Myelosuppression in the pig (Sus scrofa): uteroferrin reduces the myelosuppressive effects of 5-fluorouracil in young pigs.
The present study investigated the ability of uteroferrin to modulate the myelosuppressive effects of 5-fluorouracil (5-FU) in young pigs (Sus scrofa). Pigs (28-35 days of age; n = 6 per treatment) were infused with equal amounts of 5-FU on days 0 and 1 of the experimental period (37.5 mg/kg cumulative dose). Uteroferrin (100 micrograms/kg in 0.9% NaCl) or control (equivalent volume of 0.9% NaCl) was administered to pigs as intramuscular injections twice daily (08:00 and 20:00 hr) on days 1 through 21. Peripheral blood cell number, composition and progenitor cells were determined over 28 days. Treatment of pigs with 5-FU resulted in a rapid dose-dependent (P < 0.05) leukocytopenia. Concurrent treatment of pigs with uteroferrin reduced (P < 0.05) the rate of 5-FU-induced leukocytopenia (44 vs 77 +/- 7% decline from baseline on day 3) and enhanced (P < 0.05), the recovery from 5-FU on days 10 and 12 postinfusion. The positive effect of uteroferrin on leukocytes resulted primarily from a protection and/or enhanced recovery of neutrophils and monocytes. In addition, uteroferrin attenuated (P < 0.05) the suppression of red blood cell numbers after 5-FU administration (6.9 vs 6.1 +/- 0.2 x 10(6) cells/microliter on day 3), an affect reflected in increased hematocrit and hemoglobin concentrations. The effects of uteroferrin appeared to result from enhancement of the proliferation and/or differentiation of primitive pluripotent stem cells resistant to 5-FU, as concurrent treatment of pigs with uteroferrin resulted in a protection and/or enhanced recovery (P < 0.05) of CFU-GEMM, CFU-GM and BFU-E progenitor cells in the peripheral blood. These results are the first to demonstrate that uteroferrin can reduce the myelosuppressive effects of 5-FU in the pig and suggest that uteroferrin has hematopoietic growth factor activity in vivo.
Laurenz
J C
JC
Department of Animal Science, Texas A&M University, College Station 77843-2471, USA.
Hadjisavas
M
M
Chovanic
G W
GW
Bazer
F W
FW
D000135:Acid Phosphatase; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D004305:Dose-Response Relationship, Drug; D004906:Erythrocyte Count / Q000187:drug effects; D015672:Erythroid Precursor Cells / Q000187:drug effects; D005472:Fluorouracil / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D006400:Hematocrit; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007527:Isoenzymes; D007958:Leukocyte Count / Q000187:drug effects; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D008667:Metalloproteins / Q000494:pharmacology*; D013552:Swine; D000071681:Tartrate-Resistant Acid Phosphatase
D000964:Antimetabolites, Antineoplastic; D007527:Isoenzymes; D008667:Metalloproteins; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D005472:Fluorouracil