|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1793-1798
Anemia in Children With Cancer Is Associated With Decreased
Erythropoietic Activity and Not With Inadequate Erythropoietin
Production
By
Francis Corazza,
Yves Beguin,
Pierre Bergmann,
Marie André,
Alina Ferster,
Christine Devalck,
Pierre Fondu,
Marc Buyse, and
Eric Sariban
From the Laboratory of Hematology and of Clinical Chemistry, Brugmann
University Hospital, Brussels; the Department of Hematology, University
of Liège; Hematology-Oncology Unit, Hôpital Universitaire
des Enfants, Brussels; and the International Institute for Drug
Development, Brussels, Belgium.
 |
ABSTRACT |
A defect in erythropoietin (EPO) production has been advocated as
being the main cause of anemia presented at time of diagnosis or during
treatment by adults with solid tumors. On the basis of this defect,
anemic cancer patients, both adults and children, have been treated
with recombinant human EPO (rHuEPO). To further elucidate the
pathophysiology of anemia in children with cancer, we measured serum
soluble transferrin receptor (sTfR), a quantitative marker of
erythropoiesis, and serum EPO at time of diagnosis and during
chemotherapy in children suffering from solid tumor or leukemia. We
determined serum EPO in 111 children (55 leukemia, 56 solid tumors) at
time of diagnosis. In the last 44 patients (23 leukemia and 21 solid
tumors), sTfR levels were also measured. Serum EPO together with sTfR
levels were also determined in 60 children receiving chemotherapy (29 leukemia, 31 solid tumors). These results were compared with those
obtained from appropriate control groups. In all patients, we found a
highly significant correlation between the logarithm of EPO
(log[EPO]) and the hemoglobin (Hb) level. In all subsets of patients,
sTfR levels were inappropriately low for the degree of anemia. Neither
leukemic nor solid tumor groups showed a significant inverse
relationship between log(sTfR) and the Hb level as would be expected in
anemic patients with appropriate marrow response. Thus, in children
with cancer, anemia is associated with a decreased total bone marrow
erythropoietic activity which, in contrast to what has been reported in
anemic cancer adults, is not related to defective EPO production.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
THE LEVEL OF BONE MARROW erythropoietic
activity depends on the number of erythroid precursors involved in
proliferation and differentiation. In the human body, 80% of the
transferrin receptors are located in the erythroid marrow. Because a
constant relationship exists between membrane receptors and serum
receptors, determination of serum soluble transferrin receptors (sTfR)
has been used to assess bone marrow erythropoietic
activity.1 The late stages of erythropoiesis are mainly
dependent on erythropoietin (EPO), which induces proliferation and
terminal differentiation of committed red blood cell
progenitors. In the presence of a normal marrow stem cell reserve,
erythropoiesis increases in proportion to the degree of anemia through
an exponential increase of EPO. Thus, simultaneous determination of
sTfR levels (erythroid marrow activity) and serum EPO levels
(erythropoietin stimulation) has been used to investigate the
pathophysiology of red blood cell disorders in different clinical
settings.
Several studies of patients with hematologic malignancies have
described EPO levels appropriate for the degree of
anemia.2-4 In contrast, in patients suffering from solid
malignancies, the observed defect in EPO production has been advocated
as being the main cause of anemia presented by these patients either at time of diagnosis or during treatment.5 This defect has
been put forward as a rational basis for treating the anemia of cancer patients, both adults and children, with recombinant human EPO (rHuEPO).
In the present study, we investigated the pathophysiology of anemia
presented at time of diagnosis and during treatment by children
suffering from either solid tumors or hematologic malignancies. The
adequacy of EPO secretion in response to anemia and the total erythropoietic activity was assessed by determination of serum EPO and
sTfR levels, respectively. Our data indicate that the anemia presented
by children with cancer is due to defective erythroid progenitor
proliferation and not to inappropriate EPO secretion.
| |
MATERIALS AND METHODS |
Patient and control populations.
