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Next Article 
Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4491-4508
REVIEW ARTICLE
Emerging Applications of Recombinant Human Granulocyte-Macrophage
Colony-Stimulating Factor
By
James O. Armitage
From the Department of Internal Medicine, University of Nebraska
Medical Center, Omaha, NE.
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INTRODUCTION |
CLINICAL INDICATIONS for use of
recombinant human granulocyte-macrophage colony-stimulating factor
(rHuGM-CSF) have expanded considerably since the drug first became
available in the early 1990s for acceleration of myeloid engraftment in
neutropenic patients. Initial clinical trials of rHuGM-CSF were based
on prevailing knowledge of the biologic effects of endogenous GM-CSF at
the time and therefore concentrated on the drug's myeloproliferative effects in myelosuppressed patients. As additional information accumulated from in vitro research and from results of clinical trials,
it became apparent that rHuGM-CSF had diverse biologic effects and
played a vital role in various functions of the immune system,
including responses to inflammation and infection, as well as in
hematopoiesis. Consequently, a variety of potential clinical uses for
rHuGM-CSF are under investigation, such as prophylaxis or adjunctive
treatment of infection in high-risk settings or immunosuppressed
patient populations, use as a vaccine adjuvant, and use as
immunotherapy for malignancies.
The molecular sequence of endogenous human GM-CSF was first identified
in 1985; within a few years, three different synthetic human GM-CSFs
were produced using recombinant DNA technology and bacterial,1 mammalian,2 and yeast expression
systems.3 Sargramostim is yeast-derived rHuGM-CSF produced
using Saccharomyces cerevisiae; bacterially derived rHuGM-CSF
is produced using Escherichia coli and is termed molgramostim;
and mammalian-derived rHuGM-CSF is produced using Chinese hamster ovary
cells (CHO) and is termed regramostim. These preparations are not
identical and are differentiated by their specific amino acid sequences
and degree of glycosylation.1-3 Sargramostim has an amino
acid sequence identical to that of endogenous human GM-CSF, except that
it contains leucine instead of proline at position 23 and may have a
different carbohydrate moiety. Sargramostim is glycosylated to a lesser
extent than regramostim, and molgramostim is not glycosylated. The
degree of glycosylation of rHuGM-CSF may be an important
characteristic, because it can affect pharmacokinetics, biologic
activity, antigenicity, and toxicity.4-7
This review discusses current knowledge concerning the biologic
effects, pharmacokinetics, and emerging clinical uses of rHuGM-CSF, with a focus on the yeast-derived rHuGM-CSF, sargramostim, the only
form of synthetic rHuGM-CSF commercially available in the United
States. Information on molgramostim, the form of rHuGM-CSF available in
Europe, is also provided. Because literature reports do not always
indicate the form of rHuGM-CSF used, the term "rHuGM-CSF" is used
throughout this review to describe the drug when the expression system
was not identified or when multiple studies using different forms of
rHuGM-CSF reported similar findings.
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PHARMACOLOGY OF SARGRAMOSTIM |
Biologic effects.
GM-CSF was first identified based on its ability to stimulate the
clonal proliferation of myeloid precursors in vitro.8 Endogenous GM-CSF, a heavily glycosylated polypeptide, was the first
human myeloid hematopoietic growth factor to be molecularly cloned,
which allowed the expression of large quantities of the protein. More
than a decade of in vitro and in vivo research using murine GM-CSF and
synthetic rHuGM-CSFs has shown that the name of this CSF is
restrictive, because it describes only one aspect of the numerous
biologic effects that have now been attributed to GM-CSF. Although
GM-CSF plays a vital role in hematopoiesis by inducing the growth of
several different cell lineages, it also enhances numerous functional
activities of mature effector cells involved in antigen presentation
and cell-mediated immunity, including neutrophils, monocytes,
macrophages, and dendritic cells.9-20
The biologic effects of GM-CSF are mediated via binding to receptors
expressed on the surface of target cells. The GM-CSF receptor is
expressed on granulocyte, erythrocyte, megakaryocyte, and macrophage
progenitor cells as well as mature neutrophils, monocytes, macrophages,
dendritic cells, plasma cells, certain T lymphocytes, vascular
endothelial cells, uterine cells, and myeloid leukemia
cells.21-27 Molecular cloning studies have shown that the
GM-CSF receptor is composed of two distinct subunits,  and common
 (c; Fig
1).28 The -subunit binds GM-CSF with low affinity. The
c has no detectable binding affinity for GM-CSF on its
own, but forms a heterodimer with the -subunit that has high
affinity for GM-CSF. Whereas the -subunit is unique to the GM-CSF
receptor, c is shared with the receptors for
interleukin-3 (IL-3) and IL-5.29
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| Fig 1.
Schematic representation of the GM-CSF receptor (GMR),
which is composed of two distinct subunits, and . Binding of
rHuGM-CSF to GMR leads to formation of the signaling complex and
activation of a Janus kinase (JAK2). Regulation of gene expression by
JAK2 activates transcription proteins STAT1, STAT3, and STAT5.
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The signal transduction pathways that occur after rHuGM-CSF binds to
the GM-CSF receptor are under evaluation. There appear to be at least
two distinct signaling pathways, each involving a distinct region of
c.30 The first, which leads to induction of
c-myc and activation of DNA replication, involves activation of
a Janus kinase (JAK2) that is physically associated with
c.31 Regulation of gene expression by JAK2
appears to be mediated by production of a DNA-binding complex
containing the signal transducer and activator of transcription (STAT)
proteins STAT1, STAT3, and STAT5.32,33 The second pathway
involves activation of ras34 and mitogen-activated
protein kinases,35 with consequent induction of
c-fos and c-jun, which are genes involved in regulation
of hematopoietic differentiation.31
Pharmacokinetics.
Information regarding the pharmacokinetics of rHuGM-CSF after
intravenous or subcutaneous administration is available from studies in
healthy adults,36 adults with malignancy or myelodysplastic syndrome,6,37-40 and children with recurrent or refractory
solid tumors.41,42 Because evidence exists from animal and
clinical studies that the degree of glycosylation of synthetic
rHuGM-CSFs influences pharmacokinetic parameters,4-6 data
regarding the pharmacokinetics of sargramostim and molgramostim are
presented separately.
Studies have determined that the pharmacokinetics of sargramostim are
similar among healthy individuals and patients.39 The
pharmacokinetics of sargramostim are dependent on the route of
administration. Table 1 compares
pharmacokinetic parameters after intravenous and subcutaneous
administration of sargramostim in healthy adult males.36
Peak serum concentrations are higher after intravenous administration;
however, bioavailability (as determined by the area under the
concentration-versus-time curve) of sargramostim is similar between
administration routes. The elimination of sargramostim occurs
principally by nonrenal mechanisms.39 Serum concentrations
are more prolonged after subcutaneous administration than after
intravenous administration.36,42 The magnitude of the
percentage of increase in absolute neutrophil count with a specific
dose of sargramostim is greater after subcutaneous injection than after
2-hour intravenous infusion.39
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Table 1.
Pharmacokinetic Parameters After Intravenous and
Subcutaneous Administration of Sargramostim in Healthy
Adult Males
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The pharmacokinetics of molgramostim (0.3 to 30 µg/kg) also were
studied after subcutaneous and intravenous
administration.37 Maximum serum concentrations and area
under the concentration-versus-time curve increased with dose for both
routes of adminstration, but appeared larger after intravenous
administration in comparison to the same dose administered
subcutaneously. However, rHuGM-CSF concentrations greater than 1 ng/mL
were maintained longer after subcutaneous administration.
Immunoreactive molgramostim was detected in the urine of patients,
ranging from 0.001% to 0.2% of the injected dose, supporting nonrenal
elimation. The half-life after intravenous adminstration ranged from
0.24 to 1.18 hours; the mean half life was 3.16 hours after
subcutaneous adminstration.
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USE IN ENHANCING HEMATOPOIETIC RECOVERY AFTER CANCER CHEMOTHERAPY
AND BONE MARROW TRANSPLANTATION (BMT) |
rHuGM-CSF is classified as a multilineage CSF because it stimulates the
proliferation and differentiation of hematopoietic progenitor cells of
neutrophil, eosinophil, and monocyte colonies.43 Parenteral
administration of rHuGM-CSF induces a dose-dependent increase in
peripheral blood neutrophil counts.19,44 Sargramostim alters the kinetics of myeloid progenitor cells within the bone marrow,
causing rapid entry of cells into the cell cycle and decreasing the
cell-cycle time by as much as 33%.45 The leukocyte
response to rHuGM-CSF is reflected in peripheral blood
principally as an increase in segmented neutrophils, but also
involves an increase in monocytes and eosinophils.19,46-48
Leukocyte differentials generally demonstrate a shift to the left;
myelocytes, promyelocytes, and myeloblasts may be present. When
rHuGM-CSF is discontinued, leukocyte counts gradually decrease to
pretreatment levels.19,43
The myeloproliferative effects of rHuGM-CSF are also the result of its
interaction with other cytokines. rHuGM-CSF functions in conjunction
with erythropoietin and IL-3 to promote the proliferation and
differentiation of erythroid and megakaryocytic progenitors, respectively.8,49 The addition of thrombopoietin to early acting cytokines, such as rHuGM-CSF, increases the overall in vitro
megakaryocyte expansion compared with thrombopoietin alone and also
generates different subpopulations of CD41+ megakaryocyte
progenitors, with much less coexpression of CD42b and CD34 and slightly
more coexpression of c-kit.50 In addition, the
overall number of CD34+ cells increases approximately
fivefold with the combination of thrombopoietin and early acting
cytokines. A trial in sublethally irradiated nonhuman primates showed
that coadministration of sargramostim and thrombopoietin augmented
megakaryocyte, erythrocyte, and neutrophil recovery compared with
either cytokine alone.51
Enhancing neutrophil proliferation is an important aspect of rHuGM-CSF
function; however, effects of this multilineage growth factor on other
cells of the immune system, including monocytes and macrophages, have
been identified. Administration of rHuGM-CSF not only increases the
number of circulating monocytes, but also increases the function of
monocytes and macrophages, including oxidative metabolism,
cytotoxicity, and Fc-dependent phagocytosis.19,52,53 rHuGM-CSF enhances dendritic cell maturation, proliferation, and migration.20,54,55 In addition, class II major
histocompatibility complex (MHC) expression on macrophages and
dendritic cells is increased by rHuGM-CSF, enhancing the function of
antigen-presenting cells.56
Combined, these effects of rHuGM-CSF not only increase hematopoietic
cell counts, but also enhance immune function. The ability of rHuGM-CSF
to accelerate myeloid recovery and to prevent infection has resulted in
multiple approved indications for sargramostim and molgramostim in
their respective countries. The drugs are used in patients after
autologous BMT (AuBMT), peripheral blood progenitor cell (PBPC)
transplantation, induction therapy for acute myelogenous leukemia
(AML), engraftment delay or failure after BMT, and chemotherapy-induced
neutropenia. These uses are well established and have been recently
reviewed.57-61 Research has expanded in some of these
settings to investigate new uses of rHuGM-CSF, including use in
combination with granulocyte colony-stimulating factor (G-CSF) for PBPC
mobilization, to prime leukemic cells before or during chemotherapy for
AML, and as an adjunct to increase chemotherapy dose intensity.
PBPC mobilization in combination with G-CSF.
There has been increasing interest in combining rHuGM-CSF with other
cytokines, especially G-CSF, as a means of improving mobilization
without having to administer chemotherapy. This is especially true in
the allogeneic transplant setting, where a nontoxic mobilization
regimen that allows for collection of a sufficient number of cells to
promote engraftment in a minimum number of leukaphereses is most
critical. Lane et al62 evaluated the PBPC mobilization
efficacy of G-CSF at 10 µg/kg/d (n = 8), sargramostim at 10 µg/kg/d
(n = 5), or sargramostim plus G-CSF each at 5 µg/kg/d (n = 5) in
normal donors. The median CD34+ cell yield with the
combination regimen and with G-CSF was significantly higher than for
rHuGM-CSF alone (101 × 106, 119 × 106, and 12.6 × 106, respectively;
P < .01 for both comparisons).
An analysis of CD34+ cell subsets showed some interesting
differences between the different mobilization regimens. A higher proportion of cells in the combination regimen were
CD34+CD38 and
CD34+CD38 HLA-DR+
(Table 2). Pluripotent progenitor cells are
characterized as CD34+CD38 and are
likely responsible for long-term hematopoietic reconstitution after
transplantation. These cells can be further subdivided according to the
presence or absence of HLA-DR, with HLA-DR+ cells giving
rise to lymphoid and myeloid precursors.63 The greater
percentage of this subpopulation of cells mobilized by the combination
regimen translated into a higher overall number of
CD34+CD38HLA-DR+ cells in
leukapheresis products than products from subjects mobilized with
either G-CSF or rHuGM-CSF alone (1.41 × 106, 0.36 × 106, and 0.12 × 106,
respectively; P < .05 for all comparisons). Moreover, the
plating efficiency of colony-forming unit-granulocyte-macrophage
(CFU-GM) and burst-forming unit-erythroid (BFU-E) was
higher in cells stimulated by rHuGM-CSF than in those stimulated by
G-CSF. Whether this would correlate with more rapid engraftment is not
known, although the investigators have reported that PBPCs mobilized by
the combination regimen successfully engrafted after allogeneic PBPC
transplantation.64 Ali et al65 also compared
mobilization of PBPCs in normal donors using rHuGM-CSF at 5 µg/kg/d
plus G-CSF at 10 µg/kg/d (n = 15) versus G-CSF at 10 µg/kg/d alone
(n = 35). They found a statistically insignificant increase in
CD34+ cells in the leukapheresis products from donors
mobilized with the combination of cytokines; however, the number of
CD3+ cells in the leukapheresis product was significantly
lower with the combination regimen than with G-CSF alone, ie, 160 versus 328 × 106/kg.
Investigations are ongoing to determine optimal doses and sequence of
administration of the cytokines in combination.66,67 In a
follow-up study to that reported by Lane et al,62 healthy volunteers received either sargramostim at 10 µg/kg/d for 3 or 4 days
followed by G-CSF at 10 µg/kg/d for 2 days.66 In
comparison to the results of single-agent G-CSF for 4 days and
combination rHuGM-CSF and G-CSF for 5 days, sequential administration
failed to demonstrate any differences in the extent of mobilization as measured by CD34+ cells. In addition, the proportion of the
CD38 subset, which contains the more primitive
hemotopoietic cells, was higher with the combination of sargramostim
and G-CSF for 5 days.
Molgramostim also has been studied in combination or in sequence with
G-CSF for mobilization of PBPCs.67 The combination of the
two cytokines resulted in dramatic and sustained increases in the
number of CFU-GM per kilogram collected per harvest, with administration of G-CSF to patients already receiving molgramostim increasing the hematopoietic progenitor cell content nearly 80-fold. A
randomized trial comparing combination therapy versus G-CSF or
molgramostim (10 µg/kg) alone is ongoing. Additional trials are
required to determine the optimal scheduling of cytokine adminstration as well as apheresis scheduling.
