Synergistic effects of co-administration of angiotensin 1-7 and Neupogen on hematopoietic recovery in mice.
OBJECTIVE
Angiotensin 1-7 [A(1-7)] is a seven amino acid peptide that has been shown to increase the proliferation of epidermal stem cells after dermal injury and the number of hematopoietic progenitors in the bone marrow of myelosuppressed mice. In this study, the effect of combining A(1-7) with Neupogen on hematopoietic recovery and bone marrow progenitors was evaluated.


METHODS
Intravenous 5-fluorouracil (5FU) was administered to induce myelosuppression. Administration of A(1-7) and/or Neupogen was initiated 2 days after chemotherapy. Angiotensin II (AII) and A(1-7) binding were assessed by flow cytometric analysis. Hematopoietic progenitors were counted by colony forming assays. Recovery of formed elements in the blood was evaluated by hemocytometer.


RESULTS
Flow cytometric analysis indicated that the number of early hematopoietic progenitors (Lin(-)Sca1(+)cKit(+)) that bind AII or A(1-7) increased 5-7 days after intravenous injection of 150 mg/kg 5FU. Further, administration of A(1-7) led to a slight increase in the number of circulating leukocytes and platelets after this chemotherapeutic regimen. When given in combination with a subclinical dose of Neupogen, a synergistic effect on the number of circulating leukocytes was observed, but there was no further effect on the number of circulating platelets. In myelosuppressed mice, A(1-7) had its most profound effect on the number of hematopoietic progenitors in the bone marrow. The progenitors evaluated in the study included BFU-E, CFU-Meg, CFU-GM and CFU-GEMM. There was an increase in the number of these progenitors in the bone marrow, indicating an effect on all hematopoietic lineages. When given in combination with Neupogen, these effects were synergistic for the numbers of BFU-E and CFU-Meg (Neupogen by itself had no effect) and for the myeloid progenitors at lower doses of A(1-7).


CONCLUSIONS
These results suggest that these hematopoietic agents act at different sites within the hematopoietic cascade and that combining these two agents may be of benefit in the treatment of hematopoietic disorders.
University of Southern California, Keck School of Medicine, 1321 N Mission Road, Los Angeles, CA 90033, USA.
Dolph D
DD
Ellefson
Gere S
GS
diZerega
Theresa
T
Espinoza
Norma
N
Roda
Sonia
S
Maldonado
Kathleen E
KE
Rodgers
D000803:Angiotensin I / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D000069585:Filgrastim; D005434:Flow Cytometry; D005472:Fluorouracil / Q000633:toxicity; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D010976:Platelet Count; D011994:Recombinant Proteins
D007166:Immunosuppressive Agents; D010446:Peptide Fragments; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000803:Angiotensin I; C118790:angiotensin I (1-7); D000069585:Filgrastim; D005472:Fluorouracil