We determined serum EPO level at time of diagnosis in 111 children
admitted for leukemia (n = 55) or a solid tumor (n = 56). Diagnoses
were: acute lymphoblastic leukemia (50), acute myeloid leukemia (5),
neuroblastoma (13), brain tumor (10), nephroblastoma (9), soft tissue
sarcoma (6), non-Hodgkin's lymphoma (5), osteosarcoma (4), germinal
tumor (4), Hodgkin's disease (3), and primitive neuroectodermic tumor
(2). Among the 56 patients with a solid tumor, 6 had bone marrow
involvement by malignant cells. There were 73 boys and 38 girls. The
mean age was 5.5 ± 3.2 years (range, 1 to 15) in the leukemic group
and 6.3 ± 4.8 years (range, 0.2 to 17) in the group with solid
tumors. Blood samples at time of diagnosis were obtained before any
treatment or transfusion. The sera were kept frozen until EPO
measurement. Hemoglobin (Hb), serum creatinine, and serum albumin
levels were measured concurrently. Levels of serum sTfR were also
measured in the last 44 patients, 23 with leukemia and 19 with a solid
tumor (including 2 with bone marrow involvement). These 44 patients
were white, except for 1 African subject. The study was approved by the
institutional review board.
Among the 111 patients, 88 (51 with leukemia and 37 with a solid tumor)
were considered anemic as defined by an Hb level more than two standard
deviation (SD) below the normal mean value for age.6 No patient had hypoxemia. One patient with acute
myeloid leukemia was excluded because of concomitant acute renal
failure; all other patients had normal renal function.
We determined serum EPO together with sTfR in 60 chemotherapy-treated
children including 29 leukemic and 31 solid tumor patients. The median
duration of chemotherapy at time of study was 2 months (range, 1 to 4)
for the leukemic group and 4 months (range, 1 to 11) for the solid
tumor group. All leukemic patients were in complete remission as
assessed by bone marrow microscopic evaluation. Among the 31 solid
tumor patients, 6 had been exposed to cisplatin for a median time of 3 months (range, 1 to 6).
In leukemic patients, serum EPO and sTfR were also measured later
during the treatment: at the end of intensive treatment (n = 24, median
duration of treatment, 4.5 months; range, 4 to 6) and during
maintenance chemotherapy (n = 15, median time of treatment, 9 months;
range, 7 to 12).
The reference EPO curve was constructed using data obtained in 23 children, 17 boys and 6 girls, with iron deficiency anemia (17) or
sickle cell disease (6), two conditions where EPO production has been
shown to be appropriate to the degree of anemia.5,7 Control
children had normal renal function (creatinine: 0.5 ± 0.17 mg/dL),
no inflammation, and a good nutritional status (observed/optimal weight
ratio: 92.3 ± 13; serum albumin: 4.3 ± 0.4 g/dL).
Patients with erythroid hypoplasia have been reported to have a higher
EPO production in response to anemia as compared with patients with
nonhypoplastic anemia.8 Accordingly, to compare leukemic
patients with control patients with a similar erythroid hypoplasia, we
determined serum EPO levels in 10 anemic patients with aplastic anemia
(n = 9) or Blackfan-Diamond anemia (n = 1). The mean age in this group
was 11 ± 7 years (range, 1 to 18).
To construct the reference sTfR curve evaluating the erythropoietic
response to anemia, samples were obtained from 18 patients with
hemolytic anemia and 18 with dyserythropoietic anemia. Patients with
iron deficiency were excluded, as sTfR levels are inappropriately increased in this condition.9
EPO and sTfR immunoassays.
Immunoreactive EPO levels were measured by a commercially available
immunoradiometric assay (125I-EPO Coat RIA,
Bio-Mérieux, Marcy L'Etoile, Lyon, France) that uses two
different monoclonal antibodies raised against different epitopes of
rHuEPO. The range of normal values in 26 nonanemic healthy adults was
0.9 to 8.5 mU/mL (mean ± SD, 4.7 ± 1.9).10 The
interassay coefficient of variation ranged from 4% to 12% when EPO
concentration was 40 and 4 mU/mL, respectively. There was no influence
of sex or age on the results.
An enzyme-linked immunosorbent assay based on TfR polyclonal antibodies
was used to measure sTfR as previously published.1 Each
sample was run in triplicate. The interassay coefficient of variation
was 7.2%. With this assay, mean sTfR in 150 iron replete normal
subjects was 5,000 ± 1,050 µg/L (mean ± SD). There was no
influence of sex or age on the results.
Hemoglobin levels were determined using Bayer H2 or H3 automated
hematology analyzers (Bayer Diagnostics, Tarrytown, NY). The other
biologic parameters were measured by standard laboratory methods.
Statistical analysis.