Priming effect before or during chemotherapy for AML.
Myeloid leukemic cells and their precursors have GM-CSF receptors, and
there is in vitro evidence that the proliferation and differentiation
of these cells is supported by exposure to rHuGM-CSF.68-71 Thus, recruitment of chemoresistant resting leukemic cells into sensitive phases of the cell cycle by rHuGM-CSF may enhance the antileukemic effect of chemotherapy. The rHuGM-CSF-induced increases in leukemic cells in S phase and intracellular phosphorylation of
cytarabine have been shown to promote drug-induced cell
kill.72 In contrast to enhancing cytarabine cytotoxicity,
Lotem and Sachs73 found that the typical features of
apoptosis were prevented by rHuGM-CSF and G-CSF in a murine leukemic
cell line. The growth factors also inhibited apoptosis induced by
cytarabine, but the overall clonogenic cell reduction was not reduced.
Because contradictory laboratory data exist, it has not been possible
to predict the clinical benefit of cytokine priming before results of
studies in patients with AML.
In a multicenter, randomized trial of 114 patients (17 to 75 years of
age) with newly diagnosed AML, Büchner et al74
compared use of chemotherapy alone with use of chemotherapy
administered in conjunction with sargramostim priming. Sargramostim at
250 µg/m2 was administered once daily by subcutaneous
injection starting 24 hours before chemotherapy and continuing until
neutrophil recovery occurred after the induction courses, consolidation
course, and first two maintenance courses. Overall, 79% of
sargramostim-treated patients and 84% of controls achieved disease
remission; persistent leukemia was observed in 4% and 18% of
patients, respectively. In patients younger than 60 years of age,
complete remissions were achieved in 82% of sargramostim-treated
patients and 73% of controls, with fewer relapses in the
sargramostim-treated patients during the first 6 months (3% and 22%,
respectively).74
Similar studies in patients with newly diagnosed AML receiving
induction chemotherapy have been conducted with
molgramostim.47,75-77 Patients received molgramostim at 250 µg/m2 or 5 µg/kg/d starting either on days 1 to 3 before chemotherapy or with induction chemotherapy. Although a trend
toward benefit in disease-free survival was observed, the use of
rHuGM-CSF during induction therapy of AML does not appear to have a
significant impact on treatment outcome. The use of rHuGM-CSF for
priming remains an intriuging therapeutic approach for AML. Because
negative effects on the course of AML were rarely observed, additional studies are being conducted to determine the benefits and risks of
growth factors administered before or concurrently with chemotherapy regimens in the treatment of AML. However, the definitive results of an
ongoing ECOG trial are awaited before use of rHuGM-CSF for priming
effects can be recommended outside of a clinical trial.
Adjunctive use to increase chemotherapy dose intensity.
Adjunctive use of rHuGM-CSF may allow an increase in the dose intensity
of combination chemotherapy regimens including drugs with a primary
toxicity of myelosuppression; however, the benefits associated with
rHuGM-CSF in patients receiving dose-intensive chemotherapy may be
limited to early courses of therapy, because late-cycle
thrombocytopenia is not prevented.78-83 The ability of
sargramostim to support a multiple-cycle high-dose chemotherapy regimen
was evaluated in a phase III, double-blind, randomized trial of 56 patients with lymphoma or breast cancer. Patients received
submyeloablative doses of cyclophosphamide, etoposide, and cisplatin
(DICEP) and were randomized to receive sargramostim (250 µg/m2) or placebo subcutaneously every 12 hours.83 Sargramostim-treated patients had a significantly
decreased duration of neutropenia after the first course of
chemotherapy in comparison to patients who received placebo (10 v 12 days; P = .01), but the difference did not achieve
statistical significance after the second or third courses.
Sargramostim-treated patients experienced a statistically significant
1.5-day delay in platelet recovery during the second course. There was
no difference between the groups in numbers of hospitalizations for
febrile neutropenia or the incidence of bacteremia, although any
potential difference might have been obscured, because prophylactic
oral ciprofloxacin was administered to all patients during neutropenia.
However, the duration of hospitalization for neutropenic fever was
shorter for sargramostim-treated patients in the first course.
Importantly, the primary endpoint of this study was duration of
neutropenia during the first course of therapy. The study was stopped
because of a significant difference in duration of neutropenia;
therefore, the small number of patients potentially obscures other
clinical benefits of sargramostim therapy.83
The feasibility of EAP (etoposide, doxorubicin, cisplatin) dose
escalation using molgramostim at 10 µg/kg/d starting on day 4 and
continuing unitl recovery of granulocyte count was studied by Ford et
al.78 Intolerable myelosuppression, including grade 4 neutropenia or thrombocytopenia lasting at least 7 days, occurred in 4 of 5 patients receiving escalated doses of the EAP regimen. At the
lowest doses of each agent, 3 of 6 patients had intolerable myelosuppression. The investigators concluded that molgramostim did not
permit dose escalation of EAP.78 In contrast, molgramostim at 5 µg/kg/d allowed dose escalation of 5-fluorouracil (5-FU) with
leucovorin to 425 mg/m2/d, with further 5-FU dose
escalation according to individual tolerance.79
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USE IN INFECTIOUS DISEASE |
Modulation of host defense against bacterial and fungal infections.
There are several mechanisms by which rHuGM-CSF may enhance host
defense mechanisms against bacterial and fungal infection. Exposure of
neutrophils to rHuGM-CSF in vitro and in vivo has been shown to enhance
expression of cell surface adhesion molecules, such as -integrins,
as well as receptors for the Fc portion of IgG, and receptors for
activated complement components.84,85 Other effects of
rHuGM-CSF on neutrophils include enhanced chemotaxis,17 phagocytosis,10 leukotriene B4 synthesis, release of
arachidonic acid,86,87 and superoxide anion
generation.44,88 The upregulation of neutrophil surface
antigens combined with the induction of phagocyte migration and
increased phagocytic activity contribute to a role for rHuGM-CSF in
host defense. Sargramostim also prolongs neutrophil survival from 96 hours to at least 216 hours by preventing apoptosis.89
Finally, sargramostim induces the expression of class II MHC molecules
on neutrophils, which could potentially allow neutrophils to act as
antigen-presenting cells much like B cells, macrophages, and dendritic
cells.90,91
As a result of its multilineage activity, similar functional effects of
rHuGM-CSF have been observed in monocytes and macrophages. Administration of rHuGM-CSF increases the level of expression of a
number of receptors found on macrophages, such as CD11a, CD11b, and
CD11c, that augment adhesion-dependent phenomena and Fc RII (CDw32)
receptors that bind Ig during phagocytosis.92-94 Upregulation of these receptors would be expected to aid the phagocytic ability of macrophages. Additonally, rHuGM-CSF enhances
antibody-dependent cell cytotoxic activity, respiratory burst, and
superoxide anion generation by macrophages and
monocytes.13,17,19,52 Moreover, sargramostim significantly
counteracted dexamethasone-induced inhibition of superoxide anion
release by monocytes, and the fungicidal activity of
dexamethasone-treated monocytes against Aspergillus fumigatus was enhanced (Fig
2).95
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| Fig 2.
(A) Fumigatus hyphal damage induced by elutriated
human monocytes incubated with 500 nmol/L dexamethasone (DEX) alone and
with either 5 ng/mL sargramostim (rHuGM-CSF) or 1.2 ng/mL
interferon- (IFN). Vertical bars denote standard errors of means,
and the number of experiments performed are shown in
parentheses. *P < .05. (Reprinted with
permission.95)
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Substantial evidence exists from in vitro and in vivo studies that
rHuGM-CSF activates and enhances the ability of neutrophils and
macrophages to phagocytize and destroy bacteria and fungi. Enhancement
of the microbicidal activity of neutrophils by rHuGM-CSF was shown in
vitro against Staphylococcus aureus,96,97
Torulopsis glabrata,98 and Candida
albicans.16,88,99 Neutrophils treated with rHuGM-CSF
killed 90% of intracellular C albicans in comparison to 50%
of intracellular yeast cells killed by untreated
neutrophils.99 Similarly, enhancement of the microbicidal
activity of monocytes by rHuGM-CSF was shown in vitro against C
albicans,16 A fumigatus,95,100 Histoplasma capsulatum,101 Cryptococcus
neoformans,102 and Trypanosoma cruzi.103 Functional studies of neutrophils and
monocytes isolated from patients treated with rHuGM-CSF at 250 µg/m2/d indicate that phagocytic and cytotoxic activity
against S aureus is increased.97,104 The percentage
of S aureus phagocytosed or killed after 20 minutes
significantly increased from 62% before rHuGM-CSF treatment to 72%
during treatment (P = .0028).97
Sargramostim also promotes killing of Mycobacterium avium
complex.105-108 Significant growth inhibition of
Mycobacterium avium complex was observed in human macrophages
treated with sargramostim or tumor necrosis factor (TNF;
Table 3).108 A similar effect was observed using a mouse model of disseminated Mycobacterium avium complex infection. Significantly (P = .04) lower
concentrations of Mycobacterium avium complex were present in
the liver and spleen of mice treated with sargramostim for 14 days
compared with control mice.105 These data also suggest that
sargramostim enhances the antimycobacterial effect of clarithromycin,
azithromycin, amikacin, and ofloxacin.105,107
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Table 3.
Growth Inhibition of Mycobacterium Avium
Complex in Human Macrophages Treated With Sargramostim or
TNF108
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In other animal studies, enhancement of microbicidal activity by
rHuGM-CSF has been confirmed. Survival was significantly (P < .05) improved in neonatal rats when sargramostim was administered 6 hours before inoculation of a lethal dose of S
aureus.109 Similarly, in neutropenic mice,
administration of molgramostim 1 to 5 µg/d protected against lethal
infections of S aureus and Pseudomonas aeruginosa;
survival was significantly increased in molgramostim-treated mice
infected with either S aureus (70% v 20%,
P < .05) or P aeruginosa (50% v 0%, P
< .01).110
Recombinant murine GM-CSF protected 62% of neutropenic rats from a
lethal inoculum of C albicans and reduced lung injury. Importantly, there was no effect of murine GM-CSF on the neutrophil count, suggesting that the protective mechanism involved led to enhanced host defense mechanisms.111
Adjunctive treatment of fungal infections.
The effect of sargramostim on the incidence and severity of fungal
infections was observed in randomized, double-blind studies of the drug
in patients undergoing AuBMT and in patients with AML.112,113 Fungal infections developed in 4 AuBMT patients
who received placebo in comparison to 2 AuBMT patients who received sargramostim.112 Two of the infections in placebo-treated
patients were disseminated aspergillosis. In the phase III ECOG trial
of 99 elderly patients undergoing chemotherapy for AML, sargramostim significantly (P = .02) reduced mortality due to fungal
infection.113 One of 8 patients who received sargramostim
died as a result of fungal infection, whereas 9 of 12 placebo-treated
patients developed fatal fungal infections.
A pilot study of molgramostim as adjuvant therapy for fungal infections
was conducted in cancer patients with proven major-organ or
disseminated fungal infection.114 Of 8 evaluable patients, 6 had a neutrophil response to molgramostim; 4 of these patients were
completed cured of the fungal infection and the other 2 had a partial
response. Several case series have reported a response to adjunctive
treatment with sargramostim for fungal infections. Three human
immunodeficiency virus (HIV)-infected patients with oropharyngeal
candidiasis refractory to fluconazole at doses of 200 mg daily or
greater for at least 14 days were treated with sargramostim at 125 µg/m2/d.115 Fluconazole treatment was
maintained at the same dose. All patients experienced improvement in
signs and symptoms of oropharyngeal candidiasis by week 2. No
significant adverse events occurred, including no upregulation of HIV-1
replication, and therapy was well tolerated. When sargramostim was
discontinued, 2 of 3 patients relapsed.115
Sargramostim also has been administered to patients with rhinocerebral
and disseminated mucormycosis, a rare opportunistic infection
associated with a mortality rate exceeding 50%.116 Three
of four patients with mucormycosis have been successfully treated with
sargramostim (doses ranging from 250 to 500 µg/d for 14 days to 6 months) in combination with traditional surgical and medical treatment.
The three patients were disease-free at periods of 6 months, 18 months,
and 3 years after surgery.
HIV infection.
Initial use of sargramostim in patients with HIV infection focused on
its ability to ameliorate drug-induced
myelosuppression.117-119 In a phase I/II study in patients
with Kaposi's sarcoma who became neutropenic while receiving
zidovudine and interferon , administration of sargramostim resulted
in a prompt increase in absolute neutrophil count in all patients and
an absolute neutrophil count greater than 1,000 cells/µL within 7 days; there was no increase in p24 antigen levels.118
Sargramostim (250 or 500 µg/m2/d administered by
subcutaneous injection) also has been used to ameliorate
chemotherapy-induced neutropenia in patients with acquired
immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma receiving a
regimen of doxorubicin, bleomycin, and vincristine (ABV).117 Although both sargramostim doses allowed the
chemotherapy regimen to be continued without a dose reduction, the
lower sargramostim dose was better tolerated. In a recent study in 12 patients with advanced HIV infection (CD4+ cell count
 200/µL) who were receiving zidovudine (300 to 1,200 mg/d),
administration of sargramostim in a dosage of 50, 125, or 250 µg/m2/d by subcutaneous injection resulted in significant
increases in absolute neutrophil count and monocyte counts at all three dosage levels.119
Potential uses for the drug in HIV patients were expanded when it
became evident that rHuGM-CSF activates and enhances the ability of
neutrophils and macrophages to phagocytize bacteria, fungi, and
intracellular parasites, which has important implications for the
prophylaxis and treatment of opportunistic infections in this patient
population.
Although there were initial concerns that use of rHuGM-CSF in
HIV-infected patients might stimulate HIV replication and increase viral load, these concerns have not been substantiated. In vitro studies are somewhat conflicting regarding the effect of
rHuGM-CSF on HIV replication. Numerous studies have
demonstrated enhancement of viral replication when HIV-infected
monocytes or macrophages are exposed to rHuGM-CSF120-124;
however, three studies have reported suppression of HIV expression by
rHuGM-CSF.125-127 An additional finding from in vitro
studies is that rHuGM-CSF enhances the antiretroviral activity of some
dideoxynucleoside antiretroviral agents, such as zidovudine and
stavudine, possibly by increasing intracellular phosphorylation of
these agents to their active metabolite.124,128,129
Early clinical trials evaluating the effect of rHuGM-CSF on viral
replication in HIV patients failed to show an increase in viral load as
determined by serum p24 antigen levels as long as patients received
concurrent zidovudine117,118,130-132; however, in studies
in which molgramostim was administered without an antiretroviral, some
patients did experience an increase in serum p24 antigen levels.133,134 Subsequent trials using a more sensitive
polymerase chain reaction assay for viral load determination confirmed
that rHuGM-CSF does not result in an increase in viral load during or
after CSF therapy in HIV patients receiving concurrent
zidovudine.119,135 More recently, administration of
sargramostim to patients on stable, highly active antiretroviral
therapy including a protease inhibitor has been shown to result in no
upregulation of viral load by polymerase chain
reaction.136,137 These HIV-positive patients receiving sargramostim have experienced a significant (P = .0372)
increase in CD4 count and decrease in viral load  0.5 log.
