|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 1790-1797
Sustained Induction of Fetal Hemoglobin by Pulse Butyrate Therapy in
Sickle Cell Disease
By
George F. Atweh,
Millicent Sutton,
Imad Nassif,
Vassiliki Boosalis,
George J. Dover,
Sylvan Wallenstein,
Elizabeth Wright,
Lillian McMahon,
George Stamatoyannopoulos,
Douglas V. Faller, and
Susan P. Perrine
From the Departments of Medicine, Pediatrics and Biomathematical
Sciences, Mount Sinai School of Medicine, New York, NY; the Departments
of Pediatrics, Medicine, Pharmacology, and Experimental Therapeutics,
Hemoglobinopathy-Thalassemia Research Unit, Boston University School of
Medicine, Boston, MA; the Department of Pediatrics, Johns Hopkins
University School of Medicine, Baltimore, MD; the Division of Medical
Genetics, University of Washington School of Medicine, Seattle, WA; and
The New England Research Institute, Watertown, MA.
 |
ABSTRACT |
High levels of fetal hemoglobin (Hb F) protect from many of the
complications of sickle cell disease and lead to improved survival.
Butyrate and other short chain fatty acids were previously shown to
increase Hb F production in erythroid cells in vitro and in animal
models in vivo. However, butyrates are also known to inhibit the
proliferation of many cell types, including erythroid cells. Experience
with the use of butyrate in animal models and in early clinical trials
demonstrated that the Hb F response may be lost after prolonged
administration of high doses of butyrate. We hypothesized that this
loss of response may be a result of the antiproliferative effects of
butyrate. We designed a regimen consisting of intermittent or pulse
therapy in which butyrate was administered for 4 days followed by 10 to
24 days with no drug exposure. This pulse regimen induced fetal globin
gene expression in 9 of 11 patients. The mean Hb F in this group
increased from 7.2% to 21.0% (P < .002) after intermittent
butyrate therapy for a mean duration of 29.9 weeks. This was associated
with a parallel increase in the number of F cells and F reticulocytes.
The total hemoglobin levels also increased from a mean of 7.8 g/dL to a mean of 8.8 g/dL (P < .006). The increased levels of Hb F
were sustained in all responders, including 1 patient who has been on
pulse butyrate therapy for more than 28 months. This regimen, which
resulted in a marked and sustained increase in Hb F levels in more than
two thirds of the adult sickle cell patients enrolled in this study,
was well tolerated without adverse side effects. These encouraging
results require confirmation along with an appropriate evaluation of
clinical outcomes in a larger number of patients with sickle cell disease.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
SICKLE CELL DISEASE was first described
as a distinct clinical entity in the early part of this century.
Identification of its etiology as a single amino acid substitution of
the  -globin chain of the hemoglobin molecule marked the beginning of
the era of molecular medicine.1,2 Numerous investigations
followed to elucidate the physico-chemical properties of sickle
hemoglobin, and attempts were made to develop agents that would alter
the mutant molecule to decrease red blood cell sickling in
vivo.2-4 However, these approaches did not lead to the
development of effective therapies that impacted on the course of the
disease. It was also recognized early on that the disease does not
become clinically manifest until fetal hemoglobin (Hb F) production is
developmentally suppressed during infancy.1,2,5,6 When Hb F
was added to sickle hemoglobin in vitro at concentrations exceeding
20%, polymerization of sickle hemoglobin was
inhibited.2,5,7 Such high concentrations of Hb F were also
noted to ameliorate the clinical complications of sickle cell disease
in vivo.2,4-13 The large study of the natural history of
this disease known as the Cooperative Study of Sickle Cell Disease
(CSSCD) demonstrated that smaller increments in Hb F have some
ameliorating effects on the clinical manifestations of the disease and
that levels greater than 9% could prevent its early
mortality.13 These observations were largely responsible
for the shift of therapeutic emphasis to strategies to increase the
level of Hb F in vivo in patients with sickle cell disease.
Initial efforts to stimulate Hb F production in sickle cell disease
used S-phase-specific chemotherapeutic agents such as 5-azacytidine
and hydroxyurea.2,14-25 The Multicenter Study of Hydroxyurea (MSH), a recently completed randomized, placebo-controlled, multicenter clinical trial demonstrated a significant reduction in the
incidence of vaso-occlusive crises and acute chest syndrome in patients
who received hydroxyurea.22 The Hb F levels increased in
approximately half the adult subjects who received the drug from a mean
of 5.1% to a mean of 8.6%.23 Although mean Hb F levels of
15% to 18% have been achieved in children with sickle cell disease,
such levels were achieved only in about 25% of adult subjects
receiving the same therapy in the MSH.23-27 Because of the
modest increases in Hb F levels that were seen in adult patients treated with hydroxyurea and because of lingering concerns about potentially serious side effects of chronic administration of chemotherapeutic agents, development of safe and effective inducers of
fetal globin gene expression has been encouraged.26
Reports from several laboratories had demonstrated that butyrate and
other short chain fatty acids can selectively stimulate embryonic or
fetal globin gene expression in a variety of experimental systems.28-36 Butyrate was shown to increase the expression
of the embryonic  -globin gene in adult chickens. However, this
activation of the embryonic -globin gene required pretreatment with
5-azacytidine.37 In utero infusions of butyrate were later
shown to delay the developmental switch from  - to -globin gene
expression in sheep fetuses.29 Other studies demonstrated
that butyrate can induce -globin gene expression in adult baboons
and increase the expression of the human -globin gene in transgenic
mice.31,32 Transfection experiments also showed that
butyrate and other short chain fatty acids selectively stimulate the
activity of the human -globin gene promoter in reporter
assays.33,35 These laboratory observations provided a
rational basis for the clinical studies of butyrate that followed.