Differences between groups for mean biologic values were tested for
statistical significance using the Student's t-test. The correlation coefficients between log(EPO) or log(sTfR) and Hb levels
were computed in least squares regression equations. The slopes and
y-intercepts of the regression lines were tested for equality between
groups by Student's t-test. Furthermore, the adequacy of EPO
and sTfR levels in relation to the degree of anemia was evaluated
individually by computing the ratio between the logarithm of the
observed value and the logarithm of the expected result [O/E log(EPO)
or log(sTfR) ratios] according to the regression line constructed with
the control group. The homogeneity of variance for these parameters
among the various groups was tested by F test. All biologic values are
reported as mean ± SD.
| |
RESULTS |
Adequate EPO response at diagnosis in anemic children suffering from
leukemia or solid tumor.
Serum proteins, albumin, and creatinine levels in patients at diagnosis
were normal and not different from those in the control group. The mean
Hb level was not significantly different in patients with malignancy as
compared with control anemic patients. Mean EPO level was similar in
leukemic patients and in patients with solid tumors as compared with
control group. When log(EPO) was plotted as a function of Hb, a
significant inverse linear relationship was found
(Fig 1A and C) with equivalent coefficient
of correlation in the leukemic, solid tumor, and control groups
(Table 1). The slope and the y-intercept of
the three regression lines was not significantly different. Most
patients (73% of patients with leukemia and 86% of those with solid
tumors) fell within 95% confidence intervals of control subjects; in
only 5% (3 of 55) of leukemic patients and 14% (8 of 56) of patients
with solid tumor was a blunted EPO response observed (Fig 1A and C). As
compared with anemic controls, the mean O/E log(EPO) ratio was not
different in solid tumor patients and was even significantly elevated
in leukemic patients (Table 1). Variance of this ratio was higher in
both patient groups than in controls. In addition, the equations of the
regression lines for log(EPO), as well as the mean O/E log(EPO) ratios,
were not different when leukemic patients at time of diagnosis were
compared with patients with aplastic anemia (Table 1).
View larger version (24K):
[in this window]
[in a new window]
| Fig 1.
Relation of the serum EPO to Hb levels in patients with
leukemia studied at time of diagnosis, n = 55 (A) or during intensive
chemotherapy (CT), n = 29 (B) and in patients with solid tumor at
diagnosis, n = 56 (C), or during intensive CT, n = 31 (D). Solid
lines represent the regression lines computed in each group of
patients. Dashed lines depict the regression line and the 95%
confidence limits of the control group. In graph (D), solid triangles
represent patients receiving cisplatin (n = 6).
|
|
Decreased erythropoiesis as measured by sTfR levels in anemic cancer
children at time of diagnosis.
In both groups of cancer patients evaluated at time of diagnosis, sTfR
levels were significantly lower than in the control group (3,537 ± 2,623 µg/L, 5,923 ± 3,044 µg/L and 24,490 ± 16,130 µg/L
in leukemic, solid tumor, and control groups, respectively). In
addition, we did not observe the inverse relationship between sTfR and
Hb levels that was obtained in control anemic subjects with adequate
marrow function (Fig 2A and C). The
regression equations for the leukemic and solid tumor groups were
respectively: log(sTfR) = 3.454 + (0.004 Hb), r = .04, P
> .05; and log(sTfR) = 4.097  (0.035 Hb), r = .379, P > .05. Solid tumor patients with (n = 2) or
without (n = 19) bone marrow infiltration had similar sTfR/Hb
relationships. Eighty-seven percent of leukemic patients and 48% of
solid tumor patients had sTfR values well below the expected range
computed from the control group; therefore, the O/E log(sTfR) ratios
were significantly reduced in both groups of patients as compared with
controls (0.42 ± 0.13, 0.86 ± 0.06, and 1.00 ± 0.04 in
leukemic, solid tumor, and control groups, respectively).
View larger version (23K):
[in this window]
[in a new window]
| Fig 2.
Relation of serum sTfR to Hb levels in patients with
leukemia studied at time of diagnosis, n = 21 (A) or during intensive
CT, n = 23 (B) and in patients with solid tumor at diagnosis, n
= 21 (C), or during intensive CT, n = 30 (D). Solid lines
represent the regression lines computed in each group of patients.
Dashed lines depict the regression line and the 95% confidence limits
of the control population showing an appropriate stimulation of
erythropoiesis by the anemia.
|
|
Adequate EPO response in anemic cancer children exposed to
chemotherapy.