Interestingly, the studies by Massari et al126 and Matsuda
et al127 that reported suppression of HIV expression by
rHuGM-CSF were conducted before the role of coreceptors for HIV
infection was appreciated. Indeed, the investigators examined the
effects of rHuGM-CSF on CD4 expression as a potential mechanism for the reduction in HIV expression, but found CD4 expression to be unchanged. A recent study provides a possible mechanism for their findings. Exposure to sargramostim has recently been shown to downregulate expression of the C-C chemokine receptor CCR5, a -chemokine receptor on macrophages, and to reduce the susceptibility of macrophages to
infection by a macrophage-tropic strain of HIV.125,138 CCR5 has been shown to be the major coreceptor required for infection of
macrophages by macrophage-tropic strains of HIV.
Sargramostim-stimulated monocytes produced high levels of
-chemokines, macrophage inflammatory protein-1 (MIP-1), and
MIP-1 in the medium. This medium was able to protect bystander cells
from entry by JRFL, a macrophage-tropic strain of HIV.
Another possible role for sargramostim in HIV-infected patients is in
the prevention or treatment of opportunistic infections. Based on
results of in vitro studies demonstrating that rHuGM-CSF promotes
killing of Mycobacterium
avium-intracellulare105,107 and in vitro and murine
studies indicating that rHuGM-CSF can enhance the antimycobacterial
effects of some antimicrobial agents, including azithromycin,
ofloxacin, and clarithromycin,105,107 investigations of
sargramostim for the adjunctive treatment of Mycobacterium
avium-intracellulare were initiated. In a small study, AIDS
patients with disseminated Mycobacterium avium-intracellulare were randomized to receive azithromycin with or without sargramostim for 6 weeks.139 Mycobacteremia and monocyte function were
assessed biweekly. Mean superoxide anion production was significantly
increased in monocytes obtained from all 4 patients receiving
sargramostim (53% to 199% relative to controls) and these patients
had a 60% reduction in the number of viable intracellular
Mycobacterium avium-intracellulare per milliliter at the end of
treatment. Patients receiving azithromycin alone had no increase in
superoxide anion production and only a 28% reduction in viable
Mycobacterium avium-intracellulare per milliliter. These data
indicate that sargramostim activates monocytes in AIDS patients with
Mycobacterium avium-intracellulare bacteremia and deserves
further study as adjunctive therapy in these patients.
A multicenter phase III randomized, double-blind, placebo-controlled
trial of sargramostim in patients with advanced HIV disease is ongoing
to compare the incidence and time to first opportunistic infection or
death. Patients with CD4 count 50 cells/µL and receiving a stable
antiretroviral regimen before and during the study are eligible.
Patients are randomized to receive either sargramostim 250 µg/d 3 days per week for a minimum of 24 weeks or placebo. Secondary
objectives include incidence of AIDS-related opportunistic malignancies
and esophageal candidiasis; survival; pharmacoeconomic and
quality-of-life parameters; changes in HIV viral load or
CD4+ lymphocyte counts; incidence, degree, and duration of
neutropenia; and concurrent use of open-label cytokines.
| |
USE AS A VACCINE ADJUVANT |
rHuGM-CSF is the principal mediator of proliferation, maturation, and
migration of dendritic cells, important antigen-presenting cells that
play a major role in the induction of primary and secondary T-cell
immune responses.14,20,140 Dendritic cells display antigens on their surface in conjunction with class II major histocompatibility complex (MHC). rHuGM-CSF also increases class II MHC
expression.12 Once presented, the antigen can be recognized
by helper CD4+ T cells,141 which provide
support for the development of B cells and cytotoxic CD8+ T
cells. By augmenting antigen presentation to lymphocytes by dendritic
cells, rHuGM-CSF stimulates T-cell immune responses.12,14 rHuGM-CSF has been demonstrated to augment the primary in vitro immune
response to sheep red blood cells by murine spleen
cells.142 rHuGM-CSF also is important to the immune
response to vaccination, because it enhances expression of
costimulatory molecules such as B7 and adhesion molecules (eg,
intercellular adhesion molecule [ICAM]) that are
necessary for the interaction of antigen-presenting cells with T cells;
it also enhances production of other cytokines such as IL-1, TNF, and
IL-6, which promote expansion and differentiation of B and T
lymphocytes. In addition, rHuGM-CSF primes T cells for IL-2-induced
proliferation143 and augments lymphokine-activated killer
(LAK) cell generation in conjunction with IL-2.15,144 The
important role of rHuGM-CSF in the maturation and function of
antigen-presenting cells, such as dendritic cells and macrophages, as
well as its ability to affect T-cell immunity, provides the basis for
its potential evaluation as a vaccine adjuvant in new immunotherapy
strategies for infectious diseases and cancer.
Local injection of rHuGM-CSF would be expected to enhance vaccine
immunogenicity and would likely be well tolerated based on clinical
experience in other uses. Disis et al145 evaluated the use
of sargramostim as an adjuvant for protein- and peptide-based vaccines
in rats. Tetanus toxoid was used as the foreign antigen system, and
peptides derived from a self antigen, rat neu protein, were
used as the tumor antigen system. A series of initial experiments demonstrated that intradermal injections of sargramostim every 24 hours
for a total of five inoculations increased the number of class II
MHC+ cells in regional lymph nodes that peaked at the
fourth inoculation, whereas subcutaneous injections of sargramostim on
the same schedule increased these cells with a peak after the second
inoculation. This conditioning schema was then used, with tetanus
toxoid administered at the beginning or end of the immunization cycle.
Intradermal immunization was more effective than subcutaneous
immunization in eliciting specific immunity to the tetanus toxoid
antigen. In addition, intradermal injection of sargramostim as a single dose with antigen was similarly effective in eliciting specific antibody and cellular immunity as the use of Freund's adjuvant or alum
(Fig 3). Inoculation with rat neu
peptides and sargramostim elicited a strong delayed-type
hypersensitivity response, whereas the peptides alone were
nonimmunogenic. Sargramostim was as effective as Freund's adjuvant in
generating rat neu-specific delayed-type hypersensitivity
responses after immunization with the peptide-based vaccine. These
studies demonstrated that sargramostim was an effective adjuvant for
elicitation of immunity to both antigen systems, comparing favorably
with other standard adjuvants.
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| Fig 3.
rHuGM-CSF, as an adjuvant, elicits delayed-type
hypersensitivity (DTH) responses to tetanus toxoid (tt) similar to
those seen in animals immunized with a standard adjuvant. Rats were
injected with Freund's adjuvant (CFA) subcutaneously (sq), alum sq,
rHuGM-CSF intradermally (id) or sq (5 µg), and
phosphate-buffered saline (PBS) sq with tt at a concentration of 3 limit flocculation (Lf ) units. Immunizations were administered on 1 day only with no repeated administration of rHuGM-CSF. Six rats were
included in each experimental group. Figure represents data collected
from two separate experiments. Twenty days after immunization, a DTH
response was measured in the immunized animals. Antigen was
applied to rat ear and responses measured at 48 hours. Ear swelling of
experimental compared with control ear was measured. Results are shown
as the mean and standard deviation of measurements taken
from each experimental group. (Reprinted with
permission.145)
|
|
Results of several preliminary studies using molgramostim in
conjunction with hepatitis B141,146 and tetravalent
influenzae virus vaccine147 suggest that rHuGM-CSF may have
a potential role as an antiviral vaccine adjuvant; however, further
evaluation is needed in this setting. Its evaluation as an adjuvant to
vaccines and other immunotherapies for tumors is promising and is
discussed in the subsequent section.
| |
USE IN ANTITUMOR THERAPY |
Antitumor effects.
The functional effects of granulocytes, lymphocytes, and macrophages
are important in patients with malignancies because of the ability of
these cells to exhibit antitumor activity. In vitro, rHuGM-CSF has been
shown to slightly enhance the cytotoxic activity of peripheral blood
monocytes and lymphocytes and markedly increase antibody-dependent
cellular cytotoxicity148 and to enhance monocyte cytotoxicity against a malignant melanoma cell line.149
rHuGM-CSF has also been shown to augment the cytotoxic
activity of peripheral blood monocytes in antibody-dependent cellular
cytotoxicity against numerous human tumor cells in the presence of
various monoclonal antibodies150 and to enhance
IL-2-mediated LAK cell function.151,152 In
tumor-infiltrating macrophages, it also increases secretion of matrix
metalloelastase with subsequent production of angiostatin, which
inhibits angiogenesis and suppresses the growth of lung metastases.153 rHuGM-CSF may also enhance the
immunogenicity of tumor cells through facilitation of tumor antigen
presentation.56 In a comparative study in mice, the most
potent stimulator of specific antitumor immunity was tumor cells
engineered to secrete GM-CSF.154 Also, as previously noted,
sargramostim has been shown in rats to be an excellent adjuvant for
generation of immune responses to tumor antigen-derived
peptides.145 Thus, rHuGM-CSF might enhance functions of
cells critical for immune activation against tumor cells, alone or with
other cytokines or monoclonal antibodies, making it potentially useful
in the biotherapy of malignant diseases.
In a phase I study in patients with cancer, administration of
sargramostim enhanced monocyte antibody-dependent cellular cytotoxicity (Fig 4) and increased secretion of both
TNF and interferon.19 In another study in patients with
metastatic solid tumors, sargramostim was administered once daily for
14 days every 28 days; monocyte cytotoxicity against HT29 tumor cells
was enhanced by the cytokine treatment.46 No clinical
effects on tumor regression were apparent in either study. Sargramostim
is under evaluation in an open-label, phase II trial as surgical
adjuvant therapy in patients with advanced melanoma at very high risk
of recurrence.155 Sargramostim at 125 µg/m2/d
was administered subcutaneously for 14 days every 28 days beginning within 60 days of the last evidence of tumor. Treatment is continued until recurrence or a tumor-free interval of 1 year. An interim analysis of 25 patients demonstrated a significant prolongation of
disease-free survival (P = .04) and survival (P = .02) compared with 50 matched historical control
patients.155 These initial results are encouraging;
long-term follow-up is needed.
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| Fig 4.
Antibody-dependent cellular cytotoxicity (ADCC) of
monocytes after treatment with sargramostim. Monocytes were collected
from patients 2 days after a bolus infection (A) and 3 (B) and 10 (C)
days after the start of a continuous infusion of sargramostim.
Antibody-dependent cellular cytotoxicity activity was measured against
antibody-coated chicken erythrocytes by a
Cr51-release assay. Experimental results were compared
statistically with the average of two baseline assays. (Reprinted with
permission.19)
|
|
A phase Ib trial was conducted in 20 patients with metastatic melanoma
to evaluate the use of sargramostim as an adjuvant to R24, a murine
monoclonal antibody that mediates complement-dependent and
antibody-dependent cellular cytotoxicity of melanoma tumor targets.156 The rationale for this combination was the
hypothesis that upregulation of monocyte and granulocyte
antibody-dependent cellular cytotoxicity induced by sargramostim might
enhance antitumor activity. Sargramostim (150 µg/m2/d
administered by subcutaneous injection for 21 days) was administered alone or in conjunction with R24 (10 or 50 mg/m2
administered by continuous intravenous infusion on days 8 through 15).
Measurement of direct cytotoxicity and antibody-dependent cellular
cytotoxicity indicated that sargramostim enhanced monocyte and
granulocyte cytotoxicity by week 3 in all evaluable
patients.156 Of the 6 patients who received sargramostim
alone, 3 had no response (2 had stable disease) and 3 had disease
progression; in the 14 patients who received sargramostim plus R24, 2 had a partial response, 6 patients had no response (3 had stable
disease), and 6 developed progressive disease.156
The Pediatric Oncology Group performed a phase II study to evaluate the
use of sargramostim to enhance antibody-dependent cellular cytotoxicity
of a chimeric anti-GD2 monoclonal antibody (ch14.18) in the treatment
of recurrent or refractory neuroblastoma.157 Sargramostim
was administered in a dosage of 10 µg/kg daily for 14 days with
5-hour infusions of ch14.18 at 50 mg/m2 daily for 4 days.
Thirty-two patients who had failed to respond to 1 to 4 therapeutic
regimens, including BMT in 18 patients, received 70 courses of
treatment. In 27 patients evaluable for response, there were 1 complete
response, 3 partial responses, 1 mixed response, and 2 stable disease.
When analyzed by site of disease, in 18 patients with marrow disease,
there were 4 complete responses and 1 partial response; in 21 patients
with bone involvement, there were 1 complete response and 2 partial
responses. Two patients with large tumor masses had greater than 60%
reduction in tumor size. Among the responding patients, 4 were alive at
follow-up ranging from 9 to 20 months, whereas those with progressive
disease had a median survival of 3 months. All responding patients had an increase in neutrophil-mediated antibody-dependent cellular cytotoxicity to greater than 20 lytic units, whereas 9 of 12 patients with progressive disease had peak antibody-dependent cellular cytotoxicity activity less than 20 lytic units. These findings were the
basis for a recommendation that a phase III trial in the setting of
minimal residual disease is warranted.157
Adjuvant to tumor vaccines.
Based on enhancement of functional effects on monocytes, macrophages,
and antigen-presenting cells (dendritic cells,
macrophages),15,142 sargramostim has been studied for its
potential to enhance the immune response to antitumor immunotherapies,
including autologous tumor cell vaccines, recombinant peptide tumor
vaccines, and autologous Id-KLH tumor vaccines.
Leong et al158 administered sargramostim at 125 to 250 µg
as an adjuvant to a melanoma vaccine that consisted of irradiated autologous melanoma cells with Bacillus Calmette-Guérin vaccine (BCG vaccine) in 20 stage IV melanoma patients. Patients received multiple cycles that consisted of vaccine plus sargramostim on day 1, with local injection of sargramostim alone in the vaccine site on days
2 to 5; 48 hours before cycles 1, 3, and 4, cyclophosphamide at 300 mg/m2 was administered. Four patients showed partial to
complete responses (20%), 4 had stable disease (20%), and the
remaining 12 patients had disease progression (60%). In the responding
patients, regression of visceral metastases was observed. The results
demonstrated the ability of patients bearing a significant tumor burden
to respond specifically to their autologous melanoma.
Based on the fact that autologous tumor-derived Ig idiotype proteins
(Id) have been shown to induce effective antitumor activity in
experimental models and B-cell lymphoma, a vaccine containing autologous Id-KLH (keyhole limpet hemocyanin, a foreign protein used as
a vaccine adjuvant) conjugates was administered to patients with
multiple myeloma with either rHuGM-CSF or IL-2 as an
adjuvant.159 Results of skin testing with autologous and
unrelated Id were used to assess the specificity of the immune
response; rHuGM-CSF appeared to be a better adjuvant than IL-2 in these
patients.
Immunotherapy for AML.
