Indomethacin augments granulocyte-macrophage colony-stimulating factor-induced hematopoiesis following 5-FU treatment.
We have previously reported that granulocyte-macrophage colony-stimulating factor (GM-CSF) given after the administration of 5-fluorouracil (5-FU) results in augmented hematopoietic recovery as evidenced by increased white blood cell and neutrophil counts. Mice receiving GM-CSF following 5-FU administration were observed to have a marked elevation in splenic granulocyte-macrophage colony-forming cells (GM-CFC) and a decrease in the femoral bone marrow GM-CFC. Because GM-CSF has been shown to increase prostaglandin synthesis and prostaglandins are thought to provide a negative feedback signal to down-regulate myelopoiesis, we sought to determine if the cyclooxygenase inhibitor, indomethacin, could prevent the reduction in the number of femoral bone marrow GM-CFC seen when GM-CSF was administered following 5-FU. Groups of mice received a single 60 mg/kg i.p. injection of 5-FU followed 24 h later by twice-daily injections of 1 micrograms GM-CSF and daily injections of 3, 5, or 6 mg/kg indomethacin; the hematopoietic assays were performed on day 7 following 5-FU. Compared to those animals that received GM-CSF alone following 5-FU, mice receiving 5 mg/kg indomethacin plus GM-CSF following 5-FU had increased numbers of GM-CFC in their bone marrow (3923 +/- 634 vs 971 +/- 138; p less than 0.001) as well as increased neutrophil counts (18,995 +/- 2872 vs 11,497 +/- 2476; p less than 0.01). Indomethacin alone was, in part, capable of facilitating hematopoietic recovery following 5-FU administration, but not to the extent seen when used in combination with GM-CSF. Prostaglandin inhibitors may have a role in combination with hematopoietic growth factors in accelerating hematopoietic recovery following cytoreductive chemotherapy.
O'Reilly
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Department of Surgery, University of Vermont, Burlington 05405.
Gamelli
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D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects*; D007213:Indomethacin / Q000494:pharmacology*; D007375:Interleukin-1 / Q000096:biosynthesis; D007958:Leukocyte Count; D008297:Male; D051379:Mice
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D007375:Interleukin-1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D005472:Fluorouracil; D007213:Indomethacin