In vivo modulation of myelopoiesis by prostaglandin E2. II. Inhibition of granulocyte-monocyte progenitor cell (CFU-GM) cell-cycle rate

Abstract

The effects of in vivo administration of native prostaglandin E2 (PGE) on the cycling status of the granulocyte-monocyte progenitor cell (CFU-GM) were examined in a mouse model. In mice hematopoietically rebounding from a sublethal dose of cyclophosphamide, intravenous injection of PGE in doses ranging from 100 to 10(-4) micrograms/mouse/day over three days, significantly decreased the absolute number of CFU-GM per femur and the percentage of CFU-GM in the S-phase of the cell cycle. Administration of PGE2, 10 micrograms/mouse/day, over three days to steady-state mice resulted in significant suppression of the absolute number of CFU-GM per femur, but was without effect on CFU-GM cycling. However, when an additional PGE2 injection was included on day 4 and mice killed 6 h later, inhibition of both parameters was observed. Single bolus injection of PGE2 into steady-state mice was found to have the identical effect. Inhibition of the absolute number of CFU-GM per femur and percentage of CFU-GM in S-phase were apparent 6 h after injection of a single dose of 10 micrograms PGE, with a loss of effect on CFU-GM cycling status 12-14 h after injection. The inhibitory effect of PGE2 on the absolute number of CFU-GM per femur persisted for two days after injection. These studies confirmed the cell-cycle effects of PGE, heretofore demonstrated only in vitro; illustrated the importance of timing and dose analysis when examining the effects of hematopoietic inhibitors in vivo; and suggested that PGE2 may be useful as an adjunct to chemotherapy in ameliorating myelotoxicity. Furthermore, dose-response analysis revealed an enhanced in vivo sensitivity of macrophage progenitor cells (M-CFC) to the inhibitory effects of injected PGE2. Inhibition of in vivo incorporation of tritiated thymidine (3HTdr) into bone marrow CFU-GM by PGE could also be demonstrated.