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with vehicle or with escalating doses of (+)-SW209415 over a range of doses from the therapeutically active dose of 2.5 mg/kg up to 10-fold above this, at 25 mg/kg. Parallel pharmacokinetic experiments confirmed dose-proportion- al increases in maximum and total plasma exposure (Cmax, area under the curve) over this dosing range. Administering (+)-SW209415 did not produce any adverse effects on mouse weights (Online Supplementary Figure S12), activity, or grooming. Additionally, administering (+)-SW209415 did not have adverse effects on peripheral blood counts (Online Supplementary Figure S12) or on any of a battery of serum chemistry values (Online Supplementary Table S1). These data suggest that (+)- SW209415 is without off-target toxicity at doses of up to 10-fold over the therapeutically active range.
Discussion
In summary, (+)-SW209415, a second-generation 15- PGDH inhibitor, provides independent chemical support that 15-PGDH is a therapeutic target whose inhibition accelerates hematopoietic recovery following HSCT. Moreover, these studies show that (+)-SW209415 advan- tages hematopoietic recovery across a broad range of models that newly interrogate key features of human
A
HSCT. Firstly, these studies demonstrate that (+)- SW209415 accelerates neutrophil recovery after HSCT in mice that are also treated with G-CSF, which supports that (+)-SW209415 will provide added benefit in human HSCT. Secondly, these studies demonstrate that (+)- SW209415 promotes hematopoietic recovery following HSCT in models in which both HSC donors and HSCT recipients are older. The current findings demonstrate that the pharmacodynamic activity of 15-PGDH and the downstream responses that potentiate bone marrow recovery both remain robust in older animals. Thirdly, these findings show that (+)-SW209415 advantages hematopoietic recovery, even when recovery is independ- ently accelerated by administering a 4-fold increased num- ber of donor HSC. This observation also suggests that (+)- SW209415 would provide benefit at doses of HSC typical- ly employed in human HSCT. Fourthly, and further sup- porting potential applicability of these findings to human HSCT, (+)-SW209415 potentiates homing of human HSC (that have multilineage differentiation capacity) when assayed by xenotransplantation into lethally irradiated NSG mice. Our further findings that the efficacy of (+)- SW209415 is maximal when the drug is administered twice daily throughout the full period of bone marrow recovery informs the optimal method for administering 15-PGDH inhibitors in HSCT and also supports that the
B
Figure 7. (+)-SW209415 does not effect in vivo growth of human hematopoietic cancer cells. Irradiated (2.5Gy) 8-week old male NSG mice were transplanted with 5*106 human acute myeloid leukemia (AML) (A) or multiple myeloma (MM) cells (B). Two weeks after transplant mice began intraperitoneal treatment with either vehicle or 2.5 mg/kg (+)-SW209415 twice daily for 21 days. Upon signs of impending animal death (hunching, limited mobility) mice were sacrificed and the frequen- cy of human CD45+ cells (for AML) or human CD38+ cells (for MM) in mouse marrow was measured via flow cytometry (4 mice/arm). Graphs show means and Standard Error of Mean for animal weights and for human cancer cell numbers in the mouse bone marrow.
haematologica | 2018; 103(6)