticulum Stress and Apoptosis. IOVS 48: 1683-1690 [Abstract] [Full Text]  
• Perrine, S. P., Hermine, O., Small, T., Suarez, F., O'Reilly, R., Boulad, F., Fingeroth, J., Askin, M., Levy, A., Mentzer, S. J., Di Nicola, M., Gianni, A. M., Klein, C., Horwitz, S., Faller, D. V. (2007). A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies. Blood 109: 2571-2578 [Abstract] [Full Text]  
• He, Z., Russell, J. E. (2007). Dynamic posttranscriptional regulation of {epsilon}-globin gene expression in vivo. Blood 109: 795-801 [Abstract] [Full Text]  
• Sangerman, J., Lee, M. S., Yao, X., Oteng, E., Hsiao, C.-H., Li, W., Zein, S., Ofori-Acquah, S. F., Pace, B. S. (2006). Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves {gamma}-globin activation by CREB1 and ATF-2. Blood 108: 3590-3599 [Abstract] [Full Text]  
• Mankidy, R., Faller, D. V., Mabaera, R., Lowrey, C. H., Boosalis, M. S., White, G. L., Castaneda, S. A., Perrine, S. P. (2006). Short-chain fatty acids induce {gamma}-globin gene expression by displacement of a HDAC3-NCoR repressor complex. Blood 108: 3179-3186 [Abstract] [Full Text]  
• FATHALLAH, H., SUTTON, M., ATWEH, G. F. (2005). Pharmacological Induction of Fetal Hemoglobin: Why Haven't We Been More Successful in Thalassemia?. Ann. N. Y. Acad. Sci. 1054: 228-237 [Abstract] [Full Text]  
• Weinberg, R. S., Ji, X., Sutton, M., Perrine, S., Galperin, Y., Li, Q., Liebhaber, S. A., Stamatoyannopoulos, G., Atweh, G. F. (2005). Butyrate increases the efficiency of translation of {gamma}-globin mRNA. Blood 105: 1807-1809 [Abstract] [Full Text]  
• Jabr, F. I., Aoun, E., Azar, C., Taher, A. (2004). Diamond-Blackfan anemia responding to valproic acid. Blood 104: 3415-3415 [Full Text]  
• Camphausen, K., Scott, T., Sproull, M., Tofilon, P. J. (2004). Enhancement of Xenograft Tumor Radiosensitivity by the Histone Deacetylase Inhibitor MS-275 and Correlation with Histone Hyperacetylation. Clin. Cancer Res. 10: 6066-6071 [Abstract] [Full Text]  
• Vadolas, J., Wardan, H., Orford, M., Williamson, R., Ioannou, P. A. (2004). Cellular genomic reporter assays for screening and evaluation of inducers of fetal hemoglobin. Hum Mol Genet 13: 223-233 [Abstract] [Full Text]  
• Cao, H., Stamatoyannopoulos, G., Jung, M. (2004). Induction of human {gamma} globin gene expression by histone deacetylase inhibitors. Blood 103: 701-709 [Abstract] [Full Text]  
• Camphausen, K., Burgan, W., Cerra, M., Oswald, K. A., Trepel, J. B., Lee, M.-J., Tofilon, P. J. (2004). Enhanced Radiation-Induced Cell Killing and Prolongation of {gamma}H2AX Foci Expression by the Histone Deacetylase Inhibitor MS-275. Cancer Res. 64: 316-321 [Abstract] [Full Text]  
• Dempsey, N. J., Ojalvo, L. S., Wu, D. W., Little, J. A. (2003). Induction of an embryonic globin gene promoter by short-chain fatty acids. Blood 102: 4214-4222 [Abstract] [Full Text]  
• Fibach, E., Bianchi, N., Borgatti, M., Prus, E., Gambari, R. (2003). Mithramycin induces fetal hemoglobin production in normal and thalassemic human erythroid precursor cells. Blood 102: 1276-1281 [Abstract] [Full Text]  
• Morris, C. R., Morris, S. M. Jr., Hagar, W., van Warmerdam, J., Claster, S., Kepka-Lenhart, D., Machado, L., Kuypers, F. A., Vichinsky, E. P. (2003). Arginine Therapy: A New Treatment for Pulmonary Hypertension in Sickle Cell Disease?. Am. J. Respir. Crit. Care Med. 168: 63-69 [Abstract] [Full Text]  
