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Antimicrobial Agents and Chemotherapy, January 1999, p. 21-24, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Close Association between Clearance of Recombinant Human
Granulocyte Colony-Stimulating Factor (G-CSF) and G-CSF Receptor on
Neutrophils in Cancer Patients
Kenji
Terashi,1
Mikio
Oka,1,*
Shigehiro
Ohdo,2
Taku
Furukubo,2
Chizuko
Ikeda,2
Minoru
Fukuda,1
Hiroshi
Soda,1
Shun
Higuchi,2 and
Shigeru
Kohno1
The Second Department of Internal Medicine,
Nagasaki University School of Medicine,
Nagasaki,1 and
Division of
Pharmaceutical Science, Department of Clinical Pharmacokinetics, Kyushu
University, Fukuoka,2 Japan
Received 20 March 1998/Returned for modification 25 July
1998/Accepted 20 October 1998
 |
ABSTRACT |
Recombinant human granulocyte colony-stimulating factor (rhG-CSF)
is used to counter chemotherapy-induced neutropenia. Our previous study
showed an inverse correlation between serum rhG-CSF levels and the
number of circulating neutrophils in cancer patients (H. Takatani, H. Soda, M. Fukuda, M. Watanabe, A. Kinoshita, T. Nakamura, and
M. Oka, Antimicrob. Agents Chemother. 40:988-991, 1996). The aim of
this study was to clarify the relationship between rhG-CSF clearance
and G-CSF receptors on circulating neutrophils. In five cancer patients
receiving chemotherapy, a bolus dose of rhG-CSF (5 µg/kg) was
injected intravenously during defined phases of posttreatment
neutropenia and neutrophilia. Serum rhG-CSF levels were measured by a
chemiluminescence enzyme immunoassay and analyzed by moment analysis.
G-CSF receptors on neutrophils were detected by flow cytometry with
biotinylated rhG-CSF. rhG-CSF clearance was significantly higher at
neutrophilia than at neutropenia (1,497 ± 132 versus 995 ± 266 ml/h; P < 0.01). The percentage of G-CSF receptor-positive neutrophils, reflecting the number of G-CSF receptors
per cell, was low at neutropenia without rhG-CSF therapy (44.5% ± 22.1%) and high at neutrophilia with rhG-CSF therapy (73.0% ± 11.4%; P < 0.01). rhG-CSF clearance closely
correlated with the percentage of G-CSF receptor-positive neutrophils
(r2 = 0.91; P < 0.0001) and neutrophil count (r2 = 0.72; P < 0.005). Our results indicate that, in
cancer patients receiving chemotherapy, rhG-CSF increases the number of
G-CSF receptors per cell as well as circulating neutrophil counts,
resulting in modulation of its own clearance.
| |
INTRODUCTION |
Recombinant human granulocyte
colony-stimulating factor (rhG-CSF) is used to increase the number of
neutrophils during intensive chemotherapy. Results of recent studies,
however, have not always demonstrated a clear clinical benefit from
rhG-CSF therapy in cancer patients. Therefore, it is necessary to
identify those patients who will clearly benefit from rhG-CSF therapy
(3). The levels of rhG-CSF achieved in serum do not always
reflect the effects on neutrophils (13, 14). Nevertheless,
the pharmacokinetics and pharmacodynamics of rhG-CSF in cancer patients
are not fully understood. Serum rhG-CSF levels may vary due to several
factors such as the dose or route of rhG-CSF administration (6,
13), renal function (1), number of circulating
neutrophils (13, 14), cellularity of myeloid cells in the
bone marrow (18), circulating proteases, anti-G-CSF
antibodies, soluble G-CSF receptor, and G-CSF receptor antagonists
(9).
Previous studies, including those from our laboratories, have
demonstrated that serum rhG-CSF levels after subcutaneous
administration in cancer patients receiving chemotherapy were inversely
correlated with the number of circulating neutrophils (13,
14). Furthermore, Nicola et al. (8) suggested that
murine G-CSF was processed intracellularly through G-CSF receptors on
neutrophils in vitro. Thus, the G-CSF receptors on neutrophils may
modulate the clearance of rhG-CSF. However, previous studies had two
limitations: the influence of release of rhG-CSF from the subcutaneous
tissue and no evaluation of G-CSF receptors on circulating neutrophils.
In the present study, to exclude the kinetics in the subcutaneous tissue, rhG-CSF was administered intravenously in cancer patients. We
then measured the number of G-CSF receptors on neutrophils and
investigated the relationship between these receptors and rhG-CSF clearance.
| |
MATERIALS AND METHODS |
Patient selection.