A short-term safety trial of arginine butyrate in 6 patients with
-globin disorders demonstrated induction of -globin mRNA, -globin chain synthesis, and F reticulocytes in all 6 patients after
2 to 3 weeks of therapy.38 A hematologic response
consisting of more than 4 g/dL increase in total hemoglobin was seen in
1 patient homozygous for Hb Lepore who received extended, lower-dose therapy for 7 weeks.38 In a second 10-week study by Sher et al,39 arginine butyrate was administered to 5 patients with sickle cell disease and 5 patients with -thalassemia at high doses
(2,000 mg/kg/d) by continuous infusion (24 h/d, 6 d/wk). Increases in
Hb F levels were observed in three of the 5 patients with sickle cell
disease, with the mean Hb F increasing from 5.1% at baseline to a peak
of 9.6%.39 In other studies, sodium 4-phenylbutyrate was
also shown to increase Hb F in one third of sickle cell patients and
total hemoglobin in 4 of 8 nontransfused patients with
-thalassemia.40,41
In addition to the activation of fetal globin gene expression,
butyrates are also known to induce growth arrest in the G1 phase of the
cell cycle.42-46 Two studies in baboons demonstrated that
continuous administration of high doses of butyrate (1,000 mg/kg) or
prolonged administration of one of its metabolites, acetate, can result
in loss of initial Hb F responses.47,48 In addition, our
own experience with butyrate described in this report and the published
experience of Sher et al39 demonstrated that the initial Hb
F response to butyrate may be lost after extended periods of continuous
therapy in patients with sickle cell disease. We hypothesized that the
decrease in the high levels of Hb F after butyrate therapy may be a
result of cumulative antiproliferative effects. Thus, we designed and
evaluated an alternate regimen of therapy consisting of pulsed
administration of butyrate to avoid inhibition of growth of erythroid
cells from prolonged exposure to butyrate. More than two thirds of the
adult patients with sickle cell disease that were enrolled on this
regimen demonstrated a marked and sustained activation of Hb F production.
| |
MATERIALS AND METHODS |
Patients and treatment.
Fifteen patients with sickle cell disease were enrolled in our butyrate
studies, 6 on a pilot weekly regimen, and 11 on the pulse regimen. Two
of the patients were initially enrolled on the weekly regimen and later
re-enrolled on the pulse regimen. There were 6 male and 9 female
patients with an age range of 17 to 55 years. These studies were
approved by the Food and Drug Administration and by the Institutional
Review Boards of the Mount Sinai School of Medicine and the Boston
University School of Medicine (Boston, MA). Informed consent was
provided according to the Declaration of Helsinki. Only patients with
moderate to severe sickle cell disease, defined by three or more
hospitalizations per year for sickling complications, were eligible for
enrollment in these studies. None of the patients was on a chronic
transfusion regimen during the 3 months preceding enrollment. The
diagnosis of homozygous sickle cell disease was confirmed in all
patients by hemoglobin electrophoresis on cellulose acetate. In the 1 patient with sickle °-thalassemia, the diagnosis was confirmed
by molecular analysis.
Arginine butyrate was prepared as a sterile, nonpyrogenic 5% or 10%
solution. The drug was first infused through a central venous line over
8 to 12 hours at rates of 22 to 45 mg/kg/h, usually at night. If no
side effects occurred, the infusion rate was increased gradually to 65 to 75 mg/kg/h. Patients who were enrolled on the weekly regimen were
infused with arginine butyrate 5 nights per week in escalating doses
that ranged from 166 to 666 mg of butyric acid/kg/d. The mean duration
of therapy in patients enrolled in the weekly regimen was 15 weeks
(range, 3 to 72 weeks). The patients who were enrolled on the pulse
regimen received arginine butyrate infusions for 6 to 12 h/d to deliver
between 250 and 500 mg/kg/d, with a usual maintenance dose of 500 mg/d.
The drug was administered for 4 days, followed by 10 to 24 days with no
drug exposure before the next cycle of treatment. The mean duration of
therapy in the 11 patients enrolled on the pulse regimen was 30 weeks
(range, 7 to 112 weeks). All patients enrolled on either regimens
received ferrous sulfate (300 mg/d) on the days of butyrate infusions
and 1 mg/d of folic acid for the duration of the study. Chemistry panels, complete blood counts, and reticulocyte counts were monitored at least once weekly during the week of butyrate therapy. Serum ferritin levels were determined at least once monthly during enrollment in this study.
Analysis of F reticulocytes and Hb F levels.
The proportions of reticulocytes and mature erythrocytes that contained
Hb F (F reticulocytes and F cells) were determined as previously
described.19,38 Hb F levels in peripheral blood samples
were quantified by electrophoresis on cellulose acetate, followed by
scanning densitometry, because our experience and that of
others10 showed that this method significantly
underestimates high Hb F levels in the range achieved in this study.
