Kinetics of serum granulocyte-colony stimulating factor (G-CSF) concentration and G-CSF receptor expression during G-CSF treatment of cyclophosphamide-treated mice.
We analyzed the kinetics of leukocyte number, serum granulocyte colony stimulating factor (G-CSF) concentration, and G-CSF receptor expression in mice after recombinant human (rh) G-CSF treatment. Intraperitoneal (i.p.) injection with 200 mg/kg of cyclophosphamide (CP) induced a transient decrease of leukocyte number in blood and spleen. Daily i.p. inoculation of a low dose of rhG-CSF (1 microgram/kg/day) from day 1 of CP injection for 8 days resulted in a significant increase of spleen cell number from day 5 to day 8, while serum rhG-CSF concentration decreased to an undetectable level on day 7. Furthermore, daily i.p. inoculation of high dose rhG-CSF (100 micrograms/kg/day) for 5 days to CP-injected mice induced a significant increase of leukocytes from day 3 to day 6 in both peripheral blood and spleen, and the increase was higher than that observed after low dose G-CSF treatment. In the course of the high dose rhG-CSF treatment, however, serum rhG-CSF concentration decreased from day 3, which is earlier than the decrease of serum rhG-CSF seen after low dose rhG-CSF treatment. A reverse transcription-polymerase reaction analysis of mRNA expression showed that spleen cells from high dose rhG-CSF-treated mice on day 4 and day 6 expressed more than 10 times higher levels of membrane G-CSF receptors than did those obtained before rhG-CSF treatment. All these results suggest that decrease of serum G-CSF during daily G-CSF treatment does not always indicate neutralization of G-CSF, but implies that the inoculated G-CSF is still stimulating granulocytes and their precursors by binding to membrane G-CSF receptors which are up-regulated by G-CSF treatment. This observation is important when we measure pharmacokinetics of G-CSF in patients chronically injected with G-CSF.
Matsuzaki
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G
Department of Immunology, Kyushu University, Fukuoka, Japan.
Li
X Y
XY
Ohyama
Y
Y
Nomoto
K
K
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology*; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007274:Injections, Intraperitoneal; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009503:Neutropenia / Q000139:chemically induced / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins; D013154:Spleen / Q000166:cytology / Q000187:drug effects
D018906:Antineoplastic Agents, Alkylating; D016376:Oligonucleotides, Antisense; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide