|
|
Next Article 
Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 1787-1789
INTRODUCTION: FOCUS ON HEMATOLOGY
Induction of Fetal Hemoglobin in Sickle Cell Disease
By
H. Franklin Bunn
From the Division of Hematology, Brigham and Women's Hospital,
Boston, MA.
 |
ARTICLE |
THIS ISSUE OF BLOOD features a report by Atweh
et al1 on the induction of fetal hemoglobin (Hb F) by pulse
butyrate. This study is a solid addition to the recent and gratifying
momentum in the development of effective therapy for sickle cell
disease. Underlying this report is a series of novel and convincing in vivo studies extending from model systems in the chicken,2 sheep,3 and baboons4-6 to observations on
babies of diabetic mothers7 and on patients with metabolic
disorders8 and hemoglobinopathies,9,10 all
indicating that butyrates and other short chain fatty acids can cause
significant increases in the levels of Hb F. Our current understanding
of the molecular pathophysiology of sickle cell disease11-13 strongly indicates that patients would derive
considerable benefit from pharmacological induction of Hb F.
The gold standard to which butyrate and related compounds must be
compared is hydroxyurea, an agent now accepted as safe and effective
therapy for sickle cell disease. Initial studies on both hydroxyurea
and butyrate focused on the efficacy with which they cause upregulation
of the  globin gene, thereby increasing the production of Hb F
( 22). In the earlier clinical trials, continuous administration of intravenous (IV) butyrate initially induced a significant increase in Hb F, but with further therapy, the
levels tended to fall back toward baseline. As Atweh et al1 now report, this tachyphylaxis can be obviated by intermittent or pulse
therapy. This treatment resulted in sustained and marked increases in
the percentage of Hb F (Table 1). The
investigators compare these impressive increases with the much more
modest induction observed in the national multicenter cooperative
hydroxyurea (MSH) trial.14,15 However, this is not an apt
comparison, because the two studies differ markedly on issues of
patient compliance and study design. The pulse butyrate protocol,
involving 4-day IV infusions, necessitated full patient cooperation. In
contrast, the design of the cooperative hydroxyurea study required that each participating medical center enroll a minimum number of patients. As a result, the motivation of some of these patients was suspect and,
indeed, compliance was problematic.15 Moreover, because of
the MSH protocol design, even among patients who were fully compliant,
many were undertreated and therefore did not achieve maximal levels of
Hb F. It is likely that both patient cooperation and adequacy of
treatment were considerably greater in earlier studies of much smaller
groups of SS patients treated with hydroxyurea.16-19 As
shown in Table 1, in these smaller studies the induction of Hb F was
much more impressive than what was observed in the MSH cooperative
study. The responses achieved in the 15 adults who participated in
these studies are comparable to the robust inductions of Hb F reported
in children treated with hydroxyurea20,21 (not shown) as
well as to the responses in adults treated with pulse butyrate.
Another consideration that is important in interpreting reports on
pharmacological induction of Hb F is the antisickling effect on
individual red blood cells. In both normal individuals as well as in
patients with sickle cell disease, Hb F is distributed in only a small
proportion of cells, the so-called F cells. The remaining cells are
virtually devoid of Hb F. Before drug treatment, the F cells of most SS
patients contain approximately 15% Hb F. This amount is more than
adequate to inhibit intracellular polymerization. As shown in Table 1,
pulse butyrate results in a marked (nearly 2-fold) increase in Hb F per
F cell. This increment is wasted on the already unsickleable F cell. In
contrast, the increase in F per F cell is more modest in patients
treated with hydroxyurea (Table 1). Thus, a given increment in Hb F
resulting from hydroxyurea therapy is distributed over a larger
proportion of the patient's red blood cells and would therefore be
more likely to be clinically effective.
