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.
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
W P
WP
Petros
J
J
Rabinowitz
J P
JP
Gibbs
I H
IH
Hall
A R
AR
Stuart
W P
WP
Peters
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