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© 2011 Benito et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Recent studies indicate that interactions between leukemia cells and the bone marrow (BM) microenvironment promote leukemia cell survival and confer resistance to anti-leukemic drugs. There is evidence that BM microenvironment contains hypoxic areas that confer survival advantage to hematopoietic cells. In the present study we investigated whether hypoxia in leukemic BM contributes to the protective role of the BM microenvironment. We observed a marked expansion of hypoxic BM areas in immunodeficient mice engrafted with acute lymphoblastic leukemia (ALL) cells. Consistent with this finding, we found that hypoxia promotes chemoresistance in various ALL derived cell lines. These findings suggest to employ hypoxia-activated prodrugs to eliminate leukemia cells within hypoxic niches. Using several xenograft models, we demonstrated that administration of the hypoxia-activated dinitrobenzamide mustard, PR-104 prolonged survival and decreased leukemia burden of immune-deficient mice injected with primary acute lymphoblastic leukemia cells. Together, these findings strongly suggest that targeting hypoxia in leukemic BM is feasible and may significantly improve leukemia therapy.

Details

Title
Pronounced Hypoxia in Models of Murine and Human Leukemia: High Efficacy of Hypoxia-Activated Prodrug PR-104
Author
Benito, Juliana; Shi, Yuexi; Szymanska, Barbara; Hernan, Carol; Boehm, Ingrid; Lu, Hongbo; Konoplev, Sergej; Fang, Wendy; Zweidler-McKay, Patrick A; Campana, Dario; Borthakur, Gautam; Bueso-Ramos, Carlos; Shpall, Elizabeth; Thomas, Deborah A; Jordan, Craig T; Kantarjian, Hagop; Wilson, William R; Lock, Richard; Andreeff, Michael; Konopleva, Marina
First page
e23108
Section
Research Article
Publication year
2011
Publication date
Aug 2011
Publisher
Public Library of Science
e-ISSN
19326203
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1307534573
Copyright
© 2011 Benito et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.