Our study was conducted according to the
ethical standards of Nagasaki University. Patients were consecutively
selected if they fulfilled the following criteria: (i) presence of
histologically or cytologically confirmed malignancy; (ii) no prior
chemotherapy or radiotherapy; (iii) Eastern Cooperative Oncology Group
performance status of 2 or better; (iv) eligibility for chemotherapy;
(v) absence of metastases in bones and pleural and ascitic fluid; (vi)
adequate bone marrow function with neutrophil counts of >2,000/µl, platelet counts of >100,000/µl, and hemoglobin level of >10 g/dl; (vii) normal hepatic and renal function; and (viii) informed consent of
the patient to this study. All tests and analytical procedures were
performed during the first course of chemotherapy.
rhG-CSF administration.
Following chemotherapy, a bolus dose
of 5 µg of rhG-CSF (lenograstim; Chugai Pharmaceutical Co., Tokyo,
Japan) per kg of body weight was injected intravenously at 9 a.m.
from the first day of neutrophil count of <1,000/µl (defined
as neutropenia) to the first day when neutrophil count was >5,000/µl
(defined as neutrophilia). The dose of rhG-CSF was selected based
on results of a dose determination study in Japan. The number of
neutrophils was determined three times weekly by the method reported
previously (14).
Serum rhG-CSF levels.
Blood samples were obtained just
before and 0.5, 1, 2, 4, 6, and 8 h after rhG-CSF administration
on the first day (neutropenia) and last day (neutrophilia) of rhG-CSF
therapy. The samples were immediately centrifuged, and sera were stored
at 
20°C until assayed. Serum G-CSF levels were measured by a
chemiluminescence enzyme immunoassay which has higher sensitivity than
the standard enzyme immunoassay (4).
Serum G-CSF levels were analyzed by moment analysis (automated
pharmacokinetic analysis system; Nankodo Co., Tokyo, Japan) (20). The parameters calculated were area under the
concentration-time curve (AUC0-
), elimination half-life
(t1/2), systemic clearance (CL), and volume of
distribution (Vd).
G-CSF receptors on neutrophils.
The density of G-CSF
receptors on neutrophils was estimated by flow cytometric analysis with
biotinylated rhG-CSF, as previously described (10). For
biotin labeling of rhG-CSF, 50 µg of rhG-CSF was diluted in 2 ml of
labeling buffer (0.01 M phosphate, 0.15 M NaCl, pH 7.45). Biotinylation
was carried out by the addition of 2 µl of biotinyl
N-hydroxysuccinimide ester (EOY Laboratories, San Mateo,
Calif.) in dimethyl formamide to yield a final concentration of 50 µg/ml. The reaction lasted for 3 h with continuous shaking at
room temperature. The unbound reagent was then removed with a PD10
column equilibrated with 25 ml of labeling buffer supplemented with
0.1% bovine serum albumin. Sodium azide was added to the recovered
sample at a final concentration of 0.1%.
For preparation of leukocytes, blood samples were obtained from
patients on the days of neutropenia and neutrophilia before rhG-CSF
administration and also from three healthy individuals as a control.
Accordingly, the samples from patients contained rhG-CSF at
neutrophilia but not at neutropenia. Leukocytes were separated from
each 8-ml sample by density gradient centrifugation with Ficoll-Hypaque
(Dainippon Pharmaceutical. Co., Tokyo, Japan). Erythrocytes were
removed by using a hemolysis buffer containing 155 mM ammonium
chloride, 10 mM potassium hydrogen carbonate, and 0.1 mM EDTA-2Na.
To prepare cells for flow cytometric analysis, 5 × 10
5 cells in a 50-µl volume were added to microtubes
containing 25 ng of
biotinylated rhG-CSF in a total volume of 100 µl.
In a competition
binding assay, both biotinylated rhG-CSF and a 40-fold
excess
of unlabeled rhG-CSF (1 µg) were added to the above cell
suspension.
After a 30-min incubation at 4°C, cells were washed three
times
with ice-cold binding buffer and incubated with 10 ng of
streptavidin-phycoerythrin
conjugate (Becton Dickinson, Mountain View,
Calif.) for 30 min
at 4°C. Then, the cells were washed and
resuspended in 500 µl
of binding buffer. Detection of G-CSF receptors
was performed
with an EPICS Elite flow cytometer (Coulter Corp.,
Hialeah, Fla.).
Flow cytometric analysis.
Flow cytometric data are usually
reduced to percent positive cells, which is a count-independent measure
of the number of fluorescent cells. The number of G-CSF
receptor-positive neutrophils was obtained by comparing the histogram
in the absence of unlabeled G-CSF (total binding) with that in the
presence of excess unlabeled G-CSF (nonspecific binding). The fraction
of cells that was shifted to a greater fluorescence intensity after
specific ligand binding represented the percentage of G-CSF
receptor-positive neutrophils: (number of G-CSF receptor-positive
neutrophils)/(10,000 neutrophils analyzed) × 100 (%). The
fluorescence level that delineated fluorescent cells from
nonfluorescent cells was selected, and then the percentage of cells
with an equivalent or higher fluorescence level was calculated. The
flow cytometric analysis of each sample was performed in triplicate. The coefficient of variation for assay error was less than 5%.