However, when the Hb F levels were less than 5%, the alkali
denaturation method was used to confirm the densitometric data.
| |
RESULTS |
The first 6 patients that were enrolled in this study received butyrate
infusions on a weekly basis. The Hb F levels increased in 3 of the 6 patients (Fig 1). The Hb F response of a
very informative patient from this group who was enrolled in the weekly
regimen over a period of 16 months is presented in detail in Fig 2.
Within the first 4 months of butyrate therapy, the Hb F increased from 3.5% to 23%. The total Hb level increased in parallel with the Hb F
level during therapy from 7.5 to 10 g/dL. The patient elected to
withdraw from the study at that time and her Hb F level began to
decrease. She requested re-enrollment in the study 2 months later and
her Hb F level increased again while on butyrate to levels above 20%.
However, while on weekly therapy (except for a 2-week interruption
during the holidays), her Hb F levels gradually decreased to levels
that were only slightly higher than her baseline.
View larger version (16K):
[in this window]
[in a new window]
| Fig 1.
A bar graph that shows the initial Hb F levels ( ) and
the increment in Hb F during therapy ( ) in the 6 patients enrolled
on the weekly butyrate regimen.
|
|
The loss of the Hb F response during weekly therapy in this patient and
the reported loss of responses in sickle cell patients studied by Sher
et al39 were similar to the loss of Hb F response seen in
baboons after high-dose and prolonged administration of butyrate.47,48
This suggested the possibility that cumulative toxicity resulting from
continuous exposure to butyrate may be responsible for this loss of
response. A pulse regimen that was designed to allow recovery from the
antiproliferative effects of butyrate was investigated in 11 patients.
The characteristics of these patients and their responses are
summarized in Table 1. The Hb F levels of
the 11 patients enrolled on this regimen increased from a mean of 7.2%
at baseline to a mean of 21.0% during therapy (P = .002, paired t-test; Fig 3). The details
of the Hb F response to butyrate in 3 of the 9 responsive patients are
shown in Fig 4. Interestingly, the 2 patients who did not respond to butyrate had baseline Hb F levels less
than 2%, whereas all 9 responders had baseline Hb F levels of 2% or
more. The same was true of the patients who were enrolled on the weekly
therapy as shown in Fig 1. The F reticulocytes levels increased from a
mean of 14.0% before therapy to a mean of 26.2% during therapy
(P = .003, paired t-test). The F cells also increased
from a mean of 27.5% before therapy to a mean of 42.5% during therapy
(P = .0004, paired t-test). There was a very
significant correlation between the baseline Hb F levels and the peak
Hb F levels during therapy (r = .87 with P = .002). An equally strong correlation was found between baseline and
peak F cells (r = .93 with P < .0001) and F
reticulocyte. The Hb level increased in approximately half of the
patients from a mean of 7.8 g/dL before therapy to a mean of 8.8 g/dL
during therapy (P = .006, paired t-test). However, there was no correlation between the baseline and the peak Hb levels
achieved during therapy (r = .49 with P = .12). The absence of an increase of the total Hb levels in some
patients may be related to partial inhibition of the proliferation of
their erythroid progenitors in vivo. The initial HbF responses and the
total hemoglobin responses were maintained after prolonged
administration in all patients who received pulse butyrate. In 1 patient, the Hb F levels have been maintained in the 20% range for
more than 28 months. Interestingly, of the 5 patients who failed to
respond to the weekly or the intermittent regimen, 3 received
hydroxyurea either before or after the completion of the butyrate
study. All 3 had excellent Hb F responses to hydroxyurea, as shown in
Fig 5.
View larger version (18K):
[in this window]
[in a new window]
| Fig 2.
Bar graph illustrating the Hb F response in a patient
receiving weekly butyrate therapy. Each vertical bar
represents the average of approximately eight determinations of
hemoglobin F per month. The periods of butyrate therapy are depicted as
solid horizontal bars below the vertical bar graph and the periods of
interruption of therapy are depicted as open horizontal bars.
|
|
View larger version (23K):
[in this window]
[in a new window]
| Fig 3.
A bar graph that shows the initial Hb F levels () and
the increment in Hb F during therapy () in the 11 patients enrolled
on the pulse butyrate regimen.
|
|
View larger version (31K):
[in this window]
[in a new window]
| Fig 4.
Detailed representation of the Hb F responses to pulse
butyrate therapy in 3 adult patients with sickle cell disease. Each bar
represents the average of two fetal hemoglobin levels obtained during
the week of therapy.
|
|
View larger version (12K):
[in this window]
[in a new window]
| Fig 5.
A bar graph that shows the initial Hb F levels () and
the increment in Hb F during therapy () in the 3 butyrate
nonresponsive patients who were treated with hydroxyurea either before
or after the end of their butyrate therapy.
|
|
No symptoms attributed to arginine butyrate were observed at infusion
rates of 65 to 75 mg/kg/h at the 500 mg/kg/d dose administered in this
study. Antiemetics were usually not required, and some patients
reported an increase, rather than a decrease, in their appetite while
receiving the drug. No laboratory abnormalities were noted after
frequent monitoring of liver function tests, serum creatinine levels,
electrolyte levels, and coagulation assays. Blood urea nitrogen (BUN)
levels were frequently elevated during the infusions, presumably due to
the metabolic conversion of arginine to urea. These high BUN levels
always decreased within a few hours of completing the infusions. No
significant changes were seen in the white blood cell (WBC) counts,
platelet counts, mean corpuscular volume (MCV), mean corpuscular
hemoglobin (MCH), and mean corpuscular hemoglobin concentration
(MCHC) during the course of butyrate therapy. No adverse
side effects were observed in greater than 230 patient-weeks of
observation. Interestingly, despite iron supplementation, the serum
ferritin levels did not increase in any patient, whereas a decrease was
seen in some patients.