• Witt, O., Monkemeyer, S., Ronndahl, G., Erdlenbruch, B., Reinhardt, D., Kanbach, K., Pekrun, A. (2003). Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin. Blood 101: 2001-2007 [Abstract] [Full Text]  
• Atweh, G. F., DeSimone, J., Saunthararajah, Y., Fathallah, H., Weinberg, R. S., Nagel, R. L., Fabry, M. E., Adams, R. J. (2003). Hemoglobinopathies. ASH Education Book 2003: 14-39 [Abstract] [Full Text]  
• Mufti, G., List, A. F., Gore, S. D., Ho, A. Y.L. (2003). Myelodysplastic Syndrome. ASH Education Book 2003: 176-199 [Abstract] [Full Text]  
• Pace, B. S., White, G. L., Dover, G. J., Boosalis, M. S., Faller, D. V., Perrine, S. P. (2002). Short-chain fatty acid derivatives induce fetal globin expression and erythropoiesis in vivo. Blood 100: 4640-4648 [Abstract] [Full Text]  
• Vadolas, J., Wardan, H., Orford, M., Voullaire, L., Zaibak, F., Williamson, R., Ioannou, P. A. (2002). Development of sensitive fluorescent assays for embryonic and fetal hemoglobin inducers using the human beta -globin locus in erythropoietic cells. Blood 100: 4209-4216 [Abstract] [Full Text]  
• He, Z., Russell, J. E. (2002). A human embryonic hemoglobin inhibits Hb S polymerization in vitro and restores a normal phenotype to mouse models of sickle cell disease. Proc. Natl. Acad. Sci. USA 99: 10635-10640 [Abstract] [Full Text]  
• Ware, R. E., Eggleston, B., Redding-Lallinger, R., Wang, W. C., Smith-Whitley, K., Daeschner, C., Gee, B., Styles, L. A., Helms, R. W., Kinney, T. R., Ohene-Frempong, K. (2002). Predictors of fetal hemoglobin response in children with sickle cell anemia receiving hydroxyurea therapy. Blood 99: 10-14 [Abstract] [Full Text]  
• Boosalis, M. S., Bandyopadhyay, R., Bresnick, E. H., Pace, B. S., Van DeMark, K., Zhang, B., Faller, D. V., Perrine, S. P. (2001). Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation. Blood 97: 3259-3267 [Abstract] [Full Text]  
• Maeda, T., Towatari, M., Kosugi, H., Saito, H. (2000). Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood 96: 3847-3856 [Abstract] [Full Text]  
• Reich, S., Buhrer, C., Henze, G., Ohlendorf, D., Mesche, M., Sinha, P., Kage, A., Muller, C., Vetter, B., Kulozik, A. E. (2000). Oral isobutyramide reduces transfusion requirements in some patients with homozygous beta -thalassemia. Blood 96: 3357-3363 [Abstract] [Full Text]  
• Segain, J-P, de la Bletiere, D R., Bourreille, A, Leray, V, Gervois, N, Rosales, C, Ferrier, L, Bonnet, C, Blottiere, H M, Galmiche, J-P (2000). Butyrate inhibits inflammatory responses through NFkappa B inhibition: implications for Crohn's disease. Gut 47: 397-403 [Abstract] [Full Text]  
• Skarpidi, E., Vassilopoulos, G., Li, Q., Stamatoyannopoulos, G. (2000). Novel in vitro assay for the detection of pharmacologic inducers of fetal hemoglobin. Blood 96: 321-326 [Abstract] [Full Text]  
• Gabbianelli, M., Testa, U., Massa, A., Pelosi, E., Sposi, N. M., Riccioni, R., Luchetti, L., Peschle, C. (2000). Hemoglobin switching in unicellular erythroid culture of sibling erythroid burst-forming units: kit ligand induces a dose-dependent fetal hemoglobin reactivation potentiated by sodium butyrate. Blood 95: 3555-3561 [Abstract] [Full Text]  
• Bohmer, R. M., Campbell, T. A., Bianchi, D. W. (2000). Selectively increased growth of fetal hemoglobin-expressing adult erythroid progenitors after brief treatment of early progenitors with transforming growth factor beta. Blood 95: 2967-2974 [Abstract] [Full Text]  