The percentage of cells positive for G-CSF receptors is thought to
reflect the number of G-CSF receptors per cell, because
a good positive
correlation is observed between the number of
G-CSF receptors per cell
in the radioisotopic binding assay and
that in flow cytometric analysis
(
11,
16).
Statistical analysis.
Serum G-CSF concentrations and the
percentage of G-CSF receptor-positive neutrophils on the days of
neutropenia and neutrophilia were compared by the paired t
test. The number of circulating neutrophils was log transformed for
normalization. Correlations between the rhG-CSF clearance and the above
values were analyzed by linear regression. The coefficient of
determination (r2) was used to assess
variability in rhG-CSF clearance. A two-tailed test value of
P < 0.05 was considered significant.
| |
RESULTS |
Patient characteristics.
Five patients comprising four with
lung cancer and one with ovarian cancer met our inclusion criteria
(Table 1). The median duration of
chemotherapy-induced neutropenia (<1,000/µl), neutrophil count at
nadir, and duration of rhG-CSF therapy were 3 days, 552/µl, and 5 days, respectively. The numbers of erythrocytes, platelets, monocytes,
and lymphocytes and creatinine clearance did not change significantly
during rhG-CSF therapy (data not shown).
Pharmacokinetics of rhG-CSF.
Two hours after administration of
rhG-CSF, serum rhG-CSF levels were significantly lower at neutrophilia
than at neutropenia (Fig. 1). Serum G-CSF
concentrations before rhG-CSF injection were 0.084 ± 0.059 (mean ± standard deviation [SD]) ng/ml at neutropenia and
0.517 ± 0.248 ng/ml at neutrophilia. G-CSF levels before rhG-CSF injection were too small to influence the difference in serum G-CSF
levels after administration. The individual pharmacokinetic parameters
of rhG-CSF are summarized in Table 2.
AUC0- and t1/2 were
significantly smaller (P < 0.01) and shorter
(P < 0.05), respectively, at neutrophilia than at
neutropenia. In contrast, the CL was significantly higher at
neutrophilia than at neutropenia (P < 0.01). There was
no significant difference in Vd between the
period of neutropenia and that of neutrophilia.
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FIG. 1.
Serum G-CSF levels on the days of neutropenia and
neutrophilia after intravenous bolus injection of 5 µg of rhG-CSF per
kg. Open circles, neutropenia; closed circles, neutrophilia. Data are
expressed as means ± SDs (n = 5). *,
P < 0.05, and  , P < 0.01, versus
neutropenia value.
|
|
rhG-CSF clearance and G-CSF receptors on neutrophils.
In three
healthy individuals, the percentage of G-CSF receptor-positive
neutrophils was 84.7% ± 0.02% (mean ± SD). The percentage at
the time of chemotherapy-induced neutropenia without rhG-CSF therapy
was 44.5% ± 22.1%, which was significantly lower than that in
healthy individuals (P < 0.05). Furthermore, the
percentage at neutrophilia following rhG-CSF therapy (73.0% ± 11.4%)
was significantly higher than that at neutropenia (44.5% ± 22.1%; P < 0.01) (Fig. 2). As
shown in Fig. 3, there was a positive
correlation among CL of rhG-CSF and the number of circulating
neutrophils (r2 = 0.72; P < 0.005) and the
percentage of G-CSF receptor-positive neutrophils (r2 = 0.91; P < 0.0001).
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|
FIG. 2.
Relationship between number of circulating neutrophils
and percentage of G-CSF receptor-positive neutrophils. P
is < 0.01 between the percentages at neutropenia (open circles)
and neutrophilia (closed circles).
|
|
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FIG. 3.
Correlation between rhG-CSF clearance and number of
circulating neutrophils (upper panel) and percentage of G-CSF
receptor-positive neutrophils (lower panel). Open circles, neutropenia;
closed circles, neutrophilia.
|
|
| |
DISCUSSION |
The present study demonstrated that treatment with rhG-CSF
following chemotherapy increased the number of G-CSF receptors per cell
as well as the number of neutrophils in cancer patients. The
rhG-CSF clearance closely correlated with both the number of G-CSF
receptors per cell and that of circulating neutrophils. Results of
previous studies indicated that hematopoietic cytokines exhibit common
regulatory mechanisms, and a similar relationship between cytokine
clearance and the number of target cells has been described elsewhere
for rhG-CSF, recombinant human macrophage CSF, recombinant human
granulocyte-macrophage CSF, and rhEPO (9). In addition,
upregulation of receptor mRNA by the ligand has also been reported for
G-CSF and interleukin 2 (12, 17, 19). However, to our
knowledge, no in vivo study has previously reported the relationship
between G-CSF receptor and neutrophils or rhG-CSF clearance.