| |
DISCUSSION |
A number of clinical and experimental observations support the
hypothesis that high levels of Hb F can reduce sickling and ameliorate
the clinical severity of sickle cell disease.2,4-13 The
observations that patients from the eastern provinces of Saudi Arabia
and southern India with levels of Hb F greater than 20% generally have
a very mild clinical course provided a compelling justification for
therapeutic attempts to increase Hb F in adult life.8-11
This was further supported by extensive data collected from the
multicenter CSSCD that showed a clinical benefit associated with any
increase in Hb F with no threshold level that had to be exceeded before
these benefits are realized.13 Nonetheless, the complete
amelioration of sickling complications may require levels of Hb F in
excess of 20%.12 The MSH represents a landmark clinical
trial that demonstrated, for the first time, the clinical efficacy of
an agent that stimulates Hb F production in patients with sickle cell
disease.22 Yet, the mean increase in Hb F in the adult
subject was only 4%.23 Even more surprisingly, there was
no direct correlation between the Hb F responses and the clinical benefits in the patients who received hydroxyurea.49 These
findings suggest that hydroxyurea may have additional beneficial
effects that are not related to Hb F induction.23,49-51
Study of newborn infants born to diabetic mothers demonstrated that
high plasma levels of  -amino-n-butyric acid during gestation can be
associated with a delay in the switch from fetal to adult hemoglobin
production.52 The Hb F inducing activity of butyrate was
first demonstrated in a short-term, 2-week dose-evaluation trial of
arginine butyrate in patients with hemoglobin disorders.38 However, a subsequent 10-week trial in which patients received high
doses of butyrate for 24 h/d, 6 d/wk (with no iron supplementation) showed a significant but nonsustained increase in fetal hemoglobin in 3 of 5 patients with sickle cell disease.39 We also observed a decrease in Hb F levels after several months of weekly butyrate administration (at a much lower dose) in the patient whose course is
shown in Fig 2. This decrease in Hb F after prolonged exposure to
butyrate, considered in the context of the well-known growth-inhibitory activity of butyrate, suggested that an intermittent dosing schedule may prevent toxicity and allow more proliferation of the erythroid cells in which Hb F is induced. Thus, a pulse-dosing regimen in which
butyrate was administered for 4 days followed by a variable period of
no drug exposure was designed and tested. In addition, because some
prior studies had suggested that pharmacologic induction of Hb F may be
enhanced by iron supplements,20,21 we elected to administer
ferrous sulfate to all patients on the days of butyrate infusion. Even
though the majority of patients responded to this regimen, we cannot be
certain that iron was necessary for this response, because this study
was not designed to answer this question.
It is of interest to note that all 5 patients who did not respond to
weekly or pulse butyrate in our studies had low baseline Hb F levels
(<2%), whereas all 11 responders had higher baseline Hb F levels
( 2%). This striking correlation between baseline Hb F and response
to butyrate suggests that induction of -globin expression by
butyrate may require the fetal globin genes to be in a partially active
or accessible state at the time of exposure to butyrate. This is
consistent with experimental findings in chicken in which the induction
of embryonic globin genes required prior exposure to
5-azacytidine.37 Butyrate and related compounds are
believed to stimulate Hb F production at least in part by inhibition of
histone deacetylase.53 Histone deacetylases have recently
been shown to be recruited to specific DNA sequences by binding to
transcription complexes through their interaction with transcriptional
coactivators and corepressors.54,55 Thus, it is tempting to
speculate that the butyrate effect requires transcriptionally active
fetal globin genes whose regulatory elements are occupied by
transcription factors. These transcription factors may be responsible
for recruiting histone deacetylase and modulating the chromatin that
surrounds the fetal globin genes. Such a mechanism may also account for
the specificity of the enhancing effect of butyrate on fetal globin
gene expression.
If these correlations between baseline Hb F and response are confirmed,
the baseline Hb F levels may serve as a convenient predictor of
response to butyrate therapy. The mean level of Hb F in patients
enrolled in the CSSCD was 6.4%.13 In the MSH study in
which enrollment was limited to patients with moderate to severe disease, the mean Hb F level at baseline was 5.1%, whereas 75% of
patients had a baseline Hb F level greater than 2.5%.23
These Hb F levels are similar to the Hb F levels of patients enrolled in our study (mean, 7.1%). Therefore, if the correlation between initial Hb F and response to butyrate is confirmed, the two thirds of
patients with sickle cell disease who have baseline Hb F levels greater
than 2% may be responsive to treatment with arginine butyrate. However, these predictions require the assessment of
butyrate-responsiveness in a much larger number of patients.
It should be noted that the aim of our study was to identify an
effective dose-regimen of arginine butyrate rather than to formally
compare two dose regimens. The two groups of patients that were
enrolled on the weekly or the pulse regimens differed significantly in
multiple respects. Thus, we cannot conclude that the pulse butyrate
regimen is more effective in inducing Hb F than the weekly regimen.