To explore whether the pathophysiology of anemia observed during
treatment was similar to the one observed at time of diagnosis, EPO and
sTfR measurements were performed in patients treated by intensive
chemotherapy. Both in leukemic and solid tumor patients, the inverse
relationship between log(EPO) and Hb was conserved and was not
different from the one observed at time of diagnosis or in the control
group (Fig 1B and D and Table 1). In addition, leukemic patients all
along their treatment retained an adequate EPO response to the degree
of anemia as indicated by O/E log(EPO) ratio values close to 1 except
in the early phase of intensive chemotherapy where this ratio was even
elevated (Table 1). No leukemic patients presented a blunted EPO
response as defined by an EPO level below the lower limit of the 95%
confidence interval of the control group (Fig 1B). Only 3 of 25 patients with solid tumors not exposed to cisplatin did present a
blunted EPO response (Fig 1D); the 6 patients treated by cisplatin had
a significant lower O/E log(EPO) ratio as compared with the other
patients (Table 1).
Decreased erythropoiesis in anemic cancer children exposed to
chemotherapy.
In most treated patients (90% of leukemic patients and 69% of
patients with solid tumors), erythropoietic activity as assessed by
sTfR level was inappropriately low for the degree of anemia (Fig 2B and
D). Solid tumor patients did not show the expected inverse relationship
between sTfR and Hb: log(sTfR) = 3.329 + (0.026 Hb), r = .217, P > .05 (Fig 2D). In leukemic patients, there was even a
positive correlation between sTfR and Hb: log(sTfR) = 2.649 + (0.084 Hb), r = .602, P < .008 (Fig 2B). Altogether, these
results indicate that the anemia was associated with a lack of
erythropoietic progenitors and not with EPO deficiency.
| |
DISCUSSION |
The EPO response to anemia in patients with cancer has been a matter of
debate. Among adults with solid tumors, inadequate EPO response to the
anemia has been reported in patients at time of diagnosis or during
treatment,5,11 but this has not been a constant
finding.12,13 An EPO defect has been well documented in
patients with multiple myeloma, even in the absence of renal failure.14 However, in other hematologic malignancies,
including chronic lymphocytic leukemia,4 Hodgkin's
disease,3 and acute leukemia,2 most of the
patients showed an adequate EPO response to anemia.
Whether these findings in adults also apply to children has not been
well-demonstrated. In the present study, a significant inverse
relationship between log(EPO) and Hb was observed, either at time of
diagnosis or during chemotherapy, in children suffering from leukemia
or solid tumors. In only 10% (11 of 111) of newly diagnosed cancer
patients and 5% (3 of 54) of treated patients not exposed to cisplatin
was a blunted EPO response observed. Individual EPO response to anemia,
analyzed by computing the ratio between observed and expected log(EPO),
was also appropriate. Similar results were found when leukemic patients
at time of diagnosis were compared with patients with erythroid
hypoplasia secondary to aplastic anemia, a group of patients known to
have the highest EPO levels in response to anemia.8
Altogether, these results suggest that, in marked contrast to what has
been observed in adults,5 EPO production in response to
anemia is undamaged in most children with malignancy-associated anemia.
Leukemic patients evaluated had massive blastic infiltration of the
bone marrow explaining the absence of erythroid proliferation. In
contrast, most children with solid tumors presented without bone marrow
metastases. However, both populations presented erythroid hypoplastic
marrow as indicated by low sTfR levels; thus, it is possible that the
defect in erythroid progenitor activity observed in these patients is
secondary to the presence of soluble inhibitory factors associated with
malignancy.
Increased production of several cytokines, including interleukin-1
(IL-1),15 tumor necrosis factor-
(TNF-),16 interferon- (IFN-),17 and
transforming growth factor- (TGF-)18 has been
demonstrated in a variety of cancers. These cytokines affect erythropoiesis through different pathways.19 In vitro, they inhibit the growth of erythropoietic progenitors, decrease the sensitivity of erythropoietic cells to the trophic effect of EPO, and
suppress the hypoxia-dependent EPO production.20-22 In
vivo, these cytokines have also been reported to suppress
erythropoiesis.23-25 In addition, hematopoietically active
chemokines such as macrophage inflammatory protein-1 have been
involved in the inhibition of erythropoiesis both in
vitro26 and in vivo.27 It remains to be
determined if one or more of these factors are involved in the etiology
of cancer-associated anemia.
