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er on days 12 and 18 after BMT than those achieved in the vehicle-treated control animals, while mice that received only 7 days of (+)-SW209415 showed no significant differ- ence in neutrophil counts on day 12 and a moderate increase on day 18 (Online Supplementary Figure S6). Moreover, while mice that received (+)-SW209415 contin- uously had a nearly 4-fold increase in bone marrow SKL cells (from 3707 to 14007, P=0.0026), mice that received only 7 days of (+)-SW209415 had only a 1.54-fold increase that did not reach statistical significance (Online Supplementary Figure S7). Collectively, these observations suggest that continuous in vivo dosing with the 15-PGDH inhibitor (+)-SW209415 optimally promotes improvement in hematopoietic recovery following murine BMT.
(+)-SW209415 accelerates neutrophil recovery after bone marrow transplantation even in mice treated with granulocyte colony-stimulating factor
G-CSF (clinical names, Lenograstim and Filgrastim) is a Food and Drug Administration-approved glycoprotein that is the standard of care used to accelerate granulocyte recovery after human HSCT. As initial human studies of (+)-SW209415 would almost certainly be done in HSCT patients also receiving G-CSF, we used mice to model the effects of (+)-SW209415 in comparison to and in combina- tion with G-CSF. On post-transplant day 8 neutrophil counts were significantly higher in (+)-SW209415-treated mice (339x103 cells/mL, P<0.0001), and also in G-CSF- treated mice (295x103 cells/mL, P<0.0001), than in mice
treated with vehicle control (150x103 cells/mL). However, mice treated with the combination of (+)-SW209415 and G-CSF developed 466x103 neutrophils/mL, which was sig- nificantly higher than the levels in mice treated with either (+)-SW209415 (P=0.0041) or G-CSF (P<0.0001) alone (Figure 3). Moreover, although, as compared to vehicle control, either (+)-SW209415 or G-CSF alone significantly increased neutrophil counts on post-HSCT days 8, 12 and 18, mice treated with the combination of (+)-SW209415 and G-CSF showed the highest neutrophil counts on each of these days (P=0.002 for the combination vs. (+)- SW209415, P=0.01 for the combination vs. G-CSF) (Figure 3). Furthermore, on day 12, the increase in the number of neutrophils in mice treated with the combination of (+)- SW209415 and G-CSF (an increase of 963x103 cells/mL over that in vehicle-treated mice) essentially equaled the additive increments of the two agents when given individ- ually (412x103/mL for (+)-SW209415 and 555x103/mL for G- CSF, or the predicted additive effect of 967x103 cells/mL). Similarly, on day 8, the increase in number of neutrophils in mice treated with the combination of (+)-SW209415 and G-CSF (an increase of 316x103 cells/mL over that in the vehicle-treated mice) nearly equaled the additive incre- ments produced by the two agents when given individu- ally (189x103/mL for (+)-SW209415 and 145x103/mL for G- CSF, or the additive effect of 334x103 cells/mL). Furthermore, on post-HSCT day 18, mice treated with the combination of (+)-SW209415 plus G-CSF also showed the highest numbers of bone marrow SKL cells (Figure 3).
Figure 3. (+)-SW209415 accelerates neutrophil recovery after bone marrow transplantation (BMT) in mice treated with granulocyte colony-stimulating factor. Lethally irradiated (11 Gy) 8- week old female C57/BL6J mice were transplanted with 500x103 total bone marrow cells and treated with either vehicle, 2.5 mg/kg (+)-SW209415 (twice daily, intraperitoneally), 250 mg/kg human G-CSF (once daily, subcu- taneously), or the combination. The graphs display the means and Standard Error of Mean of peripheral blood neutrophil counts on days 8, 12, and 18 after BMT and bone marrow SKL cell numbers determined in mice sacrificed on day 18 (13 mice/arm). *Student t-test P<0.05.
haematologica | 2018; 103(6)