Because hydroxyurea was developed and is widely used as an
antineoplastic agent, there has been understandable fear that it may be
teratogenic and/or tumorigenic. This concern is heightened by the
prospect of decades of drug exposure and thus has been a major impetus
in the search for other pharmacological inducers of Hb F. Although
experience in the use of hydroxyurea in potentially child-bearing
individuals is limited, there is no apparent increase in birth defects
among infants born to mothers or fathers who were taking the drug at
the time of conception. Likewise, the risk of hydroxyurea
triggering neoplastic transformation appears to be very small. As the
report of Atweh et al1 points out, sodium butyrate
suppresses cell growth and, like hydroxyurea, has been used as an
antineoplastic agent.22 Unlike many anticancer drugs,
neither agent causes direct chemical modification of DNA and,
therefore, would not be expected to be mutagenic.
In view of the inherent complexity of both sickle cell pathophysiology
and the pharmacology of hydroxyurea and butyrate, it is critical to
examine the mechanisms underlying the efficacy of each drug. In the
case of hydroxyurea, there is convincing evidence that the drug not
only induces a robust and sustained increase in F cells, but also has
antisickling effects as assessed by a marked reduction in the fraction
of irreversibly sickled cells and hyperdense cells along with an
increase in cation content and deformability.17-19 These
highly relevant measurements need to be made on patients before and
during treatment with butyrate. Even though hydroxyurea is a
myelosuppressive agent, treatment of SS patients results in a small but
significant increase in hemoglobin levels, a paradox that can only be
explained by the drug's causing a marked amelioration in hemolysis.
This conclusion has been documented by reductions in serum
nonconjugated bilirubin and LDH and by a prolongation of red blood cell
life span.17,18 The 11 patients treated with pulse butyrate
developed a 13% increment in hemoglobin levels, comparable to what has
been observed with hydroxyurea. It will be important to learn whether
pulse butyrate is as effective as hydroxyurea in lowering hemolytic rate.
A major surprise that emerged from clinical studies of SS patients
treated with hydroxyurea is that induction of Hb F is not the only, and
perhaps not the major, contributor to the drug's efficacy. The benefit
of hydroxyurea therapy may be due in part to its well-known ability to
suppress both erythropoiesis and myelopoiesis. Reticulocytes and young
(hypodense) (SS) red blood cells have particularly enhanced adherence
to vascular endothelium. A marked decrease in the adhesion of
patients' red blood cells to cultured endothelial cells is observed
within 2 weeks after initiation of hydroxyurea therapy, coincident with
a decrease in absolute reticulocyte levels and long before there is a
significant induction of Hb F.23,24 Suppression of
neutrophil production may be an even greater contributor to the
efficacy of hydroxyurea. A detailed multivariable analysis of data from
the MSH study showed that the percentage of F cells correlated
inversely with rate of pain crises only during the initial 3 months of
therapy. In contrast, there was a strong correlation between neutrophil
count and crisis rate throughout the 2-year study.15 Thus,
the modest neutropenia that accompanies hydroxyurea treatment may
contribute to the drug's efficacy. If myelosuppression is indeed a
blessing in disguise, this benefit would not be realized with pulse
butyrate therapy, a protocol that, by design, minimizes this effect.
Considerably more inquiry at the bench and at the bedside is needed to
determine whether butyrates and/or other short chain fatty acids can
either replace or supplement the use of hydroxyurea. The development of
safe and effective oral derivatives is essential for long-term
administration in a patient group with poor IV access. One hopes that,
as we enter the next millennium, academic medical centers, the
pharmaceutical industry, government funding agencies, and patient
volunteers all have the staying power to meet this challenge.
| |
FOOTNOTES |
Address reprint requests to H. Franklin Bunn, MD, Division of
Hematology, Brigham and Women's Hospital, 221 Longwood Ave, Room
LMRC-223, Boston, MA 02115.
| |
REFERENCES |
1.
Atweh GF, Sutton M, Nassif I, Boosalis V, Dover GJ, Wallenstein S, Wright E, McMahon L, Stamatoyannopoulos G, Faller DV, Perine SP:
Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease.
Blood
93:1790, 1999[Abstract/Free Full Text]
2.
Ginder GD, Whitters MJ, Pohlman JK:
Activation of a chicken embryonic globin gene in adult erythroid cells by 5-azacytidine and sodium butyrate.