• Witt, O., Sand, K., Pekrun, A. (2000). Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways. Blood 95: 2391-2396 [Abstract] [Full Text]  
• Witzig, T. E., Timm, M., Stenson, M., Svingen, P. A., Kaufmann, S. H. (2000). Induction of Apoptosis in Malignant B Cells by Phenylbutyrate or Phenylacetate in Combination with Chemotherapeutic Agents. Clin. Cancer Res. 6: 681-692 [Abstract] [Full Text]  
• Smith, R. D., Li, J., Noguchi, C. T., Schechter, A. N. (2000). Quantitative PCR analysis of HbF inducers in primary human adult erythroid cells. Blood 95: 863-869 [Abstract] [Full Text]  
• Kien, C. L., Chang, J. C., Cooper, J. R. (2000). Butyric Acid Is Synthesized by Piglets. J. Nutr. 130: 234-237 [Abstract] [Full Text]  
• BERNHARD, D., AUSSERLECHNER, M. J., TONKO, M., LÖFFLER, M., HARTMANN, B. L., CSORDAS, A., KOFLER, R. (1999). Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts. FASEB J. 13: 1991-2001 [Abstract] [Full Text]  
• Heerdt, B. G., Houston, M. A., Anthony, G. M., Augenlicht, L. H. (1999). Initiation of Growth Arrest and Apoptosis of MCF-7 Mammary Carcinoma Cells by Tributyrin, a Triglyceride Analogue of the Short-Chain Fatty Acid Butyrate,Is Associated with Mitochondrial Activity. Cancer Res. 59: 1584-1591 [Abstract] [Full Text]  
• Steinberg, M. H. (1999). Management of Sickle Cell Disease. NEJM 340: 1021-1030 [Full Text]  
• Bunn, H. F. (1999). Induction of Fetal Hemoglobin in Sickle Cell Disease. Blood 93: 1787-1789 [Full Text]  
• Atweh, G. F., Sutton, M., Nassif, I., Boosalis, V., Dover, G. J., Wallenstein, S., Wright, E., McMahon, L., Stamatoyannopoulos, G., Faller, D. V., Perrine, S. P. (1999). Sustained Induction of Fetal Hemoglobin by Pulse Butyrate Therapy in Sickle Cell Disease. Blood 93: 1790-1797 [Abstract] [Full Text]  
• Collins, M., Kaslow, N., Doepke, K., Eckman, J., Johnson, M. (1998). Psychosocial Interventions for Children and Adolescents with Sickle Cell Disease (SCD). Journal of Black Psychology 24: 432-454 [Abstract]  
• Ikuta, T., Kan, Y. W., Swerdlow, P. S., Faller, D. V., Perrine, S. P. (1998). Alterations in Protein-DNA Interactions in the gamma -Globin Gene Promoter in Response to Butyrate Therapy. Blood 92: 2924-2933 [Abstract] [Full Text]  
• GINDER, G. D., SINGAL, R., LITTLE, J. A., DEMPSEY, N., FERRIS, R., WANG, S. Z. (1998). Silencing and Activation of Embryonic Globin Gene Expression. Ann. N. Y. Acad. Sci. 850: 70-79 [Abstract] [Full Text]  
• DOVER, G. J. (1998). Hemoglobin Switching Protocols in Thalassemia: Experience with Sodium Phenylbutyrate and Hydroxyurea. Ann. N. Y. Acad. Sci. 850: 80-86 [Abstract] [Full Text]  
• IKUTA, T., ATWEH, G., BOOSALIS, V., WHITE, G. L., DA FONSECA, S., BOOSALIS, M., FALLER, D. V., PERRINE, S. P. (1998). Cellular and Molecular Effects of a Pulse Butyrate Regimen and New Inducers of Globin Gene Expression and Hematopoiesis. Ann. N. Y. Acad. Sci. 850: 87-99 [Abstract] [Full Text]  
• OLIVIERI, N. F., REES, D. C., GINDER, G. D., THEIN, S. L., WAYE, J. S., CHANG, L., BRITTENHAM, G. M., WEATHERALL, D. J. (1998). Elimination of Transfusions Through Induction of Fetal Hemoglobin Synthesis in Cooley's Anemia. Ann. N. Y. Acad. Sci. 850: 100-109 [Abstract] [Full Text]  
• CAPPELLINI, M. D., GRAZIADEI, G., CICERI, L., COMINO, A., BIANCHI, P., POMATI, M., FIORELLI, G. (1998). Butyrate Trials. Ann. N. Y. Acad. Sci. 850: 110-119 [Abstract] [Full Text]  
