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Figure 6. (+)-SW209415 promotes bone marrow homing of human umbilical cord and human bone marrow hematopoiesis stem cells. (A) Irradiated (2.5Gy) 8- week old female NSG mice were transplanted with 20*106 CFSE-labeled total human umbilical cord blood buffy coat (3 samples transplanted into 4 mice/condition/sample) or total human marrow aspirate cells (2 samples transplanted into 3 mice/condition/sample). Mice were treated with either vehicle or 2.5 mg/kg (+)-SW209415 immediately after irradiation, after bone marrow transplantation (BMT), and 8 hours (h) after BMT. Graphs show mean and Standard Error of Mean for % of CFSE-labeled human donor cells homing to murine marrow. *Student t-test P<0.05. (B) Irradiated (2.5 Gy) 8-week old male NSG mice were trans- planted with 1*106 white blood cells from 2 unique bone marrow aspirate donors and treated with either vehicle or 2.5mg/kg (+)-SW209415 twice daily for 21 days. Peripheral blood was collected at multiple intervals after transplant and human CD45 measured via flow cytometry.
15-PGDH inhibition in multiple models of murine BMT
ranging from 3-10% of human cells (data not shown). These data support that effects of (+)-SW209415 in accelerating HSCT recovery will translate to humans as well.
(+)-SW209415 does not affect in vivo growth of human hematopoietic cancer cells
Although hematopoietic growth factors such as G-CSF have been safely administered to human HSCT patients with hematologic malignancies, concerns have been raised regarding potential effects of increasing bone mar- row PGE2 on growth of human cancer cells.26 To address this issue, we examined the effects of (+)-SW209415 on in vivo growth of xenografted cancer cells from a human AML and from a human MM, two cancers that are com- monly treated by HSCT. We established cohorts of NSG mice xenotransplanted with primitive human AML blasts or with human MM cells, and treated these mice with (+)- SW209415 2.5 mg/kg twice daily for 21 days, or with vehicle control. In both AML and MM xenotransplanted cohorts, administering (+)-SW209415 showed no effect on the rate of decline of animal weights and no effect on the number of human cancer cells that expanded in the mouse bone marrow (Figure 7A,B). While further studies with additional hematopoietic tumor models are warranted, these first experimental results do not support the hypoth- esis that a doubling of bone marrow PGE2 will potentiate the in vivo growth of human cancer cells.
A
Humans with homozygous inactivating mutations of 15-PGDH show chronically elevated PGE2 levels, but except for development of digital clubbing are otherwise phenotypically normal.27-32 However, a subset of individu- als with mutations that inactivate SLCO2A1, the trans- porter that carries PGE2 to 15-PGDH, have been reported to develop myelofibrosis.33 As myelofibrosis has been observed in only some of these individuals, the question has arisen as to whether this finding is related to the increased PGE2 seen with loss of SLCO2A1, or whether it might be due to other genetic defects in these individuals who were all offspring of consanguineous marriages. To investigate this issue, we examined bone marrow from mice following 30 days of twice daily treatment with 2.5 mg/kg (+)-SW209415 or with vehicle control. The poten- tial development of bone marrow fibrosis was assessed by reticulin staining. Essentially no myelofibrosis was detect- ed in either control or (+)-SW209415-treated mice (Online Supplementary Figure S11). While longer term studies remain warranted, these initial results mitigate concerns of bone marrow fibrosis as a potential toxicity from treat- ment with (+)-SW209415.
(+)-SW209415 does not show off-target toxicity
As an additional evaluation, we examined for potential off-target toxicities that might be induced by (+)- SW209415. Mice were treated twice daily for 21 days
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