Future directions in the treatment of AML may include immunotherapy
based on the effect of rHuGM-CSF on T-lymphocyte cytotoxic functions
and surface adhesion proteins. Several preliminary investigations have
been conducted using molgramostim in patients with AML. The effect of
molgramostim at 5 µg/kg/d on activated killer cell activity was
studied in 20 patients with AML undergoing AuBMT.160
Activated killer cell function was investigated before AuBMT, during
rHuGM-CSF therapy, and after withdrawal. The actuarial risk of relapse
was also analyzed and compared with a historical control group of 20 patients transplanted before initiation of this study. Activated killer
cell function was significantly enhanced with rHuGM-CSF (P < .001); during rHuGM-CSF treatment, median activated killer cell
function increased from 1.8% before AutoBMT to 35% and remained increased after withdrawal of rHuGM-CSF (median, 20%). After a median
follow-up of 24 months, the actuarial risk of relapse was 37.4% in
rHuGM-CSF-treated patients compared with 49.5% in controls (P = .05). Additionally, none of the 7 patients with activated killer cell
activity 20% in the first 2 to 5 weeks after AutoBMT have relapsed,
compared with 6 of 9 patients with activated killer cell
activity less than 20% (P < .02).
Exposure of AML cells to rHuGM-CSF upregulates expression of ICAM-1
(CD54) and lymphocyte function associated molecule-3 (LFA-3; CD58), but
does not increase their sensitivity to lysis by IL-2-activated natural
killer cells.161 rHuGM-CSF induces a significantly greater upregulation of ICAM-1 on leukemic CD34+ cells than their
CD34 counterparts. When AML cells are exposed to
rHuGM-CSF before incubation with killer cells, their subsequent
clonogenic activity is significantly reduced. These data suggest that
administration of effector cell activators, such as IL-2, and target
cell modulators, such as rHuGM-CSF, may have therapeutic benefit in
patients with minimal residual myeloid leukemia.
| |
OTHER POTENTIAL USES |
Mucositis, stomatitis, and diarrhea.
Mucositis, stomatitis, and diarrhea are frequent complications of
high-dose chemoradiotherapy. Mucosal epithelial cells in the
gastrointestinal tract are susceptible to direct damage from these
therapies, resulting in dysphagia and decreased oral intake and
potentially leading to airway compromise. Mucosal damage may be further
aggravated by infections or hemorrhage related to myelosuppression. rHuGM-CSF has been shown to stimulate the migration and proliferation of endothelial cells and promote keratinocyte growth, suggesting that
the growth factor has a direct effect on mucosal
cells.162,163 In addition, by decreasing the severity and
duration of neutropenia, rHuGM-CSF may reduce the severity and duration
of mucositis.
Several clinical trials evaluating sargramostim for hematopoietic
support have shown a coincidental benefit of the drug on mucositis. In
addition to enhancing myeloprotection and permitting dose-intensification of chemotherapy, the incidence of mucositis was
reduced in sarcoma patients who received sargramostim after chemotherapy.164 In a phase III placebo-controlled trial of
sargramostim in patients undergoing allogeneic BMT, 8% of
sargramostim-treated patients compared with 29% of placebo-treated
patients developed grade 3 or 4 mucositis (P = .005).165
Based on these results, several prospective trials have been conducted
to evaluate the effect of rHuGM-CSF on mucositis. In a nonrandomized
trial, the effect of sargramostim on oral mucositis was assessed in
pediatric patients undergoing stem cell transplant.166 Children who received thiotepa, etoposide, and total body irradiation followed by sargramostim experienced a significantly shorter duration of mucositis than those children who did not receive sargramostim (12.2 v 20.3 days, P = .02). However, the severity
of mucositis was similar between the groups. In this same study,
patients treated with thiotepa, etoposide, and cyclophosphamide as the
preparative regimen experienced a similar duration and severity of
mucositis regardless of whether they received sargramostim. Although
recovery of neutrophils was faster in sargramostim-treated patients,
there was no correlation between recovery of neutrophils and resolution of mucositis.
A phase I trial of sargramostim as a mucoprotectant was conducted in 10 patients with advanced head and neck cancer who received adjuvant
radiation after surgery or chemotherapy.167 Four patients developed grade 3 or worse mucositis, and the remaining 6 patients had
grade 1 or 2 mucositis. In comparison to 13 historical control patients, grade 3 or worse mucositis was reduced by half from 85% to
40% with sargramostim administration. In a phase I trial of colorectal
cancer patients receiving escalating doses of 5-FU, sargramostim used
in conjunction with leucovorin resulted in decreased rates of diarrhea
relative to historical patients.168
Topical application of molgramostim in the treatment or prevention of
mucositis has also been investigated.169,170 Of 10 BMT
patients who received molgramostim (400 µg) in 100 mL of water administered as a mouthwash and then swallowed, only grade 1 or 2 mucositis was observed; in comparison, 8 of 10 patients who did not
receive the mouthwash developed grade 4 mucositis.170 When
the molgramostim mouthwash was used as a 2-minute rinse and not
swallowed, there was no benefit with regard to mucositis; however, a
positive correlation between molgramostim dose and leukocyte recovery
was observed, providing evidence for systemic absorption and a
hematopoietic effect.169
Wound healing.
As mentioned previously, rHuGM-CSF has been shown to enhance the
migration and proliferation of endothelial cells and to promote keratinocyte growth.162,163 Animal studies have also shown
that local application of rHuGM-CSF to wounds results in increased formation of granulation tissue, increased breaking strength of incisional wounds, and reversal of wound contraction in infected wounds, resulting in a faster time to wound healing.171-173
Intradermal injections of rHuGM-CSF (molgramostim and regramostim) in
humans with lepromatous leprosy resulted in enlarged keratinocytes,
keratinocyte proliferation, thickening of the epidermis, accumulation
of Langerhans cells, and enhanced healing.174,175 A number
of case reports and small series reports have been published on the use
of rHuGM-CSF as a treatment for nonhealing wounds and
ulcers.176-178 Using various routes of rHuGM-CSF
administration (subcutaneously around the wound, incubated with skin
grafts, and as a topical application in sterile water), signs of wound
healing occurred rapidly and total wound closure was achieved between
10 days and 5 weeks after treatment.
The safety and feasibility of using molgramostim to treat patients with
vascular leg ulcers was evaluated by Arnold et al.179 Ten
patients were treated with four intradermal injections of molgramostim
at 50 µg around the perimeter of their ulcers every 2 weeks for a
total of 12 weeks. No hematological abnormalities were observed and the
injections were reported to be relatively painless. Although this study
was not designed to determine efficacy, some patients demonstrated
complete or partial healing of their ulcers.
In a double-blind, placebo-controlled study, 40 patients with chronic
leg ulcers were randomized to receive either 400 µg of rHuGM-CSF or a
similar volume of saline; equal-dose injections were administered into
four quadrants around the wound.180 The study was unblinded
prematurely and data on 25 treated patients were reported. By day 8 after treatment, a significant (P < .005) difference in mean ulcer surface area reduction was observed between the two arms in favor of rHuGM-CSF. Complete healing by week 8 was
observed in 8 of 16 patients treated with rHuGM-CSF and 1 of 9 placebo-treated patients. No significant side effects were reported
during the trial. These findings from case reports and small studies
indicate that some patients with nonhealing ulcers may benefit from
rHuGM-CSF therapy. More research is needed to determine the appropriate
dose, optimal dosing frequency, and efficacy of rHuGM-CSF in different
types of wounds and ulcers.
Hypercholesterolemia.
Elevated cholesterol concentrations result from disordered lipid
metabolism. The liver is the major site of cholesterol biosynthesis and
excretion; however, macrophages produce factors that activate cholesterol biosynthesis or excretion, and mononuclear phagocytes play
an important role in the processing and transport of
cholesterol.181 Activated T-cell products also can affect
the synthesis and accumulation of cholesterol by mononuclear
phagocytes. Therefore, rHuGM-CSF could indirectly affect cholesterol
levels by stimulating the activity of macrophages in the liver or
phagocytic cells in the circulation or present at the site of an
atherosclerotic plaque.181
The ability of regramostim to lower serum cholesterol concentrations
was reported almost a decade ago.181 Since then, efforts have focused on determining the mechanism(s) of this effect. In rabbits, the reduction in serum cholesterol is accompanied by an
increase in the levels of mRNA for very low density lipoprotein (VLDL)
receptors in muscle; the levels of LDL receptor mRNA in liver are
unchanged. These findings suggest that the cholesterol-lowering effect
of rHuGM-CSF (molgramostim) may be mediated by enhancement of
macrophage functions in lipid metabolism and the increase in mRNA for
VLDL receptor.182
Treatment of pulmonary alveolar proteinosis.
Pulmonary alveolar proteinosis includes a heterogenous group of
diseases, both congenital and acquired, that are characterized by
accumulation of large quantities of lipid- and protein-rich eosinophilic material (ie, surfactant) within the alveoli and airways.183 Murine studies indicate that mice carrying a
null allele of the GM-CSF gene develop a pulmonary abnormality that resembles alveolar proteinosis, suggesting that GM-CSF regulates the
clearance or catabolism of surfactant proteins and
lipids.184-186 Additionally, dysregulation of inflammatory
cell activity due to the lack of GM-CSF may have detrimental effects on
host defense and contribute to further lung injury.183 An
anecdotal report of rHuGM-CSF use in an adult with this disease has
been published and indicates some improvement in symptoms with cytokine
therapy.187
| |
SUMMARY AND CONCLUSIONS |
rHuGM-CSF stimulates the proliferation and differentiation of multiple
hematopoietic progenitor cells in the myeloid lineage and activates or
augments many of the functional activities of mature neutrophils,
monocytes/macrophages, and dendritic cells, enhancing host defenses
against a broad spectrum of invading microorganisms. These properties
have greatly expanded the possible therapeutic benefits of the cytokine
in a wide variety of settings (Table 4), particularly
those in which prevention of infection is desirable. The drug may be
useful as prophylaxis or adjunctive treatment of bacterial or fungal
infections in immunocompromised individuals, including cancer patients
receiving myelosuppressive chemotherapy and patients with advanced HIV
infection. In addition, exposure to rHuGM-CSF has recently been shown
to reduce the susceptibility of macrophages to infection by HIV.
Sargramostim is being evaluated as a vaccine adjuvant against
infectious diseases and malignancies and as immunotherapy in the
treatment of various malignancies, including melanoma and
neuroblastoma.
Based on the increasing variety of biologic effects being attributed to
endogenous GM-CSF, additional clinical uses for sargramostim and
molgramostim are under investigation. Because rHuGM-CSF has been shown
to stimulate the migration and proliferation of endothelial cells and
local application of rHuGM-CSF in animal studies has shown faster wound
healing times, clinical trials have evaluated rHuGM-CSF in patients
susceptible to mucosal damage, such as mucositis, stomatitis, and
diarrhea, and those with nonhealing wounds and ulcers. It is likely
that the future will see applicaton of rHuGM-CSF in a variety of
settings beyond those classically associated with myelosuppression.
| |
FOOTNOTES |
Submitted May 14, 1998;
accepted September 11, 1998.
Address reprint requests to James O. Armitage, MD, University of
Nebraska Medical Center, 600 S 42nd St, Omaha, NE 68198-3332.
| |
REFERENCES |
1.
Burgess AW, Begley CG, Johnson GR, Lopez AF, Williamson DJ, Mermod JJ, Simpson RJ, Schmitz A, DeLamarter JF:
Purification and properties of bacterially synthesized human granulocyte-macrophage colony stimulating factor.
Blood
69:43, 1987[Abstract/Free Full Text]
2.
Wong GG, Witek JS, Temple PA, Wilkens KM, Leary AC, Luxenberg DP, Jones SS, Brown EL, Kay RM, Orr EC, Shoemaker C, Golde DW, Kaufman RJ, Hewick RM, Wang EA, Clark SC:
Human GM-CSF: Molecular coloning of the complementary DNA and purification of the natural and recombinant proteins.
Science
228:819, 1985
3.
Cantrell MA, Anderson D, Cerretti DP, Price V, McKereghan K, Tushinski RJ, Mochizuki DY, Larsen A, Grabstein K, Gillis S, Cosman D:
Cloning, sequence, and expression of a human granulocyte/macrophage colony-stimulating factor.
Proc Natl Acad Sci USA
82:6250, 1985[Abstract/Free Full Text]
4.
Donahue RE, Wang EA, Kaufman RJ, Foutch L, Leary AC, Witek-Giannette JS, Metzger M, Hewick RM, Steinbrink DR, Shaw G, Kamen R, Clark SC:
Effects of N-linked carbohydrate on the in vivo properties of human GM-CSF.
Cold Spring Harb Symp Quant Biol
51:685, 1986
5.
Dorr RT:
Clinical properties of yeast-derived versus Escherichia coli-derived granulocyte-macrophage colony-stimulating factor.
Clin Ther
15:19, 1993[Medline]
[Order article via Infotrieve]
6.
Hovgaard D, Mortensen BT, Schifter S, Nissen NI:
Comparative pharmacokinetics of single-dose administration of mammalian and bacterially-derived recombinant human granulocyte-macrophage colony-stimulating factor.
Eur J Haematol
50:32, 1993[Medline]
[Order article via Infotrieve]
7.
Hussein AM, Ross M, Vredenburgh J, Meisenberg B, Hars V, Gilbert C, Petros WP, Coniglio D, Kurtzberg J, Rubin P, Peters WP:
Effects of granulocyte-macrophage colony stimulating factor produced in Chinese hamster ovary cells (regramostim) Escherichia coli (molgramostim) and yeast (sargramostim) on priming peripheral blood progenitor cells for use with autologous bone marrow after high-dose chemotherapy.
Eur J Haematol
54:281, 1995[Medline]
[Order article via Infotrieve]
8.
Nemunaitis J:
Granulocyte-macrophage-colony-stimulating factor: A review from preclinical development to clinical application.
Transfusion
33:70, 1993[Medline]
[Order article via Infotrieve]
9.
Fabian I, Shapira E, Gadish M, Kletter Y, Nagler A, Flidel O, Slavin S:
Effects of human interleukin 3, macrophage and granulocyte-macrophage colony-stimulating factor on monocyte function following autologous bone marrow transplantation.
Leuk Res
16:703, 1992[Medline]
[Order article via Infotrieve]
10.
Fleischmann J, Golde DW, Weisbart RH, Gasson JC:
Granulocyte-macrophage colony-stimulating factor enhances phagocytosis of bacteria by human neutrophils.
Blood
68:708, 1986[Abstract/Free Full Text]
11.
Ho AD, Haas R, Wulf G, Knauf W, Ehrhardt R, Heilig B, Körbling M, Schulz G, Hunstein W:
Activation of lymphocytes induced by recombinant human granulocyte-macrophage colony-stimulating factor in patients with malignant lymphoma.
Blood
75:203, 1990[Abstract/Free Full Text]
12.
Jones T, Stern A, Lin R:
Potential roles of granulocyte-macrophage colony-stimulating factor as vaccine adjuvant.
Eur J Clin Microbiol Infect Dis
13:S47, 1994 (suppl 2)
13.