Proc Natl Acad Sci USA
81:3954, 1984[Abstract/Free Full Text]
3.
Perrine SP, Rudolph A, Faller DV, Roman C, Cohen RA, Chen SJ, Kan YW:
Butyrate infusions in the ovine fetus delay the biologic clock for globin gene switching.
Proc Natl Acad Sci USA
85:8540, 1988[Abstract/Free Full Text]
4.
Constantoulakis P, Knitter G, Stamatoyannopoulos G:
On the induction of fetal hemoglobin by butyrates: In vivo and in vitro studies with sodium butyrate and comparison of combination treatments with 5-AzaC and AraC.
Blood
74:1963, 1989[Abstract/Free Full Text]
5.
Stamatoyannopoulos G, Blau CA, Nakamoto B, Josephson B, Li Q, Liakopoulou E, Pace B, Papayannopoulou T, Brusilow SW, Dover G:
Fetal hemoglobin induction by acetate, a product of butyrate catabolism.
Blood
84:3198, 1994[Abstract/Free Full Text]
6.
Liakopoulou E, Blau CA, Li Q, Josephson B, Wolf JA, Fournarakis B, Raisys V, Dover G, Papayannopoulou T, Stamatoyannopoulos G:
Stimulation of fetal hemoglobin production by short chain fatty acids.
Blood
86:3227, 1995[Abstract/Free Full Text]
7.
Perrine SP, Greene MF, Faller DV:
Delay in the fetal globin switch in infants of diabetic mothers.
N Engl J Med
312:334, 1985[Abstract]
8.
Little JA, Dempsey NJ, Tuchman M, Ginder GD:
Metabolic persistence of fetal hemoglobin.
Blood
85:1712, 1995[Abstract/Free Full Text]
9.
Perrine SP, Miller BA, Faller DV, Cohen RA, Vichinsky EP, Hurst D, Lubin BH, Papayannopoulou T:
Sodium butyrate enhances fetal globin gene expression in erythroid progenitors of patients with Hb SS and beta thalassemia.
Blood
74:454, 1989[Abstract/Free Full Text]
10.
Perrine SP, Ginder GD, Faller DV, Dover G, Ikuta T, Witkowska HE, Cai S, Vichinshy E, Olivieri N:
A short-term trial of butyrate to stimulate fetal-globin-gene expression in the  -globin disorders.
N Engl J Med
328:81, 1993[Abstract/Free Full Text]
11.
Platt OS:
Sickle cell paths converge on hydroxyurea.
Nat Med
1:307, 1995[Medline]
[Order article via Infotrieve]
12. Eaton WA, Hofrichter J: The biophysics of sickle cell
hydroxyurea therapy. 268:1142, 1995
13.
Bunn HF:
Pathogenesis and treatment of sickle cell disease.
N Engl J Med
337:762, 1997[Free Full Text]
14.
Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR:
Effect of hydroxyurea on the frequency of painful crisis in sickle cell anemia.
N Engl J Med
332:1317, 1995[Abstract/Free Full Text]
15.
Charache S, Barton FB, Moore RD, Terrin ML, Steinberg MH, Dover GJ, Ballas SK, McMahon RP, Castro O:
Hydroxyurea and sickle cell anemia: Clinical utility of a myelosuppressive "switching agent".
Medicine
75:320, 1996
16.
Charache S, Dover GJ, Moyer MA, Moore JW:
Hydroxyurea-induced augmentation of fetal hemoglobin production in patients with sickle cell anemia.
Blood
69:109, 1987[Abstract/Free Full Text]
17.
Ballas SK, Dover GJ, Charache S:
Effect of hydroxyurea on the rheological properties of sickle erythrocytes in vivo.
Am J Hematol
32:104, 1989[Medline]
[Order article via Infotrieve]
18.
Goldberg MA, Brugnara C, Dover GJ, Schapira L, Charache S, Bunn HF:
Treatment of sickle cell anemia with hydroxyurea and erythropoietin.
N Engl J Med
323:366, 1990[Abstract]
19.