In contrast to results published in adults,5 EPO response
in children under treatment for leukemia or a solid tumor was also
adequate for the degree of anemia except in those patients receiving
cisplatin. This suggests that the anemia presented by these children
was mainly due to the direct myelotoxic effect of chemotherapy and that
inadequate EPO response plays a very minor role, if any, in the
etiology of the anemia.
Treatment with rHuEPO has been partially effective in the treatment of
the anemia of cancer patients receiving or not receiving chemotherapy.28,29 However, only a minority of the patients show a complete response, and the doses required are considerably larger than those used in renal failure patients. In contrast to this
latter population, many cancer patients fail to respond to high doses
of rHuEPO. Although algorithms have been proposed, there is no
convenient and reliable predictor of response to rHuEPO in
adults.30 The small studies conducted in children with
solid tumors show a minor effectiveness of rHuEPO with only a small reduction in transfusion needs.31,32 Although rHuEPO use
has not been associated with important toxicity in adult cancer
patients, the risks of rHuEPO treatment in children has yet to be
defined.
In conclusion, our data indicate that the mechanisms of cancer anemia
in children differ from the ones reported in adults. In our study,
anemia was associated with early defective erythropoiesis and not with
inadequate EPO production. Thus, treatment of anemic cancer children
with rHuEPO might be of limited efficacy because mechanisms others than
a defective EPO response negatively control marrow erythropoietic
activity. Administration of growth factors known to promote the growth
of more primitive cells might be of interest. In addition, agents such
as antiinflammatory compounds33 and monoclonal antibodies
capable of reversing the effects of inhibitory cytokines might also be
of potential clinical use.
| |
FOOTNOTES |
Submitted March 5, 1998;
accepted April 28, 1998.
Supported in part by Grants No. 3.4555.91, 7.4511.93, 3.4621.94, and
7.4552.95 from the Fond National de la Recherche Scientifique (FNRS),
Belgium. Y.B. is a Senior Research Associate of the FNRS, Belgium.
Address reprint requests to Francis Corazza, MD, Laboratory of
Hematology, Brugmann University Hospital, 4 Place Van Gehuchten, B-1020
Brussels, Belgium.
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.
| |
ACKNOWLEDGMENT |
The authors thank Jean-Marie Giot for his expert technical assistance.
| |
REFERENCES |
1.
Beguin Y,
Clemons G,
Pootrakul P,
Fillet G:
Quantitative assessment of erythropoiesis and functional classification of anemia based on measurements of serum transferrin receptor and erythropoietin.
Blood
81:1067,
1993[Abstract/Free Full Text]
2.
Hellebostad M,
Marstrander J,
Slrdhl SH,
Cotes M,
Refsum HE:
Serum immunoreactive erythropoietin in children with acute leukemia at various stages of disease and the effects of treatment.
Eur J Haematol
44:159,
1990[Medline]
[Order article via Infotrieve]
3.
Pohl C,
Schobert I,
Moter A,
Woll EM,
Schwonzen M,
Hiersche A,
Diehl V:
Serum erythropoietin levels in patients with Hodgkin's lymphoma at the time of diagnosis.
Ann Oncol
3:172,
1992
4.
Beguin Y,
Lampertz S,
Fillet G:
Serum erythropoietin in chronic lymphocytic leukemia.
Br J Hematol
93:154,
1996[Medline]
[Order article via Infotrieve]
5.
Miller CB,
Jones RJ,
Piantadosi S,
Abeloff MD,
Spivak JL:
Decreased erythropoietin response in patients with the anemia of cancer.
N Engl J Med
322:1689,
1990[Abstract]
6. Nathan DG, Orkin SH: Nathan and Oski's Hematology of Infancy and
Childhood (ed 5). Philadelphia, PA, Saunders, 1998, Appendix
11
7.
Erslev AJ,
Wilson J,
Caro J:
Erythropoietin titers in anemic, non uremic patients.
J Lab Clin Med
109:429,
1987[Medline]
[Order article via Infotrieve]
8.
Schrezenmeier H,
Noé G,
Raghavachar A,
Rich IN,
Heimpel H,
Kubanek B:
Serum erythropoietin and serum transferrin receptor levels in aplastic anemia.
Br J Hematol
88:286,
1994[Medline]
[Order article via Infotrieve]
9.