Perkins RC, Vadhan-Raj S, Scheule RK, Hamilton R, Holian A:
Effects of continuous high dose rhGM-CSF on human monocyte activity.
Am J Hematol
43:279, 1993[Medline]
[Order article via Infotrieve]
14.
Sallusto F, Lanzavecchia A:
Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor .
J Exp Med
179:1109, 1994[Abstract/Free Full Text]
15.
Schiller JH, Hank JA, Khorsand M, Storer B, Borchert A, Huseby-Moore K, Burns D, Wesly O, Albertini MR, Wilding G, Sondel PM:
Clinical and immunological effects of granulocyte-macrophage colony-stimulating factor coadministered with interleukin 2: A phase IB study.
Clin Cancer Res
2:319, 1996[Abstract/Free Full Text]
16.
Smith PD, Lamerson CL, Banks SM, Saini SS, Wahl LM, Calderone RA, Wahl SM:
Granulocyte-macrophage colony-stimulating factor augments human monocyte fungicidal activity for Candida albicans.
J Infect Dis
161:999, 1990[Medline]
[Order article via Infotrieve]
17.
Wang JM, Colella S, Allavena P, Mantovani A:
Chemotactic activity of human recombinant granulocyte-macrophage colony-stimulating factor.
Immunology
60:439, 1987[Medline]
[Order article via Infotrieve]
18.
Weisbart RH, Kwan L, Golde DW, Gasson JC:
Human GM-CSF primes neutrophils for enhanced oxidative metabolism in response to the major physiological chemoattractants.
Blood
69:18, 1987[Abstract/Free Full Text]
19.
Wing EJ, Magee M, Whiteside TL, Kaplan SS, Shadduck RK:
Recombinant human granulocyte/macrophage colony-stimulating factor enhances monocyte cytotoxicity and secretion of tumor necrosis factor and interferon in cancer patients.
Blood
73:643, 1989[Abstract/Free Full Text]
20.
Young JW, Szabolcs P, Moore MAS:
Identification of dendritic cell colony-forming units among normal human CD34+ bone marrow progenitors that are expanded by c-kit-ligand and yield pure dendritic cell colonies in the presence of granulocyte/macrophage colony-stimulating factor and tumor necrosis factor .
J Exp Med
182:1111, 1995[Abstract/Free Full Text]
21.
Colotta F, Bussolino F, Polentarutti N, Guglielmetti A, Sironi M, Bocchietto E, De Rossi M, Mantovani A:
Differential expression of the common and specific chains of the receptors for GM-CSF, IL-3, and IL-5 in endothelial cells.
Exp Cell Res
206:311, 1993[Medline]
[Order article via Infotrieve]
22.
DiPersio JF, Hedvat C, Ford CF, Golde DW, Gasson JC:
Characterization of the soluble human granulocyte-macrophage colony-stimulating factor receptor complex.
J Biol Chem
266:279, 1991[Abstract/Free Full Text]
23.
Jokhi PP, King A, Jubinsky PT, Loke YW:
Demonstration of the low affinity subunit of the granulocyte-macrophage colony-stimulating factor receptor (GM-CSF-R) on human trophoblast and uterine cells.
J Reprod Immunol
26:147, 1994[Medline]
[Order article via Infotrieve]
24.
Lanza F, Castagnari B, Rigolin G, Moretti S, Latorraca A, Ferrari L, Bardi A, Castoldi G:
Flow cytometry measurement of GM-CSF receptors in acute leukemic blasts, and normal hemopoietic cells.
Leukemia
11:1700, 1997[Medline]
[Order article via Infotrieve]
25.
Park LS, Friend D, Gillis S, Urdal DL:
Characterization of the cell surface receptor for human granulocyte/macrophage colony-stimulating factor.
Exp Med
164:251, 1986
26.
Santiago-Schwarz F, Divaris N, Kay C, Carsons SE:
Mechanisms of tumor necrosis factor-granulocyte-macrophage colony-stimulating factor-induced dendritic cell development.
Blood
82:3019, 1993[Abstract/Free Full Text]
27.
Till KJ, Burthem J, Lopez A, Cawley JC:
Granulocyte-macrophage colony-stimulating factor receptor: Stage-specific expression and function on late B cells.
Blood
88:479, 1996[Abstract/Free Full Text]
28.
Hayashida K, Kitamura T, Gorman DM, Arai K, Yokota T, Miyajima A:
Molecular cloning of a second subunit of the receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF): Reconstitution of a high-affinity GM-CSF receptor.
Proc Natl Acad Sci USA
87:9655, 1990[Abstract/Free Full Text]
29.
Miyajima A, Mui AL-F, Ogorochi T, Sakamaki K:
Receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5.
Blood
82:1960, 1993[Free Full Text]
30.
Sato N, Sakamaki K, Terada N, Arai K, Miyajima A:
Signal transduction by the high-affinity GM-CSF receptor: Two distinct cytoplasmic regions of the common subunit responsible for different signaling.
EMBO J
12:4181, 1993[Medline]
[Order article via Infotrieve]
31.
Quelle FW, Sato N, Witthuhn BA, Inhorn RC, Eder M, Miyajima A, Griffin JD, Ihle JN:
JAK2 associates with c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region.
Mol Cell Biol
14:4335, 1994[Abstract/Free Full Text]
32.
Mui AL-F, Wakao H, O'Farrell A-M, Harada N, Miyajima A:
Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two STAT5 homologs.
EMBO J
14:1166, 1995[Medline]
[Order article via Infotrieve]
33.
Wang Y, Morella KK, Ripperger J, Lai C-F, Gearing DP, Fey GH, Campos SP, Baumann H:
Receptors for interluekin-3 (IL-3) and growth hormone mediate an IL-6-type transcriptional induction in the presence of JAK2 or STAT3.
Blood
86:1671, 1995[Abstract/Free Full Text]
34.
Satoh T, Nakafuka M, Miyajima A, Kaziro Y:
Involvement of ras p21 protein in signal-transduction pathways from interkeukin 2, interleukin 3, and granulocyte/macrophage colony-stimulating factor, but not from interleukin 4.
Proc Natl Acad Sci USA
88:3314, 1991[Abstract/Free Full Text]
35.
Okuda K, Sanghera JS, Pelech SL, Kanakura Y, Hallek M, Griffin JD, Druker BJ:
Granulocyte-macrophage colony-stimulating factor, interleukin-3, and steel factor induce rapid tyrosine phosphorylation of p42 and p44 MAP kinase.
Blood
79:2880, 1992[Abstract/Free Full Text]
36.
Leukine (sargramostim) prescribing information. Seattle, WA, Immunex, 1996.
37.
Cebon JS, Bury RW, Lieschke GJ, Morstyn G:
The effects of dose and route of administration on the pharmacokinetics of granulocyte-macrophage colony-stimulating factor.
Eur J Cancer
26:1064, 1990
38.
Herrmann F, Schulz G, Lindemann A, Meyenburg W, Oster W, Krumwieh D, Mertelsmann R:
Hematopoietic responses in patients with advanced malignancy treated with recombinant human granulocyte-macrophage colony-stimulating factor.
J Clin Oncol
7:159, 1989[Abstract]
39.
Schwinghammer TL, Shadduck RK, Waheed A, Evans C, Sulecki M, Rosenfeld CS:
Pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) after intravenous infusion and subcutaneous injection.
Pharmacotherapy
2:105, 1991 (abstr 60)
40.
Shadduck RK, Waheed A, Evans C, Sulecki M, Rosenfeld CS:
Serum and urinary levels of recombinant human granulocyte-macrophage colony-stimulating factor: Assessment after intravenous infusion and subcutaneous injection.
Exp Hematol
18:601, 1990 (abstr 201)
41.
Furman WL, Fairclough DL, Huhn RD, Pratt CB, Stute N, Petros WP, Evans WE, Bowman LC, Douglass EC, Santana VM, Meyer WH, Crist WM:
Therapeutic effects and pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor in childhood cancer patients receiving myelosuppressive chemotherapy.
J Clin Oncol
9:1022, 1991[Abstract]
42.
Stute N, Furman WL, Schell M, Evans WE:
Pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor in children after intravenous and subcutaneous administration.
J Pharm Sci
84:824, 1995[Medline]
[Order article via Infotrieve]
43.
Metcalf D:
The molecular biology and functions of the granulocyte-macrophage colony-stimulating factors.
Blood
67:257, 1986[Abstract/Free Full Text]
44.
Kaplan SS, Basford RE, Wing EJ, Shadduck RK:
The effect of recombinant human granulocyte macrophage colony-stimulating factor on neutrophil activation in patients with refractory carcinoma.
Blood
73:636, 1989[Abstract/Free Full Text]
45.
Broxmeyer HE, Cooper S, Vadhan-Raj S:
Cell cycle status of erythroid (BFU-E) progenitor cells from the bone marrows of patients on a clinical trial with purified recombinant human granulocyte-macrophage colony-stimulating factor.
Exp Hematol
17:455, 1989[Medline]
[Order article via Infotrieve]
46.
Chachoua A, Oratz R, Hoogmoed R, Caron D, Peace D, Liebes L, Blum RH, Vilcek J:
Monocyte activation following systemic administration of granulocyte-macrophage colony-stimulating factor.
J Immunother
15:217, 1994[Medline]
[Order article via Infotrieve]
47.
Löwenberg B, Suciu S, Zittoun R, Ossenkoppele G, Boogaerts MA, Wijermans P, Vellenga E, Berneman Z, Dekker AW, Sonneveld P, Stryckmans P, Solbu G, Dardenne M, de Witte Th, Archimbaud E:
GM-CSF during as well as after induction chemotherapy (CT) in elderly patients with acute myeloid leukemia (AML). The EORTC-HOVON phase III trial (AML 11).
Blood
86:433a, 1995 (abstr, suppl 1)
48.
Steis RG, VanderMolen LA, Longo DL, Clark JW, Smith JW II, Kopp WC, Ruscetti FW, Creekmore SP, Elwood LJ, Hursey J, Urba WJ:
Recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy: A phase Ib trial.
J Natl Cancer Inst
82:697, 1990[Abstract/Free Full Text]
49.
Ruef C, Coleman DL:
Granulocyte-macrophage colony-stimulating factor: pleiotropic cytokine with potential clinical usefulness.
Rev Infect Dis
12:41, 1990[Medline]
[Order article via Infotrieve]
50.
Birkmann J, Oez S, Smetak M, Kaiser G, Kappauf H, Gallmeier WM:
Effects of recombinant human thrombopoietin alone and in combination with erythropoietin and early-acting cytokines on human mobilized purified CD34+ progenitor cells cultured in serum-depleted medium.
Stem Cells
15:18, 1997[Medline]
[Order article via Infotrieve]
51.
Neelis KJ, Hartong SCC, Egeland T, Thomas GR, Eaton DL, Wagemaker G:
The efficacy of single-dose administration of thrombopoietin with coadministration of either granulocyte/macrophage or granulocyte colony-stimulating factor in myelosuppressed rhesus monkeys.
Blood
90:2565, 1997[Abstract/Free Full Text].
52.
Coleman DL, Chodakewitz JA, Bartiss AH, Mellors JW:
Granulocyte-macrophage colony-stimulating factor enhances selective effector functions of tissue-derived macrophages.
Blood
72:573, 1988[Abstract/Free Full Text]
53.
Wiltschke C, Krainer M, Wagner A, Linkesch W, Zielinski CC:
Influence of in vivo administration of GM-CSF and G-CSF on monocyte cytotoxicity.
Exp Hematol
23:402, 1995[Medline]
[Order article via Infotrieve]
54.
Szabolcs P, Avigan D, Gezelter S, Ciocon DH, Moore MAS, Steinman RM, Young JW:
Dendritic cells and macrophages can mature independently from a human bone marrow-derived, post-colony-forming unit intermediate.
Blood
87:4520, 1996[Abstract/Free Full Text]
55.
Szabolcs P, Moore MAS, Young JW:
Expansion of immunostimulatory dendritic cells among the myeloid progeny of human CD34+ bone marrow precursors cultured with c-kit ligand, granulocyte-macrophage colony-stimulating factor, and TNF-.
J Immunol
154:5851, 1995[Abstract]
56.
Fischer H-G, Frosch S, Reske K, Reske-Kunz AB:
Granulocyte-macrophage colony-stimulating factor activates macrophages derived from bone marrow cultures to synthesis of MHC class II molecules and to augmented antigen presentation function.
J Immunol
141:3882, 1988[Abstract]
57.
Ganser A, Heil G:
Use of hematopoietic growth factors in the treatment of acute myelogenous leukemia.
Curr Opin Hematol
4:191, 1997[Medline]
[Order article via Infotrieve]
58.
Geller RB:
Use of cytokines in the treatment of acute myelocytic leukemia: A critical review.
J Clin Oncol
14:1371, 1996[Abstract/Free Full Text]
59.
Lieschke GJ, Foote M, Morstyn G:
Hematopoietic growth factors in cancer chemotherapy.
Cancer Chemother Biol Response Modif
17:363, 1997[Medline]
[Order article via Infotrieve]
60.
Lifton R, Bennett JM:
Clinical use of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in neutropenia associated with malignancy.
Hematol Oncol Clin North Am
10:825, 1996[Medline]
[Order article via Infotrieve]
61.
Montemurro F, Gallicchio M, Aglietta M:
Prevention and treatment of febrile neutropenia [Italian].
Tumori
83:S15, 1997[Medline]
[Order article via Infotrieve] (suppl)
62.
Lane TA, Law P, Maruyama M, Young D, Burgess J, Mullen M, Mealiffe M, Terstappen LWMM, Hardwick A, Moubayed M, Oldham F, Corringham RET, Ho AD:
Harvesting and enrichment of hematopoietic progenitor cells mobilized into the peripheral blood of normal donors by granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF: Potential role in allogeneic marrow transplantation.
Blood
85:275, 1995[Abstract/Free Full Text]
63.
Huang S, Terstappen LWMM:
Lymphoid and myeloid differentiation of single human CD34+, HLA-DR+, CD38 hematopoietic stem cells.
Blood
83:1515, 1994[Abstract/Free Full Text]
64.
Corringham RET, Ho AD:
Rapid and sustained allogeneic transplantation using immunoselected CD34+-selected peripheral blood progenitor cells mobilized by recombinant granulocyte- and granulocyte-macrophage colony-stimulating factors.
Blood
86:2052, 1995[Free Full Text]
65.
Ali SM, Brown RA, Adkins DR, Todd G, Haug JS, Goodnough LT, DiPersio JF:
Analysis of lymphocyte subsets and peripheral blood progenitor cells (PBPC) in apheresis products from normal donors mobilized with either G-CSF or concurrent G-CSF and GM-CSF.
Blood
90:2511, 1997 (abstr, suppl 1)
66.
Law P, Young D, Peterson S, Lane TA, Ho AD:
Mobilization and collection of peripheral blood progenitor cells (PBPC) from normal subjects treated sequentially with GM-CSF and G-CSF.
Blood
88:397a, 1996 (abstr, suppl 1)
67.
