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Haematologica. 2018 Jun;103(6):1054-1064. doi: 10.3324/haematol.2017.178376. Epub 2018 Feb 22.

A second-generation 15-PGDH inhibitor promotes bone marrow transplant recovery independently of age, transplant dose and granulocyte colony-stimulating factor support.

Author information

1
Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
2
Department of Pathology, Ulsan University College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
3
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
4
University Hospitals Seidman Cancer Center, Cleveland, OH, USA.
5
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
6
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
7
Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
8
Department of Medicine, Case Western Reserve University, Cleveland, OH, USA sxm10@case.edu.

Abstract

Hematopoietic stem cell transplantation following myeloablative chemotherapy is a curative treatment for many hematopoietic malignancies. However, profound granulocytopenia during the interval between transplantation and marrow recovery exposes recipients to risks of fatal infection, a significant source of transplant-associated morbidity and mortality. We have previously described the discovery of a small molecule, SW033291, that potently inhibits the prostaglandin degrading enzyme 15-PGDH, increases bone marrow prostaglandin E2, and accelerates hematopoietic recovery following murine transplant. Here we describe the efficacy of (+)-SW209415, a second-generation 15-PGDH inhibitor, in an expanded range of models relevant to human transplantation. (+)-SW209415 is 10,000-fold more soluble, providing the potential for intravenous delivery, while maintaining potency in inhibiting 15-PGDH, increasing in vivo prostaglandin E2, and accelerating hematopoietic regeneration following transplantation. In additional models, (+)-SW209415: (i) demonstrated synergy with granulocyte colony-stimulating factor, the current standard of care; (ii) maintained efficacy as transplant cell dose was escalated; (iii) maintained efficacy when transplant donors and recipients were aged; and (iv) potentiated homing in xenotransplants using human hematopoietic stem cells. (+)-SW209415 showed no adverse effects, no potentiation of in vivo growth of human myeloma and leukemia xenografts, and, on chronic high-dose administration, no toxicity as assessed by weight, blood counts and serum chemistry. These studies provide independent chemical confirmation of the activity of 15-PGDH inhibitors in potentiating hematopoietic recovery, extend the range of models in which inhibiting 15-PGDH demonstrates activity, allay concerns regarding potential for adverse effects from increasing prostaglandin E2, and thereby, advance 15-PGDH as a therapeutic target for potentiating hematopoietic stem cell transplantation.

PMID:
29472361
PMCID:
PMC6058768
DOI:
10.3324/haematol.2017.178376
[Indexed for MEDLINE]
Free PMC Article

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