Interestingly, the 2 patients who were treated with both regimens had
identical Hb F responses to both. However, a loss of Hb F response has
not been seen in any patient enrolled on the pulse regimen. In
addition, the pulse regimen is more acceptable to patients and requires
significantly less resources than the weekly regimen. Thus, it would be
difficult to justify the weekly administration of butyrate to sickle
cell patients in future clinical studies.
The studies described in this report do not allow us to make statements
about the relative efficacy of butyrate and hydroxyurea in inducing Hb
F levels in patients with sickle cell disease. Nonetheless, a few
important differences are apparent when the findings of our study are
compared with those of the MSH and other hydroxyurea studies. First,
the Hb F responses in patients treated with hydroxyurea usually require
several months of treatment and in some patients may not peak before 2 years.27 In contrast, some increase in Hb F is usually seen
within days of exposure to butyrate in the majority of responsive
patients, and the peak is achieved within a few (3 to 4) months. This
rapid response may help avoid long courses of unnecessary treatment in
butyrate nonresponsive patients if these observations are confirmed in larger studies. Second, in the MSH, there was no correlation between the initial Hb F level and the response to therapy.23
However, in a recent study of hydroxyurea in children with sickle cell disease, a strong correlation was noted between the initial Hb F and
the magnitude of the Hb F response. Similarly, the response to butyrate
correlates with the initial Hb F and may require some baseline activity
of the fetal globin genes.27 Third, all three butyrate
nonresponsive patients who received hydroxyurea had excellent Hb F
responses. This demonstrates that failure to respond to one Hb F
inducing agent does not necessarily predict failure to respond to
another and confirms that the two agents increase Hb F by different mechanisms. This also raises the possibility that combination or
sequential administration of hydroxyurea followed by butyrate may be
effective in patients who do not achieve a sufficient Hb F response to
either agent alone.
We noted a marked decrease in the number of days of hospitalization for
sickle cell disease-related complications during butyrate therapy in
the 5 responsive patients who received treatment for 6 months or
longer. In contrast, no decrease in hospital days was noted in the 2 patients whose Hb F levels did not increase during therapy. Two
responsive patients who could not be transfused due to extensive
alloantibodies underwent successful total hip replacements while on
butyrate without prior transfusions. However, it should be noted that
the study described in this report was not a randomized,
placebo-controlled clinical trial designed to assess clinical
end-points. Thus, despite the favorable observations noted here,
definitive conclusions about clinical efficacy should be withheld until
an appropriately designed larger clinical trial is conducted.
The pulse butyrate regimen in which therapy is limited to 4 days every
4 weeks (that can be administered in an outpatient setting) is
acceptable to many patients with severe sickle cell disease who would
otherwise require frequent hospitalizations for complications of sickle
cell disease. Nonetheless, this regimen still requires prolonged
intravenous administration of arginine butyrate through a central
venous line with all the associated risks, costs, and inconvenience.
Although home therapy has been used for more than 3 years in selected
patients with thalassemia, this option is not suitable for all
patients. Orally bioavailable compounds such as the recently identified
fatty acid derivatives have the potential to make a significant impact
on sickle cell disease.56,57
In summary, the studies described in this report have defined a
therapeutic approach that results in sustained induction of Hb F to
levels that have been demonstrated to result in significant amelioration of the clinical complications of sickle cell disease. The
marked responses that were seen in the patients enrolled in these
studies demonstrate that developmentally suppressed fetal globin genes
can be reactivated to a very significant level by butyrate exposure in
adult patients with sickle cell disease. These encouraging results
should be confirmed in a larger study that will also include a
prospective evaluation of the effects of pulse butyrate therapy on
clinical outcome.
| |
ACKNOWLEDGMENT |
This manuscript is dedicated in memoriam to Wayne Turner. The authors
appreciate the expert technical assistance of Abbie Mays and Shirley Purvis.
| |
FOOTNOTES |
Submitted July 28, 1998; accepted November 5, 1998.
Supported by Grant No. FDR-001084 from the Food and Drug
Administration, by gifts from Hannah and Lawrence Langsam, by the W.H.
Roberts Foundation, and by Grants No. HL-54184, HL-37118, HL-15157,
RR-00523, and RR-0007 to the General Clinical Research Center of Mount
Sinai School of Medicine from the National Institutes of Health.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to George F. Atweh, MD, Division of
Hematology-Box 1079, Mount Sinai School of Medicine, One Gustave Levy
Place, New York, NY 10029.
| |
REFERENCES |
1.
Conley CL:
Sickle cell anemia The first molecular disease, in
Wintrobe MM
(ed):
Blood, Pure and Eloquent: A Story of Discovery, of People, and of Ideas. New York, NY, McGraw-Hill, 1980, p 319.
2.
Bunn HF:
Pathogenesis and treatment of sickle cell disease.
N Engl J Med
337:762, 1997[Free Full Text]
3.
Ingram VM:
A specific chemical difference between the globins of normal human and sickle cell anemia haemoglobin.
Nature
178:792, 1956[Medline]
[Order article via Infotrieve]
4.
Brittenham GM, Schechter AN, Noguchi CT:
Hemoglobin S polymerization. Primary determinant of the hemolytic and clinical severity of the sickling syndromes.
Blood
65:183, 1985[Abstract/Free Full Text]
5.
Wood WG, Bunch C, Kelly S, Gunn Y, Breckon G:
Control of haemoglobin switching by a developmental clock.
Nature
313:320, 1985[Medline]
[Order article via Infotrieve]
6.