Winter JN, Lazarus HM, Rademaker A, Villa M, Mangan C, Tallman M, Jahnke L, Gordon L, Newman S, Byrd K, Cooper BW, Horvath N, Crum E, Stadtmauer EA, Conklin E, Bauman A, Martin J, Goolsby C, Gerson ST, Bender J, O'Gorman M:
Phase I/II study of combined granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor administration for the mobilization of hematopoietic progenitor cells.
J Clin Oncol
14:277, 1996[Abstract]
68.
Griffin JD, Young D, Herrmann F, Wiper D, Wagner K, Sabbath KD:
Effects of recombinant human GM-CSF on proliferation of clonogenic cells in acute myeloblastic leukemia.
Blood
67:1448, 1986[Abstract/Free Full Text]
69.
Kelleher C, Miyauchi J, Wong G, Clark S, Minden MD, McCulloch EA:
Synergism between recombinant growth factors, GM-CSF and G-CSF, acting on the blast cells of acute myeloblastic leukemia.
Blood
69:1498, 1987[Abstract/Free Full Text]
70.
Miyauchi J, Kelleher CA, Yang YC, Wong GG, Clark SC, Minden MD, Minkin S, McCulloch EA:
The effect of three recombinant growth factors, IL-3, GM-CSF, and G-CSF, on the blast cells of acute myeloblastic leukemia maintained in short-term suspension culture.
Blood
70:657, 1987[Abstract/Free Full Text]
71.
Vellenga E, Young DC, Wagner K, Wiper D, Ostapovicz D, Griffin JD:
The effect of GM-CSF and G-CSF in promoting growth of clonogenic cells in acute myeloblastic leukemia.
Blood
69:1771, 1987[Abstract/Free Full Text]
72.
Cannistra SA, Groshek P, Griffin JD:
Granulocyte-macrophage colony-stimulating factor enhances the cytotoxic effects of cytosine arabinoside in acute myeloblastic leukemia and in the myeloid blast crisis phase of chronic myeloid leukemia.
Leukemia
3:328, 1989[Medline]
[Order article via Infotrieve]
73.
Lotem J, Sachs L:
Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor 1 and cancer chemotherapy compounds in myeloid leukemic cells.
Blood
80:1750, 1992[Abstract/Free Full Text]
74.
Büchner T, Hiddemann W, Wörmann B, Zühlsdorf M, Rottmann R, Innig G, Maschmeier G, Ludwig W-D, Sauerland M-C, Heinecke A:
Hematopoietic growth factors in acute myeloid leukemia: Supportive and priming effects.
Semin Oncol
24:124, 1997[Medline]
[Order article via Infotrieve]
75.
Hansen PB, Johnsen HE, Jensen L, Gaarsdal E, Simonsen K, Ralfkiaer E:
Priming and treatment with molgramostim (rhGM-CSF) in adult high-risk acute myeloid leukemia during induction chemotherapy: A prospective, randomized pilot study.
Eur J Haematol
54:296, 1995[Medline]
[Order article via Infotrieve]
76.
Heil G, Chadid L, Hoelzer D, Seipelt G, Mitrou P, Huber Ch, Kolbe K, Mertelsmann R, Lindemann A, Frisch J, Nicolay U, Gaus W, Heimpel H:
GM-CSF in a double-blind randomized, placebo controlled trial in therapy of adult patients with de novo acute myeloid leukemia (AML).
Leukemia
9:3, 1995[Medline]
[Order article via Infotrieve]
77.
Zittoun R, Suciu S, Mandelli F, de Witte T, Thaler J, Stryckmans P, Hayat M, Peetermans M, Cadiou M, Solbu G, Petti MC, Willemze R:
Granulocyte-macrophage colony-stimulating factor associated with induction treatment of acute myelogenous leukemia: A randomized trial by the European Organization for Research and Treatment of Cancer Leukemia Cooperative Group.
J Clin Oncol
14:2150, 1996[Abstract/Free Full Text]
78.
Ford PA, Arbuck SG, Minniti C, Miller LL, DeMaria D, O'Dwyer PJ:
Phase I trial of etoposide, doxorubicin and cisplatin (EAP) in combination with GM-CSF.
Eur J Cancer
32:631, 1996
79.
Grem JL, McAtee N, Murphy RF, Hamilton JM, Balis F, Steinberg S, Arbuck SG, Setser A, Jordan E, Chen A, Kohler DR, Kotite B, Allegra CJ:
Phase I and pharmacokinetic study of recombinant human granulocyte-macrophage colony-stimulating factor given in combination with fluorouracil plus calcium leucovorin in metastatic gastrointestinal adenocarcinoma.
J Clin Oncol
12:560, 1994[Abstract]
80.
Lachance DH, Oette D, Schold SC Jr, Brown M, Kurtzberg J, Graham ML, Tien R, Felsberg G, Colvin OM, Moghrabi A, Browning I, Hockenberger B, Stewart E, Ferrell L, Kerby T, Duncan-Brown M, Golembe B, Fuchs H, Fredericks R, Hayes FA, Rubin AS, Bigner DD, Friedman HS:
Dose escalation trial of cyclophosphamide with sargramostim in the treatment of central nervous system (CNS) neoplasms.
Med Pediatr Oncol
24:241, 1995[Medline]
[Order article via Infotrieve]
81.
Moghrabi A, Fuchs H, Brown M, Schold SC Jr, Graham M, Kurtzberg J, Tien R, Felsberg G, Lachance DH, Colvin OM, Oette D, Allegretta GJ, Hockenberger B, Stewart E, Ferrell L, Kerby T, Duncan-Brown M, Bigner DD, Friedman HS:
Cyclophosphamide in combination with sargramostim for treatment of recurrent medulloblastoma.
Med Pediatr Oncol
25:190, 1995[Medline]
[Order article via Infotrieve]
82.
Neidhart JA, Mangalik A, Stidley CA, Tebich SL, Sarmiento LE, Pfile JE, Oette DH, Oldham FB:
Dosing regimen of granulocyte-macrophage colony-stimulating factor to support dose-intensive chemotherapy.
J Clin Oncol
10:1460, 1992[Abstract/Free Full Text]
83.
Yau JC, Neidhart JA, Triozzi P, Verma S, Nemunaitis J, Quick DP, Mayernik DG, Oette DH, Hayes FA, Holcenberg J:
Randomized placebo-controlled trial of granulocyte-macrophage colony-stimulating-factor support for dose-intensive cyclophosphamide, etoposide, and cisplatin.
Am J Hematol
51:289, 1996[Medline]
[Order article via Infotrieve]
84.
Bober LA, Grace MJ, Pugliese-Sivo C, Rojas-Triana A, Waters T, Sullivan LM, Narula SK:
The effect of GM-CSF and G-CSF on human neutrophil function.
Immunopharmacology
29:111, 1995[Medline]
[Order article via Infotrieve]
85.
Lopez AF, Williamson DJ, Gamble JR, Begley CG, Harlan JM, Klebanoff SJ, Waltersdorph A, Wong G, Clark SC, Vadas MA:
Recombinant human granulocyte-macrophage colony-stimulating factor stimulates in vitro mature human neutrophil and eosinophil function, surface receptor expression, and survival.
J Clin Invest
78:1220, 1986.
86.
DiPersio JF, Billing P, Williams R, Gasson JC:
Human granulocyte-macrophage colony-stimulating factor and other cytokines prime human neutrophils for enhanced arachidonic acid release and leukotriene B4 synthesis.
J Immunol
140:4315, 1988[Abstract]
87.
Silberstein DS, Owen WF, Gasson JC, DiPersio JF, Golde DW, Bina JC, Soberman R, Austen KF, David JR:
Enhancement of human eosinophil cytotoxicity and leukotriene synthesis by biosynthetic (recombinant) granulocyte-macrophage colony-stimulating factor.
J Immunol
137:3290, 1986[Abstract]
88.
Gadish M, Kletter Y, Flidel O, Nagler A, Slavin S, Fabian I:
Effects of recombinant human granulocyte and granulocyte-macrophage colony-stimulating factors on neutrophil function following autologous bone marrow transplantation.
Leuk Res
15:1175, 1991[Medline]
[Order article via Infotrieve]
89.
Brach MA, deVos S, Gruss H-J, Herrmann F:
Prolongation of survival of human polymorphonuclear neutrophils by granulocyte-macrophage colony-stimulating factor is caused by inhibition of programmed cell death.
Blood
80:2920, 1992[Abstract/Free Full Text]
90.
Gosselin EJ, Wardwell K, Rigby WFC, Guyre PM:
Induction of MHC class II on human polymorphonuclear neutrophils by granulocyte/macrophage colony-stimulating factor, IFN-, and IL-3.
J Immunol
151:1482, 1993[Abstract]
91.
Mudzinski SP, Christian TP, Guo TL, Cirenza E, Hazlett KR, Gosselin EJ:
Expression of HLA-DR (major histocompatability complex class II) on neutrophils from patients treated with granulocyte-macrophage colony-stimulating factor for mobilization of stem cells.
Blood
86:2452, 1995[Free Full Text]
92.
Phillips N, Jacobs S, Stoller R, Earle M, Przepiorka D, Shadduck RK:
Effect of recombinant human granulocyte-macrophage colony-stimulating factor on myelopoiesis in patients with refractory metastatic carcinoma.
Blood
74:26, 1989[Abstract/Free Full Text]
93.
Rossman MD, Ruiz P, Comber P, Gomez F, Rottem M, Schreiber AD:
Modulation of macrophage Fc receptors by rGM-CSF.
Exp Hematol
21:177, 1993[Medline]
[Order article via Infotrieve]
94.
Williams MA, Kelsey SM, Collins PW, Gutteridge CN, Newland AC:
Administration of rHuGM-CSF activates monocyte reactive oxygen species secretion and adhesion molecule expression in vivo in patients following high-dose chemotherapy.
Br J Haematol
90:31, 1995[Medline]
[Order article via Infotrieve]
95.
Roilides E, Blake C, Holmes A, Pizzo PA, Walsh TJ:
Granulocyte-macrophage colony-stimulating factor and interferon- prevent dexamethasone-induced immunosuppression of antifungal monocyte activity against Aspergillus fumigatus hyphae.
J Med Vet Mycol
34:63, 1996[Medline]
[Order article via Infotrieve]
96.
Roilides E, Mertins S, Eddy J, Walsh TJ, Pizzo PA, Rubin M:
Impairment of neutrophil chemotactic and bactericidal function in children infected with human immunodeficiency virus type 1 and partial reversal after in vitro exposure to granulocyte-macrophage colony-stimulating factor.
J Pediatr
117:531, 1990[Medline]
[Order article via Infotrieve]
97.
Verhoef G, Boogaerts M:
In vivo administration of granulocyte-macrophage colony stimulating factor enhances neutrophil function in patients with myelodysplastic syndromes.
Br J Haematol
79:177, 1991[Medline]
[Order article via Infotrieve]
98.
Kowanko IC, Ferrante A, Harvey DP, Carman KL:
Granulocyte-macrophage colony-stimulating factor augments neutrophil killing of Torulopsis glabrata and stimulates neutrophil respiratory burst and degranulation.
Clin Exp Immunol
83:225, 1991[Medline]
[Order article via Infotrieve]
99.
Richardson MD, Brownlie CED, Shankland GS:
Enhanced phagocytosis and intracellular killing of Candida albicans by GM-CSF-activated human neutrophils.
J Med Vet Mycol
30:433, 1992[Medline]
[Order article via Infotrieve]
100.
Roilides E, Holmes A, Blake C, Venzon D, Pizzo PA, Walsh TJ:
Antifungal activity of elutriated human monocytes against Aspergillus fumigatus hyphae: enhancement by granulocyte-macrophage colony-stimulating factor and interferon-.
J Infect Dis
170:894, 1994[Medline]
[Order article via Infotrieve]
101.
Newman SL, Gootee L:
Colony-stimulating factors activate human macrophages to inhibit intracellular growth of Histoplasma capsulatum yeasts.
Infect Immunity
60:4593, 1992[Abstract/Free Full Text]
102.
Collins HL, Bancroft GJ:
Cytokine enhancement of complement-dependent phagocytosis by macrophages: Synergy of tumor necrosis factor- and granulocyte-macrophage colony-stimulating factor for phagocytosis of Cryptococcus neoformans.
Eur J Immunol
22:1447, 1992[Medline]
[Order article via Infotrieve]b
103.
Reed SG, Nathan CF, Pihl DL, Rodricks P, Shanebeck K, Conlon PJ, Grabstein KH:
Recombinant granulocyte/macrophage colony-stimulating factor activates macrophages to inhibit Trypanosoma cruzi and release hydrogen peroxide.
J Exp Med
166:1734, 1987[Abstract/Free Full Text]
104.
Nemunaitis J, Gordon A, Cox J, Kerr R, Hanson T, Courtney A, Mever W:
Phase II pilot trial comparing neutrophil and monocyte function by microbicidal assay in oncology patients receiving rhG-CSF, rhGM-CSF or no cytokine after cytotoxic chemotherapy.
Blood
84:135, 1994 (abstr, suppl 1)
105.
Bermudez LE, Martinelli J, Petrofsky M, Kolonoski P, Young LS:
Recombinant granulocyte-macrophage colony-stimulating factor enhances the effects of antibiotics against Mycobacterium avium complex infection in the beige mouse model.
J Infect Dis
169:575, 1994[Medline]
[Order article via Infotrieve]
106.
Bermudez LEM, Young LS:
Recombinant granulocyte-macrophage colony-stimulating factor activates human macrophages to inhibit growth or kill Mycobacterium avium complex.
J Leukoc Biol
48:67, 1990[Abstract]
107.
Onyeji CO, Nightingale CH, Tessier PR, Nicolau DP, Bow LM:
Activities of clarithromycin, azithromycin, and ofloxacin in combination with liposomal or unencapsulated granulocyte-macrophage colony-stimulating factor against intramacrophage Mycobacterium avium-Mycobacterium intracellulare.
J Infect Dis
172:810, 1995[Medline]
[Order article via Infotrieve]
108.
Suzuki K, Lee WJ, Hashimoto T, Tanaka E, Murayama T, Amitani R, Yamamoto K, Kuze F:
Recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) or tumour necrosis factor-alpha (TNF-) activate human alveolar macrophages to inhibit growth of Mycobacterium avium complex.
Clin Exp Immunol
98:169, 1994[Medline]
[Order article via Infotrieve]
109.
Frenck RW, Sarman G, Harper TE, Buescher ES:
The ability of recombinant murine granulocyte-macrophage colony-stimulating factor to protect neonatal rats from septic death due to Staphylococcus aureus.
J Infect Dis
162:109, 1990[Medline]
[Order article via Infotrieve]
110.
Mayer P, Schütze E, Lam C, Kricek F, Liehl E:
Recombinant murine granulocyte-macrophage colony-stimulating factor augments neutrophil recovery and enhances resistance to infections in myelosuppressed mice.
J Infect Dis
163:584, 1991[Medline]
[Order article via Infotrieve]
111.
