In vivo modulation of hematopoiesis by a novel hematoregulatory peptide.
The hematoregulatory peptide dimer, HP5B, enhances myelopoiesis by stimulating stromal cell cytokine production. However, the disulfide bridge of this peptide is susceptible to reduction, leading to the formation of monomeric pentapeptide, HP5, a direct-acting inhibitor of myelopoiesis. We have replaced the disulfide (S-S) bond of HP5B dimer with an isosteric ethylene (CH2-CH2) group, creating a new, nonreducible, metabolically more stable peptide (SK&F 107647). This novel peptide was tested in vitro and in vivo for hematopoietic effects. In vitro, SK&F 107647 has no direct colony-stimulating activity (CSA). Stimulation of murine stromal cells with SK&F 107647 results in production and release of CSA at concentrations as low as 0.01 ng/mL, at least 10-fold lower than observed with HP5B dimer. Injection of SK&F 107647 in normal mice results in a two- to six-fold increase in serum CSA, which becomes maximal at 6 hours postinjection. Administration of peptide daily over 4 days (q.d. x 4) by both parenteral and oral routes results in significant increases in absolute numbers of granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells, as well as stimulating their cell cycle rates. A doubling in day 8 CFU-S was also observed in SK&F 107647-treated mice. Continuous subcutaneous (s.c.) infusion of SK&F 107647 in femorally cannulated rats demonstrated modest but significant elevation of peripheral blood neutrophil and monocyte counts within 7 days. SK&F 107647 represents a novel synthetic hematoregulatory peptide that shares biological and/or modulatory activities with natural hematopoietic cytokines.
Pelus
L M
LM
Department of Anti-Infectives, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
King
A G
AG
Broxmeyer
H E
HE
DeMarsh
P L
PL
Petteway
S R
SR
Bhatnagar
P K
PK
D000284:Administration, Oral; D000818:Animals; D001853:Bone Marrow / Q000502:physiology; D001854:Bone Marrow Cells; D002453:Cell Cycle; D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000097:blood / Q000378:metabolism; D004220:Disulfides; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D007263:Infusions, Parenteral; D007279:Injections, Subcutaneous; D007962:Leukocytes / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology / Q000502:physiology; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D011916:Rats, Inbred F344; D013154:Spleen / Q000166:cytology / Q000502:physiology; D015854:Up-Regulation
D003115:Colony-Stimulating Factors; D004220:Disulfides; D006131:Growth Inhibitors; D009842:Oligopeptides; C086049:SK&F 107647; C040758:hemoregulatory peptide 5b; D011761:Pyrrolidonecarboxylic Acid