Punnonen K,
Irjala K,
Rajamaki A:
Iron-deficiency anemia is associated with high concentrations of transferrin receptor in serum.
Clin Chem
40:774,
1994[Abstract/Free Full Text]
10.
André M,
Ferster A,
Toppet M,
Fondu P,
Dratwa M,
Bergmann P:
Performance of an immunoradiometric assay of erythropoietin and results for specimens from anemic and polycythemic patients.
Clin Chem
38:758,
1992[Abstract/Free Full Text]
11.
Wood PA,
Hrushesky WJM:
Cisplatin-associated anemia: An erythropoietin deficiency syndrome.
J Clin Invest
95:1650,
1995
12.
Smith DH,
Goldwasser E,
Vokes EE:
Serum immunoerythropoietin levels in patients with cancer receiving cisplatin-based chemotherapy.
Cancer
68:1101,
1991[Medline]
[Order article via Infotrieve]
13.
Urabe A,
Mitani K,
Yoshinaga K,
lki S,
Yagisawa M,
Ohbayashi Y,
Takaku F:
Serum erythropoietin titers in hematological malignancies and related diseases.
Int J Cell Cloning
10:333,
1992[Abstract]
14.
Beguin Y,
Yerna M,
Loo M,
Weber M,
Fillet G:
Erythropoiesis in multiple myeloma: Defective red cell production due to inappropriate erythropoietin production.
Br J Haematol
82:648,
1992[Medline]
[Order article via Infotrieve]
15.
Rodriguez-Cimadevilla JC,
Beauchemin V,
Villeneuve L,
Letendre F,
Shaw A,
Hoang T:
Coordinate secretion of interleukin-1 beta and granulocyte-macrophage colony-stimulating factor by the blast cells of acute myeloblastic leukemia: Role of interleukin-1 as an endogenous inducer.
Blood
76:1481,
1990[Abstract/Free Full Text]
16.
Balkwill F,
Osborne R,
Burke F,
Naylor S,
Talbot D,
Durbin H,
Tavernier J,
Fiers-W:
Evidence for tumor necrosis factor/cachectin production in cancer.
Lancet
2:1229,
1987[Medline]
[Order article via Infotrieve]
17.
Naumovski L,
Utz PJ,
Bergstrom SK,
Morgan R,
Molina A,
Toole JJ,
Glader BE,
McFall P,
Weiss LM,
Warnke R,
Smith SD:
SUP-HD1: A new Hodgkin's disease-derived cell line with lymphoid features produces interferon-gamma.
Blood
74:2733,
1989[Abstract/Free Full Text]
18.
Kremer JP,
Reisbach G,
Nerl C,
Dormer P:
B-cell chronic lymphocytic leukemia cells express and release transforming growth factor-beta.
Br J Haematol
80:480,
1992[Medline]
[Order article via Infotrieve]
19.
Means RT:
Pathogenesis of the anemia of chronic disease: A cytokine-mediated anemia.
Stem Cells
13:32,
1995[Abstract]
20.
Jelkmann W,
Pagel H,
Wolff M,
Fandrey J:
Monokines inhibiting erythropoietin production in human hepatoma cultures and isolated perfused rat kidneys.
Life Sci
50:301,
1991
21.
Faquin WC,
Schneider TJ,
Goldberg MA:
Effect of inflammatory cytokines on hypoxia-induced erythropoietin production.
Blood
79:1987,
1992[Abstract/Free Full Text]
22.
Rusten LS,
Jacobsen SEW:
Tumor necrosis factor (TNF)- directly inhibits human erythropoiesis in vitro: Role of p55 and p75 TNF receptors.
Blood
85:989,
1995[Abstract/Free Full Text]
23.
Johnson CS,
Keckler DJ,
Topper MI,
Braunschweiger PG,
Furmanski P:
In vivo hematopoietic effect of recombinant interleukin-1 in mice: Stimulation of granulocytic, monocytic, megakaryocytic, and early erythroid progenitors; suppression of late stage erythropoiesis, and reversal of erythroid suppression with erythropoietin.
Blood
73:678,
1989[Abstract/Free Full Text]
24.
Mamus SW,
Beck-Schroeder SK,
Zanjani ED:
Suppression of normal human erythropoiesis by gamma interferon in vitro: Role of monocytes and T-lymphocytes.
J Clin Invest
75:1496,
1985
25.
