title: Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104.
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.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Juliana
authors.initials: J
authors.lastname: Benito
authors.forename: Yuexi
authors.initials: Y
authors.lastname: Shi
authors.forename: Barbara
authors.initials: B
authors.lastname: Szymanska
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.forename: Ingrid
authors.initials: I
authors.lastname: Boehm
authors.forename: Hongbo
authors.initials: H
authors.lastname: Lu
authors.forename: Sergej
authors.initials: S
authors.lastname: Konoplev
authors.forename: Wendy
authors.initials: W
authors.lastname: Fang
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Zweidler-McKay
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueso-Ramos
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Shpall
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Thomas
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
authors.forename: Richard
authors.initials: R
authors.lastname: Lock
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012074:Remission Induction; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; C522381:PR-104; D011355:Prodrugs; D017493:Leukocyte Common Antigens