Orringer EP, Blythe DS, Johnson AE, Phillips GJ, Dover GJ, Parker JC:
Effects of hydroxyurea on hemoglobin F and water content in the red blood cells of dogs and of patients with sickle cell anemia.
Blood
78:212, 1991[Abstract/Free Full Text]
20.
Ferster A, Vermylen C, Cornu G, Buyse M, Corazza F, Devalck C, Fondu P, Toppet M, Sariban E:
Hydroxyurea for treatment of severe sickle cell anemia: A pediatric clinical trial.
Blood
88:1960, 1996[Abstract/Free Full Text]
21.
Maier-Redelsperger M, deMontalambert M, Flahault A, Neonata MG, Ducrocq R, Masson M-P, Girot R, Elion J:
Fetal hemoglobin and F-cell responses to long-term hydroxyurea treatment in young sickle cell patients.
Blood
91:4472, 1998[Abstract/Free Full Text]
22.
Perrine SP, Olivieri NF, Faller DV, Vichinsky EP, Dover GJ, Ginder GD:
Butyrate derivatives. New agents for stimulating fetal globin production in the beta-globin disorders.
Am J Pediatr Hematol Oncol
16:67, 1994[Medline]
[Order article via Infotrieve]
23.
Bridges KR, Barabino GD, Brugnara C, Cho MR, Christoph GW, Dover G, Ewenstein BM, Golan DE, Guttmann CRG, Hofrichter J, Mulkern RV, Zhang B, Eaton WA:
A multiparameter analysis of sickle erythrocytes in patients undergoing hydroxyurea therapy.
Blood
88:4701, 1996[Abstract/Free Full Text]
24.
Styles LA, Lubin B, Vichinsky E, Lawrence S, Hua M, Test S, Kuypers F:
Decrease of very late activation antigen-4 and CD36 on reticulocytes in sickle cell patients treated with hydroxyurea.
Blood
89:2554, 1997[Abstract/Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
S. P. Perrine
Hemoglobin F: new targets, new path
Blood,
August 1, 2006;
108(3):
783 - 784.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Hanawa, P. W. Hargrove, S. Kepes, D. K. Srivastava, A. W. Nienhuis, and D. A. Persons
Extended {beta}-globin locus control region elements promote consistent therapeutic expression of a {gamma}-globin lentiviral vector in murine {beta}-thalassemia
Blood,
October 15, 2004;
104(8):
2281 - 2290.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Zimmerman, W. H. Schultz, J. S. Davis, C. V. Pickens, N. A. Mortier, T. A. Howard, and R. E. Ware
Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease
Blood,
March 15, 2004;
103(6):
2039 - 2045.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. J. Dempsey, L. S. Ojalvo, D. W. Wu, and J. A. Little
Induction of an embryonic globin gene promoter by short-chain fatty acids
Blood,
December 1, 2003;
102(12):
4214 - 4222.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. F. Atweh, J. DeSimone, Y. Saunthararajah, H. Fathallah, R. S. Weinberg, R. L. Nagel, M. E. Fabry, and R. J. Adams
Hemoglobinopathies
Hematology,
January 1, 2003;
2003(1):
14 - 39.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. S. Pace, G. L. White, G. J. Dover, M. S. Boosalis, D. V. Faller, and S. P. Perrine
Short-chain fatty acid derivatives induce fetal globin expression and erythropoiesis in vivo
Blood,
December 15, 2002;
100(13):
4640 - 4648.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. L. Nagel
The Challenge of Painful Crisis in Sickle Cell Disease
JAMA,
November 7, 2001;
286(17):
2152 - 2153.
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. J. Lonergan, D. B. Cline, and S. L. Abbondanzo
Sickle Cell Anemia
RadioGraphics,
July 1, 2001;
21(4):
971 - 994.
[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]
|
|
|
|
|
|
|
M. Koshy, L. Dorn, L. Bressler, R. Molokie, D. Lavelle, N. Talischy, R. Hoffman, W. van Overveld, and J. DeSimone
2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia
Blood,
October 1, 2000;
96(7):
2379 - 2384.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
TOP
ARTICLE
REFERENCES