Miller KL,
Carlino JA,
Ogawa Y,
Avis PD,
Carroll KG:
Alterations in erythropoiesis in TGF-beta 1-treated mice.
Exp Hematol
20:951,
1992[Medline]
[Order article via Infotrieve]
26.
Broxmeyer HE,
Sherry B,
Cooper S,
Lu L,
Maze R,
Beckmann R,
Cerami A,
Ralph P:
Comparative analysis of the suppressive effects of the human macrophage inflammatory protein family of cytokines (chemokines) on proliferation of myeloid progenitor cells.
J Immunol
150:3448,
1993[Abstract]
27.
Cooper S,
Mantel C,
Broxmeyer HE:
Myelosuppressive effects in vivo with very low dosages of monomeric recombinant murine macrophage inflammatory protein-1.
Exp Hematol
22:186,
1994[Medline]
[Order article via Infotrieve]
28.
Glaspy J,
Bukowski R,
Steinberg D,
Taylor C,
Tchekmedyian S,
Vadhan-Raj S:
Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice.
J Clin Oncol
15:1218,
1997[Abstract/Free Full Text]
29.
Cascinu S,
Fedeli A,
Del Ferro E,
Luzi Fedeli S,
Catalano G:
Recombinant human erythropoietin treatment in cisplatin-associated anemia: A randomized, double-blind trial with placebo.
J Clin Oncol
12:1058,
1994[Abstract/Free Full Text]
30.
Henry D,
Abels R,
Larholt K:
Prediction of response to recombinant human erythropoietin (r-HuEPO) therapy in cancer patients.
Blood
85:1676,
1995[Free Full Text]
31.
Beck MN,
Beck D:
Recombinant erythropoietin in acute chemotherapy-induced anemia of children with cancer.
Med Pediatr Oncol
25:17,
1995[Medline]
[Order article via Infotrieve]
32.
Porter JC,
Leahey A,
Polise K,
Bunin G,
Manno CS:
Recombinant human erythropoietin reduces the needs for erythrocyte and platelet transfusions in pediatric patients with sarcoma: A randomized, double-blind, placebo-controlled trial.
J Pediatr
129:656,
1996[Medline]
[Order article via Infotrieve]
33. (abstr)
Teicher BA,
Kakeji Y,
Rice G,
Singer J:
Lisofylline (LSF) accelerates hematopoietic recovery and enhances tumor response after high dose chemotherapy.
Blood
88:346a,
1996
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
A. G. Shankar
The Role of Recombinant Erythropoietin in Childhood Cancer
Oncologist,
February 1, 2008;
13(2):
157 - 166.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. N. Roy, H. H. Mak, I. Akpan, G. Losyev, D. Zurakowski, and N. C. Andrews
Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation
Blood,
May 1, 2007;
109(9):
4038 - 4044.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Theurl, V. Mattle, M. Seifert, M. Mariani, C. Marth, and G. Weiss
Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease
Blood,
May 15, 2006;
107(10):
4142 - 4148.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Dallalio, E. Law, and R. T. Means Jr
Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations
Blood,
April 1, 2006;
107(7):
2702 - 2704.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Corazza, C. Hermans, S. D'Hondt, A. Ferster, A. Kentos, Y. Benoit, and E. Sariban
Circulating thrombopoietin as an in vivo growth factor for blast cells in acute myeloid leukemia
Blood,
March 15, 2006;
107(6):
2525 - 2530.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Marec-Berard, J. Y. Blay, M. Schell, M. Buclon, C. Demaret, and I. Ray-Coquard
Risk Model Predictive of Severe Anemia Requiring RBC Transfusion After Chemotherapy in Pediatric Solid Tumor Patients
J. Clin. Oncol.,
November 15, 2003;
21(22):
4235 - 4238.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Brugnara
Iron Deficiency and Erythropoiesis: New Diagnostic Approaches
Clin. Chem.,
October 1, 2003;
49(10):
1573 - 1578.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Zeuner, F. Pedini, M. Signore, U. Testa, E. Pelosi, C. Peschle, and R. De Maria
Stem cell factor protects erythroid precursor cells from chemotherapeutic agents via up-regulation of BCL-2 family proteins
Blood,
July 1, 2003;
102(1):
87 - 93.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. T. Goodnough, B. Skikne, and C. Brugnara
Erythropoietin, iron, and erythropoiesis
Blood,
August 1, 2000;
96(3):
823 - 833.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Abstract
Introduction
Abstract