rhG-CSF is eliminated through saturable and unsaturable mechanisms. In
a rat model, a high dose of rhG-CSF decreases clearance to a plateau
level, and clearance of a high dose of rhG-CSF is abrogated by
nephrectomy (15). In humans, a high intravenous dose of
rhG-CSF (
10 µg/kg) also decreases clearance to a plateau level
(6). Clearance of rhG-CSF administered subcutaneously is
inversely correlated with circulating neutrophil counts (13, 14), and clearance of rhG-CSF administered intravenously
decreases in patients with renal failure (1). These
findings indicate that saturable and unsaturable clearance
mechanisms of rhG-CSF mainly involve the neutrophils and kidneys,
respectively. In this study, since creatinine clearance did not change
during rhG-CSF therapy, the kidney was probably not involved in the
observed change in rhG-CSF clearance.
At the time of chemotherapy-induced neutropenia, the number of G-CSF
receptors per cell decreased to almost half the level found in healthy
individuals. G-CSF receptors are normally present on myeloid progenitor
cells to peripheral neutrophils (2). The number of receptors
per cell increases with differentiation, and neutrophils in bone marrow
have fewer receptors than do peripheral neutrophils
(1). On the other hand, chemotherapy has been shown to
inhibit the functions of peripheral neutrophils, but to our knowledge,
no study of G-CSF receptors has been reported. There are two possible
explanations for the reduced number of G-CSF receptors per cell
observed in the present study: (i) increased release of neutrophils
from bone marrow and (ii) direct inhibition by chemotherapy.
Treatment with rhG-CSF increased the percentage of G-CSF
receptor-positive neutrophils to 73.0%. In a series of
preliminary studies, when the neutrophil count spontaneously returned
to the prechemotherapy level without rhG-CSF therapy, the percentage of
G-CSF receptor-positive neutrophils remained low (51.5% ± 11.8%; n = 4). Other investigators have shown that rhG-CSF
enhances the expression of G-CSF receptor mRNA in human neutrophils in
vitro (17), supporting our results in vivo. Steinman and
Tweardy (12) reported that the upregulation of murine G-CSF
receptor mRNA by rhG-CSF is rapid and due to transcriptional activation
without the synthesis of new protein. rhG-CSF increased not only the
number of circulating neutrophils but also the density of neutrophil G-CSF receptors, which accelerated the increase in the total number of
G-CSF receptors. We also showed that rhG-CSF clearance closely correlated with the number of G-CSF receptors per neutrophil. Accordingly, rhG-CSF is thought to be eliminated through G-CSF receptors on neutrophils rather than by nonspecific endocytosis by neutrophils.
G-CSF receptors are also expressed on platelets, monocytes, endothelial
cells, and certain cancer cell lines (2). Soluble G-CSF receptors, anti-G-CSF antibodies, proteases, and G-CSF
receptor antagonists such as complement component C5a are present
in peripheral blood (2, 9). Accordingly, these receptors and
substances may modify G-CSF clearance. However, platelet and monocyte
counts did not change significantly in this study, and the density of G-CSF receptors on neutrophils accounted for as much as 91% of rhG-CSF
clearance. In rats treated with cyclophosphamide, rhG-CSF enhanced the
expression of G-CSF receptor mRNA on bone marrow cells but not that of
soluble G-CSF receptors when serum rhG-CSF levels dropped
(7). Although rhG-CSF therapy induces circulating anti-G-CSF antibodies, the antibodies do not inhibit cytokine function (5). To our knowledge, no study has previously
reported the in vivo role of circulating proteases, receptor
antagonists, or G-CSF receptors in cancer cell lines. These findings
suggest that G-CSF receptors on cells other than neutrophils and
circulating G-CSF-related substances are unlikely to contribute to
changes in rhG-CSF clearance following chemotherapy.
In conclusion, rhG-CSF increased the density of G-CSF receptors on
neutrophils, which closely correlated with rhG-CSF clearance. The
pharmacokinetics of rhG-CSF are probably modulated in a complex fashion, and further studies are necessary to determine the optimal usage of rhG-CSF.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: The Second
Department of Internal Medicine, Nagasaki University School of
Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. Phone:
81-(95)-849-7274. Fax: 81-(95)-849-7285. E-mail:
okamikio{at}net.nagasaki-u.ac.jp.
| |
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Antimicrobial Agents and Chemotherapy, January 1999, p. 21-24, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