Lechner AJ, Lamprech KE, Potthoff LH, Tredway TL, Matuschak GM:
Recombinant GM-CSF reduces lung injury and mortality during neutropenic Candida sepsis.
Am J Physiol
266:L561, 1994[Abstract/Free Full Text]
112.
Nemunaitis J, Rabinowe SN, Singer JW, Bierman PJ, Vose JM, Freedman AS, Onetto N, Gillis S, Oette D, Gold M, Buckner CD, Hansen JA, Ritz J, Appelbaum FR, Armitage JO, Nadler LM:
Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer.
N Engl J Med
324:1773, 1991[Abstract]
113.
Rowe JM, Rubin A, Mazza JJ, Bennett JM, Paietta E, Anderson JW, Ghalie R, Wiernick PH:
Incidence of infections in adult patients (>55 years) with acute myeloid leukemia treated with yeast-derived GM-CSF (sargramostim): Results of a double-blind prospective study by the Eastern Cooperative Oncology Group, in
Hiddemann W,
Buchner T,
Wormann B,
Schellong L,
Ritter J,
Creutzig U
(eds):
Acute Leukemias V: Experimental Approaches and Management of Refractory Disease. Berlin, Germany, Springer-Verlag, 1996, p 178.
114.
Bodey GP, Anaissie E, Gutterman J, Vadhan-Raj S:
Role of granulocyte-macrophage colony-stimulating factor as adjuvant therapy of fungal infection in patients with cancer.
Clin Infect Dis
17:705, 1993[Medline]
[Order article via Infotrieve]
115.
Swindells S, Kleinschmidt DR, Hayes FA:
Pilot study of adjunctive Gm-CSF (yeast-derived) for fluconazole-resistant oral candidiasis in HIV-1 infection.
Infect Dis Clin Prac
6:278, 1997
116.
Palau LA, Pankey GA:
Resolution of rhinocerebral and disseminated mucormycosis with adjuvant administration of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). Proceedings of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy Toronto, Ontario, Canada. Washington, DC, American Society for Microbiology, 1997, p 374 (abstr LM-55)
117.
Gill PS, Bernstein-Singer M, Espina BM, Rarick M, Magy F, Montgomery T, Berry MS, Levine A:
Adriamycin, bleomycin and vincristine chemotherapy with recombinant granulocyte-macrophage colony-stimulating factor in the treatment of AIDS-related Kaposi's sarcoma.
AIDS
6:1477, 1992[Medline]
[Order article via Infotrieve]
118.
Scadden DT, Bering HA, Levine JD, Bresnahan J, Evans L, Epstein C, Groopman JE:
Granulocyte-macrophage colony-stimulating factor mitigates the neutropenia of combined interferon alfa and zidovudine treatment of acquired immune deficiency syndrome-associated Kaposi's sarcoma.
J Clin Oncol
9:802, 1991[Abstract]
119.
Scadden DT, Pickus O, Hammer SM, Stretcher B, Bresnahan J, Gere J, McGrath J, Agosti JM:
Lack of in vivo effect of granulocyte-macrophage colony-stimulating factor on human immunodeficiency virus type 1.
AIDS Res Human Retrovir
12:1151, 1996[Medline]
[Order article via Infotrieve]
120.
Folks TM, Justement J, Kinter A, Dinarello CA, Fauci AS:
Cytokine-induced expressin of HIV-1 in a chronically infected promonocyte cell line.
Science
238:800, 1987[Abstract/Free Full Text]
121.
Hammer SM, Gillis JM, Pinkson P, Rose RM:
Effect of zidovudine and granulocyte-macrophage colony-stimulating factor on human immunodeficiency virus replication in alveolar macrophages.
Blood
75:1215, 1990[Abstract/Free Full Text]
122.
Kitano K, Abboud CN, Ryan DH, Quan SG, Baldwin GC, Golde DW:
Macrophage-active colony-stimulating factors enhance human immunodeficiency virus type 1 infection in bone marrow stem cells.
Blood
77:1699, 1991[Abstract/Free Full Text]
123.
Koyanagi Y, O'Brien WA, Zhao JQ, Golde DW, Gasson JC, Chen ISY:
Cytokines alter production of HIV-1 from primary mononuclear phagocytes.
Science
241:1673, 1988[Abstract/Free Full Text]
124.
Perno C-F, Cooney DA, Gao W-Y, Hao Z, Johns DG, Foli A, Hartman NR, Caliò R, Broder S, Yarchoan R:
Effects of bone marrow stimulatory cytokines on human immunodeficiency virus replication and the antiviral activity of dideoxynucleosides in cultures of monocyte/macrophages.
Blood
80:995, 1992[Abstract/Free Full Text]
125.
DiMarzio P, Mariani R, Tse J, Thomas EK, Landau NR:
GM-CSF or CD40L suppresses chemokine receptor expression and HIV-1 entry in human monocytes and macrophages. Program and Abstracts of the 5th Conference on Retroviruses and Opportunistic Infections. Chicago, IL. Alexandria, VA, Foundation of Retrovirology and Human Health, 1998, p 86 (abstr 37)
126.
Massari F, Poli G, Fauci AS:
GM-CSF inhibition of susceptibility of M-CSF treated human monocytes to in vitro infection with HIV. Proceedings of the Fifth International Conference on AIDS. Montreal, Quebec, Canada. Ottawa, Ontario, Canada, International Development Research Center, 1989, p 610 (abstr WCP 109)
127.
Matsuda S, Akagawa K, Honda M, Yokota Y, Takebe Y, Takemori T:
Suppression of HIV replication in human monocyte-derived macrophages induced by granulocyte/macrophasge colony-stimulating factor.
AIDS Res Hum Retroviruses
11:1031, 1995[Medline]
[Order article via Infotrieve]
128.
Hammer SM, Gillis JM:
Synergistic activity of granulocyte-macrophage colony-stimulating factor and 3 -azido-3-deoxythymidine against human immunodeficiency virus in vitro.
Antimicrob Agents Chemother
31:1046, 1987[Abstract/Free Full Text]
129.
Perno C-F, Yarchoan R, Cooney DA, Hartman NR, Webb DS, Hao Z, Mitsuya H, Johns DG, Broder S:
Replication of human immunodeficiency virus in monocytes. Granulocyte/macrophage colony-stimulating factor (GM-CSF) potentiates viral production yet enhances the antiviral effect mediated by 3-azido-23-dideoxythymidine (AZT) and other dideoxynucleoside congeners of thymidine.
J Exp Med
169:933, 1989[Abstract/Free Full Text]
130.
Bakker PJM, Danner SA, ten Napel CHH, Kroon FP, Sprenger HG, van Leusen R, Meenhorst PL, Muusers A, Veenhof CHN:
Treatment of poor prognosis epidemic Kaposi's sarcoma with doxorubicin, bleomycin, vindesine and recombinant human granulocyte-macrophage colony stimulating factor (rh GM-CSF).
Eur J Cancer
31A:188, 1995
131.
Hardy WD:
Combined ganciclovir and recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of cytomegalovirus retinitis in AIDS patients.
J AIDS
4:S22, 1991 (suppl 1)
132.
Krown SE, Paredes J, Bundow D, Polsky B, Gold JWM, Flomenberg N:
Interferon-, zidovudine, and granulocyte-macrophage colony-stimulating factor: A phase I AIDS Clinical Trials Group study in patients with Kaposi's sarcoma associated with AIDS.
J Clin Oncol
10:1344, 1992[Abstract/Free Full Text]
133.
Kaplan LD, Kahn JO, Crowe S, Northfelt D, Neville P, Grossberg H, Abrams DI, Tracey J, Mills J, Volberding PA:
Clinical and virologic effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma: Results of a randomized trial.
J Clin Oncol
9:929, 1991[Abstract]
134.
Pluda JM, Yarchoan R, Smith PD, McAtee N, Shay LE, Oette D, Maha M, Wahl SM, Myers CE, Broder S:
Subcutaneous recombinant granulocyte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection.
Blood
76:463, 1990[Abstract/Free Full Text]
135.
Davison FD, Kaczmarski RS, Pozniak A, Mufti GJ, Sutherland S:
Quantification of HIV by PCR in monocytes and lymphocytes in patients receiving antiviral treatment and low dose recombinant human granulocyte macrophage colony stimulating factor.
J Clin Pathol
47:855, 1994[Abstract/Free Full Text]
136.
Bernstein AP, Brooks S, Hayes FA, Gould M, Jacob S, Tomasi TB:
A pilot study in the use of GM-CSF in human immunodeficiency virus (HIV) infected individuals.
Blood
90:133a, 1997 (abstr, suppl 1)
137.
Skowron G, Stein D, Drusano G, Melbourne K, Mongillo A, Whitmore J, Echols R, Gilbert M:
Safety and anti-HIV effect of GM-CSF in patients on highly active anti-retroviral therapy. Program and Abstracts of the 5th Conference on Retroviruses and Opportunistic Infections. Chicago, IL. Alexandria, VA, Foundation of Retrovirology and Human Health, 1998, p 267 (abstr 615)
138.
DiMarzio P, Tse J, Landau NR:
Chemokine receptor regulation and HIV type 1 tropism in monocyte-macrophages.
AIDS Res Hum Retrovirus
14:129, 1998[Medline]
[Order article via Infotrieve]
139.
Kemper C, Bermudez L, Agosti J, Deresinski S:
Immunomodulatory therapy of Mycobacterium avium (MAC) bacteremia in AIDS with rhGM-CSF. Thirty-fifth Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy San Francisco, CA. Washington, DC, American Society of Microbiology, 1995, p 177 (abstr G109)
140.
Caux C, Dezutter-Dambuyant C, Schmitt D, Banchereau J:
GM-CSF and TNF- cooperate in the generation of dendritic Langerhans cells.
Nature
360:258, 1992[Medline]
[Order article via Infotrieve]
141.
Tarr PE, Lin R, Mueller EA, Kovarik JM, Guillaume M, Jones TC:
Evaluation of tolerability and antibody response after recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and a single dose of recombinant hepatitis B vaccine.
Vaccine
14:1199, 1996[Medline]
[Order article via Infotrieve]
142.
Morrissey PJ, Bressler L, Park LS, Alpert A, Gillis S:
Granulocyte-macrophage colony-stimulating factor augments the primary antibody response by enhancing the function of antigen-presenting cells.
J Immunol
139:1113, 1987[Abstract]
143.
Al-Aoukaty A, Giaid A, Sinoff C, Ho AD, Maghazachi AA:
Priming effects of granulocyte-macrophage colony-stimulating factor are coupled to cholera toxin-sensitive guanine nucleotide binding protein in human T lymphocytes.
Blood
83:1299, 1994[Abstract/Free Full Text]
144.
Stewart-Akers AM, Cairns JS, Tweardy DJ, McCarthy SA:
Effect of granulocyte-macrophage colony-stimulating factor on lymphokine-activated killer cell induction.
Blood
81:2671, 1993[Abstract/Free Full Text]
145.
Disis ML, Bernhard H, Shiota FM, Hand SL, Gralow JR, Husaby ES, Gillis S, Cheever MA:
Granulocyte-macrophage colony-stimulating factor: An effective adjuvant for protein and peptide-based vaccines.
Blood
88:202, 1996[Abstract/Free Full Text]
146.
Hess G, Kreiter F, Kösters W, Deusch K:
The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on hepatitis B vaccination in haemodialysis patients.
J Viral Hepatitis
3:149, 1996[Medline]
[Order article via Infotrieve]
147.
Taglietti M, Rouzier-Panis R, Aymard M, Garaud JJ:
A double-blind, placebo-controlled study to assess the immune response to flu vaccine following a single dose of rhGM-CSF in elderly people. Abstracts of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Orlando, FL. Washington, DC, American Society for Microbiology, 1994, p 266 (abstr H76)
148.
Masucci G, Wersäll P, Ragnhammar P, Mellstedt H:
Granulocyte-monocyte-colony-stimulating factor augments the cytotoxic capacity of lymphocytes and monocytes in antibody dependent cellular cytotoxicity.
Cancer Immunol Immunother
29:288, 1989[Medline]
[Order article via Infotrieve]
149.
Grabstein KH, Urdal DL, Tushinski RJ, Mochizuki DY, Price VL, Cantrell MA, Gillis S, Conlon PJ:
Induction of macrophage tumoricidal activity by granuloctye-macrophage colony-stimulating factors.
Science
232:506, 1986[Abstract/Free Full Text]
150.
Ragnhammar P, Frödin J-E, Trotta PP, Mellstedt H:
Cytotoxicity of white blood cells activated by granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor and macrophage-colony-stimulating factor against tumor cells in the presence of various monoclonal antibodies.
Cancer Immunol Immunother
39:254, 1994[Medline]
[Order article via Infotrieve]
151.
Baxevanis CN, Dedoussis GVZ, Papadopoulos NG, Missitzis I, Beroukas C, Stathopoulos GP, Papamichail M:
Enhanced human lymphokine-activated killer cell function after brief exposure to granulocyte-macrophage-colony stimulating factor.
Cancer
76:1253, 1995[Medline]
[Order article via Infotrieve]
152.
Epling-Burnette PK, Wei S, Blanchard DK, Spranzi E, Djeu JY:
Coinduction of granulocyte-macrophage colony-stimulating factor release and lymphokine-activated killer cell susceptibility in monocytes by interleukin-2 via interleukin-2 receptor .
Blood
81:3130, 1993[Abstract/Free Full Text]
153.
Dong Z, Kumar R, Yang X, Fidler IJ:
Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma.
Cell
88:801, 1997[Medline]
[Order article via Infotrieve]
154.
Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levistsky H, Brose K, Jackson V, Hamada H, Pardoll D, Mulligan RC:
Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity.
Proc Natl Acad Sci USA
90:3539, 1993[Abstract/Free Full Text]
155.
Spitler LE, Grossbard ML, Ernstoff MS, Silver G, Jacobs M, Hayes FA, Soong SJ:
Adjuvant therapy of stage III and IV malignant melanoma using yeast derived, GM-CSF.
Melanoma Res
7:160, 1997
156.
Chachoua A, Oratz R, Liebes L, Alter RS, Felice A, Peace D, Vilcek J, Blum RH:
Phase Ib trial of granulocyte-macrophage colony-stimulating factor combined with murine monoclonal antibody R24 in patients with metastatic melanoma.
J Immunother
16:132, 1994
157.
Yu AL, Batova A, Alvarado C, Rao VJ, Castleberry RP:
Usefulness of a chimeric anti-GD2 (ch14.18) and GM-CSF for refractory neuroblastoma: A POG phase II study.
Proc Am Soc Clin Oncol
16:513a, 1997 (abstr)
158.
Leong SPL, Enders-Zohr P, Zhou YM, Allen RE Jr, Sagebiel RW, Glassberg AB, Hayes FA:
Active specific immunotherapy with GM-CSF as an adjuvant to autologous melanoma (AM) vaccine in metastatic melanoma.
Proc Am Soc Clin Oncol
15:437, 1996 (abstr 1360)
159.