• MACMILLAN, M. L., FOULADI, M., NISBET-BROWN, E., WAYE, J. S., OLIVIERI, N. F. (1998). Treatment of Two Infants with Cooley's Anemia with Sodium Phenylbutyrate. Ann. N. Y. Acad. Sci. 850: 452-454 [Full Text]  
• Peters, A., Rohloff, D., Kohlmann, T., Renner, F., Jantschek, G., Kerner, W., Lorenz Fehm, H. (1998). Fetal Hemoglobin in Starvation Ketosis of Young Women. Blood 91: 691-694 [Abstract] [Full Text]  
• Bunn, H. F. (1997). Pathogenesis and Treatment of Sickle Cell Disease. NEJM 337: 762-769 [Full Text]  
• Adams-Graves, P., Kedar, A., Koshy, M., Steinberg, M., Veith, R., Ward, D., Crawford, R., Edwards, S., Bustrack, J., Emanuele, M. (1997). RheothRx (Poloxamer 188) Injection for the Acute Painful Episode of Sickle Cell Disease: A Pilot Study. Blood 90: 2041-2046 [Abstract] [Full Text]  
• McCaffrey, P. G., Newsome, D. A., Fibach, E., Yoshida, M., Su, M. S.-S. (1997). Induction of gamma -Globin by Histone Deacetylase Inhibitors. Blood 90: 2075-2083 [Abstract] [Full Text]  
• Chen, W. Y., Bailey, E. C., McCune, S. L., Dong, J.-Y., Townes, T. M. (1997). Reactivation of silenced, virally transduced genes by inhibitors of histone deacetylase. Proc. Natl. Acad. Sci. USA 94: 5798-5803 [Abstract] [Full Text]  
• Weaver, G. A., Tangel, C. T., Krause, J. A., Parfitt, M. M., Jenkins, P. L., Rader, J. M., Lewis, B. A., Miller, T. L., Wolin, M. J. (1997). Acarbose Enhances Human Colonic Butyrate Production. J. Nutr. 127: 717-723 [Abstract] [Full Text]  
• RUBENSTEIN, R. C., ZEITLIN, P. L. (1997). A Pilot Clinical Trial of Oral Sodium 4-Phenylbutyrate (Buphenyl) in Delta F508-Homozygous Cystic Fibrosis Patients . Partial Restoration of Nasal Epithelial CFTR Function. Am. J. Respir. Crit. Care Med. 157: 484-490 [Abstract] [Full Text]  
• Brauer, M., Al-Momen, A.-K., Faller, D. V., Olivieri, N. F. (1995). Butyrate Treatment in {beta}-Hemoglobinopathies. NEJM 333: 1287-1288 [Full Text]  
• Sher, G. D., Ginder, G. D., Little, J., Yang, S., Dover, G. J., Olivieri, N. F. (1995). Extended Therapy with Intravenous Arginine Butyrate in Patients with {beta}-Hemoglobinopathies. NEJM 332: 1606-1610 [Abstract] [Full Text]  
• Galanello, R., Cao, A., Olivieri, N. (1994). Induction of Fetal Hemoglobin in the Presence of Increased 3-Hydroxybutyric Acid Associated with {beta}-Ketothiolase Deficiency. NEJM 331: 746-747 [Full Text]  
• Griffin, T. C., McIntire, D., Buchanan, G. R. (1994). High-Dose Intravenous Methylprednisolone Therapy for Pain in Children and Adolescents with Sickle Cell Disease. NEJM 330: 733-737 [Abstract] [Full Text]  
• Desforges, J. F. (1993). My Life at the Journal, 1961-1993. NEJM 329: 1038-1039 [Full Text]  
• Lowrey, C. H., Nienhuis, A. W. (1993). Treatment with Azacitidine of Patients with End-Stage {beta}-Thalassemia. NEJM 329: 845-848 [Full Text]  
• Weatherall, D.J. (1993). The Treatment of Thalassemia -- Slow Progress and New Dilemmas. NEJM 329: 877-879 [Full Text]  
• Blau, C. A. (1993). Therapy for Globin-Chain Disorders. NEJM 329: 364-364 [Full Text]  
• (1993). NEW APPROACHES TO SICKLE-CELL ANEMIA AND BETA- THALASSEMIA. JWatch General 1993: 7-7 [Full Text]  
• Bunn, H. F. (1993). Reversing Ontogeny. NEJM 328: 129-131 [Full Text]  
• Kang, H.-L., Benzer, S., Min, K.-T. (2002). Life extension in Drosophila by feeding a drug. Proc. Natl. Acad. Sci. USA 99: 838-843 [Abstract] [Full Text]