Stamatoyannopoulos JA, Nienhuis AW:
Therapeutic approaches to hemoglobin switching in treatment of the hemoglobinopathies.
Annu Rev Med
43:487, 1992[Medline]
[Order article via Infotrieve]
7.
Nagel RL, Bookchin RM:
Structural bases of the inhibitory effects of Hb F and A2 on the polymerization of Hb S.
Proc Natl Acad Sci USA
76:670, 1979[Abstract/Free Full Text]
8.
Perrine RP:
Benign sickle cell anemia.
Lancet
2:1163, 1972[Medline]
[Order article via Infotrieve]
9.
Brittenham G, Lozoff B, Harris JW, Sharma VS, Narasimhan S:
Sickle cell anemia and trait in a population in southern India.
Am J Hematol
2:25, 1977[Medline]
[Order article via Infotrieve]
10.
Wood WG, Pembrey ME, Serjeant GR, Perrine RP, Weatherall DJ:
Hb F synthesis in sickle cell anaemia: A comparison of Saudi Arab cases with those of African origin.
Br J Haematol
45:431, 1980[Medline]
[Order article via Infotrieve]
11.
Perrine RP:
Natural history of sickle cell anemia in Saudi Arabs.
Ann Intern Med
88:1, 1978
12.
Noguchi CT, Rodgers GP, Serjeant G, Schechter AN:
Levels of fetal hemoglobin necessary for treatment of sickle cell disease.
N Engl J Med
318:96, 1988[Medline]
[Order article via Infotrieve]
13.
Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP:
Mortality in sickle cell disease: Life expectancy and risk factors for early death.
N Engl J Med
330:1639, 1994[Abstract/Free Full Text]
14.
DeSimone J, Heller P, Hall L, Zwiers D:
5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons.
Proc Natl Acad Sci USA
79:4428, 1982[Abstract/Free Full Text]
15.
Ley TJ, DeSimone J, Anagnou NP:
5-Azacytidine selectively increases -globin synthesis in a patient with + thalassemia.
N Engl J Med
307:1469, 1982[Abstract]
16.
Ley TJ, DeSimone J, Noguchi CT:
5-Azacytidine increases -globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia.
Blood
62:370, 1983[Abstract/Free Full Text]
17.
McDonagh KT, Dover GJ, Donahue RE, Nathan DG:
Hydroxyurea-induced Hb F production in anemic primates: Augmentation by erythropoietin, growth factors, and sodium butyrate.
Exp Hematol
20:1156, 1992[Medline]
[Order article via Infotrieve]
18.
Dover GJ, Humphries RK, Moore JG:
Hydroxyurea induction of hemoglobin F production in sickle cell disease: Relationship between cytotoxicity and F-cell production.
Blood
67:735, 1986[Abstract/Free Full Text]
19.
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]
20.
Rodgers GP, Dover GJ, Uyesaka N, Noguchi CT, Schechter AN, Nienhuis AW:
Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease.
N Engl J Med
328:73, 1993[Abstract/Free Full Text]
21.
Nagel RL, Vichinsky E, Shah M:
F-reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: A double blind study.
Blood
81:9, 1993[Abstract/Free Full Text]
22.
Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR:
Multicenter study of hydroxyurea in sickle cell anemia: Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia.
N Engl J Med
332:1317, 1995[Abstract/Free Full Text]
23.
Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, Dover GJ, and Multicenter Study of Hydroxyurea:
Fetal hemoglobin in sickle cell anemia: Determinants of response to hydroxyurea.
Blood
89:1078, 1997[Abstract/Free Full Text]
24.
Ohene-Frempong HK, Bulgarelli W, Schursky HM:
Hydroxyurea increases Hb F production in children with sickle cell disease.
Blood
82:3258, 1993
25.
Ferster A, Vermylen C, Cornu G:
Hydroxyurea for treatment of severe sickle cell anemia: A pediatric trial.
Blood
88:1960, 1996[Abstract/Free Full Text]
26.
Schechter AN, Rodgers G:
Hydroxyurea in sickle cell disease.
N Engl J Med
334:333, 1996[Free Full Text]
27.
Maier-Redelsperger M, deMontalembert M, Flahault A, Neonato 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]
28.
Partington GA, Yarwood NJ, Rutherford TR:
Human globin gene transcription in injected Xenopus oocytes: Enhancement by sodium butyrate.
EMBO J
3:2787, 1984[Medline]
[Order article via Infotrieve]
29.
Perrine SP, Rudolph A, Faller DV:
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]
30.
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 thalassemia.
Blood
74:454, 1989[Abstract/Free Full Text]
31.
Constantoulakis P, Knitter G, Stamatoyannopoulous 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]
32.
Blau A, Constantoulakis P, Shaw CM, Stamatoyannopoulos G:
Fetal hemoglobin induction with butyric acid: Efficacy and toxicity.
Blood
81:529, 1993[Abstract/Free Full Text]
33.
Safaya S, Ibrahim A, Reider RF:
Augmentation of globin gene promoter activity by carboxylic acids and components of the human -globin locus control region.
Blood
84:3929, 1994[Abstract/Free Full Text]
34.
Liakopoulou E, Blau C, Li Q:
Stimulation of fetal hemoglobin production by short chain fatty acids.
Blood
86:3227, 1995[Abstract/Free Full Text]
35.
