Oncotarget

Research Papers:

The poison oligonucleotide F10 is highly effective against acute lymphoblastic leukemia while sparing normal hematopoietic cells

Timothy S. Pardee _, Kristin Stadelman, Jamie Jennings-Gee, David L. Caudell and William H. Gmeiner

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Oncotarget. 2014; 5:4170-4179. https://doi.org/10.18632/oncotarget.1937

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Abstract

Timothy S. Pardee1,2,3, Kristin Stadelman1,2, Jamie Jennings-Gee3, David L. Caudell4 and William H. Gmeiner3

1 Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC

2 Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC

3 Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC

4 Department of Pathology, Section of Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC

Correspondence:

Timothy S. Pardee, email:

Keywords: Acute lymphoblastic leukemia, Fluoropyrimidine, novel therapy

Received: April 22, 2014 Accepted: April 30, 2014 Published: May 1, 2014

Abstract

F10 is an oligonucleotide based on the thymidylate synthase (TS) inhibitory 5-fluorouracil (5-FU) metabolite, 5-fluoro-2’-deoxyuridine-5’-O-monophosphate. We sought to determine the activity of F10 against preclinical models of acute lymphoblastic leukemia (ALL). F10 treatment resulted in robust induction of apoptosis that could not be equaled by 100 fold more 5-FU. F10 was more potent than Ara-C and doxorubicin against a panel of murine and human ALL cells with an average IC50 value of 1.48 nM (range 0.07 to 5.4 nM). F10 was more than 1000 times more potent than 5-FU. In vivo, F10 treatment significantly increased survival in 2 separate syngeneic ALL mouse models and 3 separate xenograft models. F10 also protected mice from leukemia-induced weight loss. In ALL cells made resistant to Ara-C, F10 remained highly active in vitro and in vivo. Using labeled F10, uptake by the ALL cell lines DG75 and SUP-B15 was rapid and profoundly temperature-dependent. Both cell lines demonstrated increased uptake compared to normal murine lineage- depleted marrow cells. Consistent with this decreased uptake, F10 treatment did not alter the ability of human hematopoietic stem cells to engraft in immunodeficient mice.


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