Cyclooxygenase-2 is essential for normal recovery from 5-fluorouracil-induced myelotoxicity in mice.
Cyclooxygenase (COX) plays a key regulatory role in prostaglandin synthesis. COX-2 is inducible and is the major isoform of inflammatory cells. COX-2-deficient mice were shown to have normal basal hematopoiesis and hematology. We hypothesized that COX-2 induction plays a role in the recovery phase of 5-fluorouracil (5-FU) induced bone marrow injury, because significant macrophage-driven phagocytic removal of necrotic debris and stromal cell reorganization of repopulating marrow occur after 5-FU induction of bone marrow necrosis. Hematologic recovery was markedly delayed with moderately severe leukopenia, thrombocytopenia and reticulocytopenia compared to heterozygotes on day 8 or 12 in Cox-2-/- mice. Mild anemia was present in 5-FU-treated Cox-2-/- and Cox-2+/- mice on days 8 and 12, which was more severe in Cox-2-/- mice. Cox-2-/- mice had markedly decreased bone marrow cell counts per femur and reduced numbers of erythroid and myeloid colony-forming cells compared to heterozygote mice on days 8 and 12 post 5-FU. Histologic examination of 5-FU-treated Cox-2-/- mice revealed a failure to repopulate the intact marrow stroma with hematopoietic cells. Accelerated erythropoiesis following phenylhydrazine-induced hemolytic anemia, however, was comparable between Cox-2-/- and Cox+/- mice, as were induced levels of renal erythropoietin mRNA. COX-2 induction is likely a central event in the accelerated hematopoiesis following myelotoxic injury, because recovery from 5-FU-induced myeloablation is markedly impaired in Cox-2-/- mice but is normal after phenylhydrazine induction of anemia.
Lorenz
M
M
DuPont Pharmaceuticals, Preclinical Research and Development, Safety Assessment, Newark, DE 19714-0030, USA.
Slaughter
H S
HS
Wescott
D M
DM
Carter
S I
SI
Schnyder
B
B
Dinchuk
J E
JE
Car
B D
BD
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001856:Bone Marrow Examination; D002452:Cell Count / Q000187:drug effects; D051546:Cyclooxygenase 2; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000378:metabolism; D005472:Fluorouracil / Q000633:toxicity*; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000378:metabolism; D019891:Leukopoiesis / Q000187:drug effects*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010659:Phenylhydrazines / Q000633:toxicity; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013997:Time Factors
D007527:Isoenzymes; D010659:Phenylhydrazines; D012333:RNA, Messenger; C030299:phenylhydrazine; D004921:Erythropoietin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005472:Fluorouracil