Massaia M, Battaglio S, Beggiato E, Bianchi A, Borrione P, Mariani S, Napoli P, Peola S, Boccadoro M, Pileri A:
Vaccination with Id/KLH and local cytokines (IL2/GM-CSF) in advanced multiple myeloma patients. Proceedings of the Keystone Symposia. Silverthorne, CO, Keystone Symposia, 1997, p 59 (abstr 517)
160.
Richard C, Baro J, Bello-Fernandez C, Hermida G, Calavia J, Olalla I, Alsar MJ, Loyola I, Cuadrado MA, Iriondo A, Conde E, Zubizarreta A:
Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) administration after autologous bone marrow transplantation for acute myeloblastic leukemia enhances activated killer cell function and may diminish leukemic relapse.
Bone Marrow Transplant
15:721, 1995[Medline]
[Order article via Infotrieve]
161.
Bendall LJ, Kortlepel K, Gottlieb DJ:
GM-CSF enhances IL-2-activated natural killer cell lysis of clonogenic AML cells by upregulating target cell expression of ICAM-1.
Leukemia
9:677, 1995[Medline]
[Order article via Infotrieve]
162.
Bussolino F, Wang JM, Defilippi P, Turrini F, Sanavio F, Edgell C-JS, Aglietta M, Arese P, Mantovani A:
Granulocyte- and granulocyte-macrophage-colony stimulating factors induce human endothelial cells to migrate and proliferate.
Nature
337:471, 1989[Medline]
[Order article via Infotrieve]
163.
Hancock GE, Kaplan G, Cohn ZA:
Keratinocyte growth regulation by the products of immune cells.
J Exp Med
168:1395, 1988[Abstract/Free Full Text]
164.
Vadhan-Raj S, Broxmeyer HE, Hittelman WN, Papadopoulos NE, Chawla SP, Fenoglio C, Cooper S, Buescher ES, Frenck RW Jr, Holian A, Perkins RC, Scheule RK, Gutterman JU, Salem P, Benjamin RS:
Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma: Protection at the progenitor cell level.
J Clin Oncol
10:1266, 1992[Abstract/Free Full Text]
165.
Nemunaitis J, Rosenfeld CS, Ash R, Freedman MH, Deeg HJ, Appelbaum F, Singer JW, Flomenberg N, Dalton W, Elfenbein GJ, Rifkin R, Rubin A, Agosti J, Hayes FA, Holcenberg J, Shadduck RK:
Phase III randomized, double-blind placebo-controlled trial of rhGM-CSF following allogeneic bone marrow transplantation.
Bone Marrow Transplant
15:949, 1995[Medline]
[Order article via Infotrieve]
166.
Gordon B, Spadinger A, Hodges E, Ruby E, Stanley R, Coccia P:
Effect of granulocyte-macrophage colony-stimulating factor on oral mucositis after hematopoietic stem-cell transplantation.
J Clin Oncol
12:1917, 1994[Abstract/Free Full Text]
167.
Dunphy F, Kim H, Dunleavy T, Harrison B, Boyd J, Petruska P:
Granulocyte monocyte colony stimulating factor (GM-CSF) ameliorates radiation mucositis.
Blood
90:184b, 1997 (abstr 3552, suppl 1)
168.
Meropol NJ, Petrelli NJ, Rustum YM, Rodriguez-Bigas M, Proefrock A, Frank C, Creaven PJ:
Granulocyte-macrophage colony-stimulating factor (GM-CSF) as a diarrhea protectant in patients treated with 5-fluorouracil (FU) and leucovorin (LV).
Proc Am Soc Clin Oncol
14:263, 1995 (abstr 724)
169.
Cartee L, Petros WP, Rosner Gl, Gilbert C, Moore S, Affronti ML, Hoke JA, Hussein AM, Ross M, Rubin P, Vredenburgh JJ, Peters WP:
Evaluation of GM-CSF mouthwash for prevention of chemotherapy-induced mucositis: A randomized, double-blind, dose-ranging study.
Cytokine
7:471, 1995[Medline]
[Order article via Infotrieve]
170.
Ovilla-Martinez R, Rubio ME, Borbolla JR, Gonzale-Llaven JE:
GM-CSF mouthwashes as treatment for mucositis in BMT patients.
Blood
84:717a, 1994 (abstr 2853, suppl 1)
171.
Jyung RW, Wu L, Pierce GF, MustoeTA:
Granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor: Differential action on incisional wound healing.
Surgery
115:325, 1994[Medline]
[Order article via Infotrieve]
172.
Kucukcelebi A, Carp SS, Hayward PG, Hui P-S, Cowan WT, Ko F, Cooper DM, Robson MC:
Granulocyte-macrophage colony stimulating factor reverses the inhibition of wound contraction caused by bacterial contamination.
Wounds
4:241, 1992
173.
Vyalov S, Desmoulière A, Gabbiani G:
GM-CSF-induced granulation tissue formation: Relationships between macrophage and myofibroblast accumulation.
Arch B Cell Pathol
63:231, 1993
174.
Braunstein S, Kaplan G, Gottlieb AB, Schwartz M, Walsh G, Abalos RM, Fajardo TT, Guido LS, Krueger JG:
GM-CSF activates regenerative epidermal growth and stimulates keratinocyte proliferation in human skin in vivo.
J Invest Dermatol
103:601, 1994[Medline]
[Order article via Infotrieve]
175.
Kaplan G, Walsh G, Guido LS, Meyn P, Burkhardt RA, Abalos RM, Barker J, Frindt PA, Fajardo TT, Celona R, Cohn ZA:
Novel responses of human skin to intradermal recombinant granuloctye/macrophage-colony-stimulating factor: Langerhans cell recruitment, keratinocyte growth, and enhanced wound healing.
J Exp Med
175:1717, 1992[Abstract/Free Full Text]
176.
Marques da Costa R, Aniceto C, Jesus FM, Mendes M:
Quick healing of leg ulcers after molgramostim.
Lancet
344:481, 1994
177.
Pojda Z, Struzyna J:
Treatment of non-healing ulcers with rhGM-CSF and skin grafts.
Lancet
343:1100, 1994[Medline]
[Order article via Infotrieve]
178.
Raderer M, Kornek G, Hejna M, Koperna K, Scheithauer W, Base W:
Topical granulocyte-macrophage colony-stimulating factor in patients with cancer and impaired wound healing.
J Natl Cancer Instit
89:263, 1997[Free Full Text]
179.
Arnold F, O'Brien J, Cherry G:
Granulocyte monocyte-colony stimulating factor as an agent for wound healing.
J Wound Care
4:400, 1995[Medline]
[Order article via Infotrieve]
180.
Marques da Costa R, Jesus FM, Aniceto C, Mendes M:
Double-blind randomized placebo-controlled trial of the use of granulocyte-macrophage colony-stimulating factor in chronic leg ulcers.
Am J Surg
173:165, 1997[Medline]
[Order article via Infotrieve]
181.
Nimer SD, Champlin RE, Golde DW:
Serum cholesterol-lowering activity of granulocyte-macrophage colony-stimulating factor.
JAMA
260:3297, 1988[Abstract/Free Full Text]
182.
Ishibashi T, Yokoyama K, Shindo J, Hamazaki Y, Endo Y, Sato T, Takahashi S, Kawarabayasi Y, Shiomi M, Yamamoto T, Maruyama Y:
Potent cholesterol-lowering effect by human granulocyte-macrophage colony-stimulating factor in rabbits. Possible implications of enhancement of macrophage functions and an increase in mRNA for VLDL receptor.
Arterioscler Thromb
14:1534, 1994[Abstract/Free Full Text]
183.
Hallman M, Merritt TA:
Lack of GM-CSF as a cause of pulmonary alveolar proteinosis.
J Clin Invest
97:589, 1996[Medline]
[Order article via Infotrieve] (editorial)
184.
Dranoff G, Crawford AD, Sadelain M, Ream B, Rashid A, Bronson RT, Dickersin GR, Bachurski CJ, Mark EL, Whitsett JA, Mulligan RC:
Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis.
Science
264:713, 1994[Abstract/Free Full Text]
185.
Huffman JA, Hull WM, Dranoff G, Mulligan RC, Whitsett JA:
Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice.
J Clin Invest
97:649, 1996[Medline]
[Order article via Infotrieve]
186.
Ikegami M, Ueda T, Hull W, Whitsett JA, Mulligan RC, Dranoff G, Jobe AH:
Surfactant metabolism in transgenic mice after granulocyte macrophage-colony stimulating factor ablation.
Am J Physiol
270:L650, 1996[Abstract/Free Full Text]
187.
Seymour JF, Dunn AR, Vincent JM, Presneill JJ, Pain MC:
Efficacy of granulocyte-macrophage colony-stimulating factor in acquired alveolar proteinosis.
N Engl J Med
335:1924, 1996[Free Full Text] (letter)
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C. Dumas, A. Muyombwe, G. Roy, C. Matte, M. Ouellette, M. Olivier, and B. Papadopoulou
Recombinant Leishmania major Secreting Biologically Active Granulocyte-Macrophage Colony-Stimulating Factor Survives Poorly in Macrophages In Vitro and Delays Disease Development in Mice
Infect. Immun.,
November 1, 2003;
71(11):
6499 - 6509.
[Abstract]
[Full Text]
[PDF]
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J. A. Willment, H.-H. Lin, D. M. Reid, P. R. Taylor, D. L. Williams, S. Y. C. Wong, S. Gordon, and G. D. Brown
Dectin-1 Expression and Function Are Enhanced on Alternatively Activated and GM-CSF-Treated Macrophages and Are Negatively Regulated by IL-10, Dexamethasone, and Lipopolysaccharide
J. Immunol.,
November 1, 2003;
171(9):
4569 - 4573.
[Abstract]
[Full Text]
[PDF]
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J. Y. Channon, K. A. Miselis, L. A. Minns, C. Dutta, and L. H. Kasper
Toxoplasma gondii Induces Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Secretion by Human Fibroblasts: Implications for Neutrophil Apoptosis
Infect. Immun.,
November 1, 2002;
70(11):
6048 - 6057.
[Abstract]
[Full Text]
[PDF]
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J. F. Seymour and J. J. Presneill
Pulmonary Alveolar Proteinosis: Progress in the First 44 Years
Am. J. Respir. Crit. Care Med.,
July 15, 2002;
166(2):
215 - 235.
[Abstract]
[Full Text]
[PDF]
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M. Santosuosso, M. Divangahi, A. Zganiacz, and Z. Xing
Reduced tissue macrophage population in the lung by anticancer agent cyclophosphamide: restoration by local granulocyte macrophage-colony-stimulating factor gene transfer
Blood,
February 15, 2002;
99(4):
1246 - 1252.
[Abstract]
[Full Text]
[PDF]
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S. A. Bouwhuis, S. N. Markovic, M. T. McEvoy, and M. R. Pittelkow
Extracorporeal Photopheresis and Adjuvant Aerosolized Granulocyte-Macrophage Colony-Stimulating Factor for Sezary Syndrome
Mayo Clin. Proc.,
February 1, 2002;
77(2):
197 - 200.
[Abstract]
[PDF]
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C. E. Dearden, E. Matutes, B. Cazin, G. E. Tjonnfjord, A. Parreira, B. Nomdedeu, P. Leoni, F. J. Clark, D. Radia, S. M. B. Rassam, et al.
High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H
Blood,
September 15, 2001;
98(6):
1721 - 1726.
[Abstract]
[Full Text]
[PDF]
|
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K. Kedzierska, N. J. Vardaxis, A. Jaworowski, and S. M. Crowe
Fc{gamma}R-mediated phagocytosis by human macrophages involves Hck, Syk, and Pyk2 and is augmented by GM-CSF
J. Leukoc. Biol.,
August 1, 2001;
70(2):
322 - 328.
[Abstract]
[Full Text]
[PDF]
|
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G. M. Crooks, Q.-L. Hao, D. Petersen, L. W. Barsky, and D. Bockstoce
IL-3 Increases Production of B Lymphoid Progenitors from Human CD34+CD38- Cells
J. Immunol.,
September 1, 2000;
165(5):
2382 - 2389.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
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N. Modi and R. Carr
Promising stratagems for reducing the burden of neonatal sepsis
Arch. Dis. Child. Fetal Neonatal Ed.,
September 1, 2000;
83(2):
150F - 153.
[Full Text]
|
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|
|
|
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G. Swanson, K. Bergstrom, E. Stump, T. Miyahara, and E. T. Herfindal
Growth Factor Usage Patterns and Outcomes in the Community Setting: Collection Through a Practice-Based Computerized Clinical Information System
J. Clin. Oncol.,
April 1, 2000;
18(8):
1764 - 1770.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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K. Kaushansky
Blood: New designs for a new millennium
Blood,
January 1, 2000;
95(1):
1 - 6.
[Full Text]
[PDF]
|
|
|
|
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T. Greiner, J. O. Armitage, and T. G. Gross
Atypical Lymphoproliferative Diseases
Hematology,
January 1, 2000;
2000(1):
133 - 146.
[Abstract]
[Full Text]
[PDF]
|
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E. G. MacEwen, I. D. Kurzman, D. M. Vail, R. R. Dubielzig, K. Everlith, B. R. Madewell, C. O. Rodriguez Jr., B. Phillips, C. H. Zwahlen, J. Obradovich, et al.
Adjuvant Therapy for Melanoma in Dogs: Results of Randomized Clinical Trials Using Surgery, Liposome-encapsulated Muramyl Tripeptide, and Granulocyte Macrophage Colony-stimulating Factor
Clin. Cancer Res.,
December 1, 1999;
5(12):
4249 - 4258.
[Abstract]
[Full Text]
[PDF]
|
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|
|
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F. Vinante, M. Marchi, A. Rigo, P. Scapini, G. Pizzolo, and M. A. Cassatella
Granulocyte-Macrophage Colony-Stimulating Factor Induces Expression of Heparin-Binding Epidermal Growth Factor-Like Growth Factor/Diphtheria Toxin Receptor and Sensitivity to Diphtheria Toxin in Human Neutrophils
Blood,
November 1, 1999;
94(9):
3169 - 3177.
[Abstract]
[Full Text]
[PDF]
|
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P. M. Anderson, S. N. Markovic, J. A. Sloan, M. L. Clawson, M. Wylam, C. A. S. Arndt, W. A. Smithson, P. Burch, M. Gornet, and E. Rahman
Aerosol Granulocyte Macrophage-Colony Stimulating Factor: A Low Toxicity, Lung-specific Biological Therapy in Patients with Lung Metastases
Clin. Cancer Res.,
September 1, 1999;
5(9):
2316 - 2323.
[Abstract]
[Full Text]
[PDF]
|
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|
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A. H. Honkoop, S. A. Luykx-de Bakker, K. Hoekman, S. Meyer, O. W.M. Meyer, C. J. van Groeningen, P. J. van Diest, E. Boven, E. van der Wall, G. Giaccone, et al.
Prolonged Neoadjuvant Chemotherapy with GM-CSF in Locally Advanced Breast Cancer
Oncologist,
April 1, 1999;
4(2):
106 - 111.
[Abstract]
[Full Text]
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Top
Introduction
Conclusions