Effect of plasma TNF-alpha on filgrastim-stimulated hematopoiesis in mice and humans.
OBJECTIVE
To delineate possible explanations for a nonmonotone hematopoiesis, dose-response curve with filgrastim therapy after high-dose chemotherapy


METHODS
Sequential two-phase study.


METHODS
University teaching hospital and basic pharmaceutical sciences laboratory.


METHODS
Thirty-nine patients with breast cancer or melanoma and 15 normal CF-1 male mice.


METHODS
Serial blood samples were obtained from patients after high-dose chemotherapy to evaluate hematopoiesis and tumor necrosis factor-alpha (TNF-alpha) concentrations. Murine hematopoiesis was induced by filgrastim with or without coadministration of lipopolysaccharide.


RESULTS
Detection of plasma TNF-alpha in patients corresponded to substantially slower recovery of granulocytes, erythrocytes, and platelets, and was directly proportional to the prescribed dosage of filgrastim. Lipopolysaccharide stimulated the secretion of TNF-alpha in mice and totally aberrated filgrastim-induced granulopoiesis.


CONCLUSIONS
This in vivo evidence suggests that regulatory pathways involving endogenous cytokines may override the effect of recombinant cytokines.
Petros
W P
WP
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Rabinowitz
J
J
Gibbs
J P
JP
Hall
I H
IH
Stuart
A R
AR
Peters
W P
WP
D000328:Adult; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D000069585:Filgrastim; D006023:Glycoproteins / Q000008:administration & dosage / Q000627:therapeutic use; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000627:therapeutic use; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy; D051379:Mice; D008875:Middle Aged; D015999:Multivariate Analysis; D011994:Recombinant Proteins; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000378:metabolism
D006023:Glycoproteins; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C082856:regramostim; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000069585:Filgrastim