Perrine SP, Dover GH, Daftari P, Walsh CT, Jin YX, Mays A, Faller DV:
Isobutyramide, an orally bioavailable butyrate analogue, stimulates fetal globin gene expression in vitro and in vivo.
Br J Haematol
88:555, 1994[Medline]
[Order article via Infotrieve]
36.
Burns LJ, Glauber JG, Ginder GD:
Butyrate induces selective transcriptional activation of a hypomethylated embryonic globin gene in adult erythroid cells.
Blood
72:1536, 1988[Abstract/Free Full Text]
37.
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]
38.
Perrine SP, Ginder GD, Faller DV, Dover GH, Ikuta T, Witkowska HE, Cai SP, Vichinsky EP, Olivieri NF:
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]
39.
Sher GD, Entsuah B, Ginder G, Dover G, Berkovitch M, Lewis N, Perrine S, Olivieri NF:
Intravenous arginine butyrate increases -globin mRNA, F-reticulocytes and hemoglobin F in patients with sickle cell disease. 19th Annual Meeting of the National Sickle Cell Disease Program., 1994, p 177.
40.
Dover GJ, Brusilow S, Charache S:
Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate.
Blood
84:339, 1994[Abstract/Free Full Text]
41.
Collins AF, Pearson HA, Giardina P, McDonagh KT, Brusilow SW, Dover GJ:
Oral sodium phenylbutyrate therapy in homozygous thalassemia: A clinical trial.
Blood
85:43, 1995[Abstract/Free Full Text]
42.
Wintersberger E, Mudrak I, Wintersberger U:
Butyrate inhibits mouse fibroblasts at a control point in the G1 phase.
J Cell Biochem
21:239, 1983[Medline]
[Order article via Infotrieve]
43.
Toscani A, Soprano DR, Soprano KJ:
Molecular analysis of sodium butyrate induced growth arrest.
Oncogene Res
3:223, 1988[Medline]
[Order article via Infotrieve]
44.
Charollais RH, Buguet C, Mester J:
Butyrate blocks the accumulation of CDC2 mRNA in late G1 phase but inhibits both the early and late G1 progression in chemically transformed mouse fibroblasts BP-A31.
J Cell Physiol
145:46, 1990[Medline]
[Order article via Infotrieve]
45.
Fibach E, Prosmanne J, Rodgers GP, Samid D:
Enhanced fetal hemoglobin production by phenylacetate and 4 phenylbutyrate in erythroid precursors derived from normal donors and patients with sickle cell anemia and -thalassemia.
Blood
82:2203, 1993[Abstract/Free Full Text]
46.
Vaziri C, Stice LL, Faller DV:
Butyrate-induced G1 arrest results from p21-independent disruption of retinoblastoma-mediated signals.
Cell Growth Differ
9:465, 1998[Abstract]
47.
Faller DV, Perrine SP:
Butyrate in the treatment of sickle cell disease and thalassemia.
Curr Opin Hematol
2:109, 1995[Medline]
[Order article via Infotrieve]
48.
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]
49.
Charache S, Barton FB, Moore RD:
Hydroxyurea and sickle cell anemia: Clinical utility of a myelosuppressive "switching" agent: The Multicenter Study of Hydroxyurea in Sickle Cell Anemia.
Medicine
75:300, 1996[Medline]
[Order article via Infotrieve]
50.
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]
51.
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]
52.
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]
53.
McCaffrey PG, Newsome DA, Fibach E, Yoshida M, Su MS:
Induction of -globin by histone deacetylase inhibitors.
Blood
90:2075, 1997[Abstract/Free Full Text]
54.
Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M, Laherty CD, Torchia J, Yang WM, Brard G, Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK, Rosenfeld MG:
A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression.
Nature
387:43, 1997[Medline]
[Order article via Infotrieve]
55.
Laherty CD, Yang WM, Sun JM, Davie JR, Seto E, Eisenman RN:
Histone deacetylases associated with the mSin3 corepressor mediate mad transciptional repression.
Cell
89:349, 1997[Medline]
[Order article via Infotrieve]
56.
Torkelson S, White GL, Phipps K:
Erythroid progenitor proliferation is stimulated by phenoxyacetic and phenylalkyl acids.
Blood Cells Mol Dis
20:150, 1996
57.
Boosalis MS, Ikuta T, Pace BS:
Abrogation of IL-3 requirements and stimulation of hematopoietic cell proliferation in vitro and in vivo by carboxylic acids.
Blood Cells Mol Dis
23:434, 1997[Medline]
[Order article via Infotrieve]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
H. Bhatia, J. L. Hallock, A. Dutta, S. Karkashon, L. S. Sterner, T. Miyazaki, A. Dean, and J. A. Little
Short-chain fatty acid-mediated effects on erythropoiesis in primary definitive erythroid cells
Blood,
June 18, 2009;
113(25):
6440 - 6448.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Mai, K. Jelicic, D. Rotili, A. Di Noia, E. Alfani, S. Valente, L. Altucci, A. Nebbioso, S. Massa, R. Galanello, et al.
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.,
November 1, 2007;
72(5):
1111 - 1123.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Fathallah, R. S. Weinberg, Y. Galperin, M. Sutton, and G. F. Atweh
Role of epigenetic modifications in normal globin gene regulation and butyrate-mediated induction of fetal hemoglobin
Blood,
November 1, 2007;
110(9):
3391 - 3397.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. P. Perrine, O. Hermine, T. Small, F. Suarez, R. O'Reilly, F. Boulad, J. Fingeroth, M. Askin, A. Levy, S. J. Mentzer, et al.
A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies
Blood,
March 15, 2007;
109(6):
2571 - 2578.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Mercuri, E. Bertini, S. Messina, A. Solari, A. D'Amico, C. Angelozzi, R. Battini, A. Berardinelli, P. Boffi, C. Bruno, et al.
Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy
Neurology,
January 2, 2007;
68(1):
51 - 55.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
S. P. Perrine
Hemoglobin F: new targets, new path
Blood,
August 1, 2006;
108(3):
783 - 784.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Bank
Regulation of human fetal hemoglobin: new players, new complexities
Blood,
January 15, 2006;
107(2):
435 - 443.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Fathallah and G. F. Atweh
Induction of Fetal Hemoglobin in the Treatment of Sickle Cell Disease
Hematology,
January 1, 2006;
2006(1):
58 - 62.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. S. Weinberg, X. Ji, M. Sutton, S. Perrine, Y. Galperin, Q. Li, S. A. Liebhaber, G. Stamatoyannopoulos, and G. F. Atweh
Butyrate increases the efficiency of translation of {gamma}-globin mRNA
Blood,
February 15, 2005;
105(4):
1807 - 1809.
[Abstract]
[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]
|
|
|
|
|
|
|
H. Cao, G. Stamatoyannopoulos, and M. Jung
Induction of human {gamma} globin gene expression by histone deacetylase inhibitors
Blood,
January 15, 2004;
103(2):
701 - 709.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Wright, P. L. Zeitlin, L. Cebotaru, S. E. Guggino, and W. B. Guggino
Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins
Physiol Genomics,
January 15, 2004;
16(2):
204 - 211.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. R. Buchanan, M. R. DeBaun, C. T. Quinn, and M. H. Steinberg
Sickle Cell Disease
Hematology,
January 1, 2004;
2004(1):
35 - 47.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. F. Atweh
Hypomethylation therapy for hemoglobin disorders is back at center stage
Blood,
December 1, 2003;
102(12):
3855 - 3856.
[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]
|
|
|
|
|
|
|
M. Gabbianelli, U. Testa, A. Massa, O. Morsilli, E. Saulle, N. M. Sposi, E. Petrucci, G. Mariani, and C. Peschle
HbF reactivation in sibling BFU-E colonies: synergistic interaction of kit ligand with low-dose dexamethasone
Blood,
April 1, 2003;
101(7):
2826 - 2832.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Wojda, K. R. Leigh, J. M. Njoroge, K. A. Jackson, B. Natarajan, M. Stitely, and J. L. Miller
Fetal hemoglobin modulation during human erythropoiesis: stem cell factor has "late" effects related to the expression pattern of CD117
Blood,
January 15, 2003;
101(2):
492 - 497.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Mufti, A. F. List, S. D. Gore, and A. Y.L. Ho
Myelodysplastic Syndrome
Hematology,
January 1, 2003;
2003(1):
176 - 199.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
T. Ikuta, S. Ausenda, and M. D. Cappellini
Mechanism for fetal globin gene expression: Role of the soluble guanylate cyclase-cGMP-dependent protein kinase pathway
PNAS,
February 1, 2001;
(2001)
41599798.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
R. D. Smith, J. D. Malley, and A. N. Schechter
Quantitative analysis of globin gene induction in single human erythroleukemic cells
Nucleic Acids Res.,
December 15, 2000;
28(24):
4998 - 5004.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Maeda, M. Towatari, H. Kosugi, and H. Saito
Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells
Blood,
December 1, 2000;
96(12):
3847 - 3856.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Reich, C. Buhrer, G. Henze, D. Ohlendorf, M. Mesche, P. Sinha, A. Kage, C. Muller, B. Vetter, and A. E. Kulozik
Oral isobutyramide reduces transfusion requirements in some patients with homozygous beta -thalassemia
Blood,
November 15, 2000;
96(10):
3357 - 3363.
[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]
|
|
|
|
|
|
|
M. Gabbianelli, U. Testa, A. Massa, E. Pelosi, N. M. Sposi, R. Riccioni, L. Luchetti, and C. Peschle
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,
June 1, 2000;
95(11):
3555 - 3561.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Witt, K. Sand, and A. Pekrun
Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways
Blood,
April 1, 2000;
95(7):
2391 - 2396.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. D. Smith, J. Li, C. T. Noguchi, and A. N. Schechter
Quantitative PCR analysis of HbF inducers in primary human adult erythroid cells
Blood,
February 1, 2000;
95(3):
863 - 869.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. F. Rosse, M. Narla, L. D. Petz, and M. H. Steinberg
New Views of Sickle Cell Disease Pathophysiology and Treatment
Hematology,
January 1, 2000;
2000(1):
2 - 17.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. F. Olivieri
The {beta}-Thalassemias
N. Engl. J. Med.,
July 8, 1999;
341(2):
99 - 109.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. F. Bunn
Induction of Fetal Hemoglobin in Sickle Cell Disease
Blood,
March 15, 1999;
93(6):
1787 - 1789.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ikuta, S. Ausenda, and M. D. Cappellini
Mechanism for fetal globin gene expression: Role of the soluble guanylate cyclase-cGMP-dependent protein kinase pathway
PNAS,
February 13, 2001;
98(4):
1847 - 1852.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION