title: Continuous delivery of human type I interferons (alpha/beta) has significant activity against acute myeloid leukemia cells in vitro and in a xenograft model.
abstract: In this study, we focused primarily on the antileukemic activity of interferon-beta (IFN-beta) in a murine xenograft model of acute myeloid leukemia (AML). Bolus administration of recombinant IFN-beta via the subcutaneous or intravenous route failed to show efficacy in mice injected with AML cells despite achieving peak plasma IFN-beta levels of more than 200 IU/mL. In contrast, stable expression of IFN-beta following adeno-associated virus (AAV) vector-mediated gene transfer resulted in significant antileukemic activity against primary AML cells derived from patients with poor prognostic markers. An almost linear relationship was observed with stable plasma levels of IFN-beta and antileukemic activity in mice. Even levels below 10 IU/mL were able to reduce tumor load by 50-fold when compared with control animals. These levels of IFN-beta are likely to be nontoxic in humans. Therefore, approaches capable of maintaining stable plasma levels of IFN-beta merit further clinical evaluation in patients with AML.
authors.affiliation: Department of Haematology, University College London, UK, and Division of Experimental Hematology, Department of Surgery, St. Jude's Children's Research Hospital, Memphis, TN, USA.
authors.forename: Reuben
authors.initials: R
authors.lastname: Benjamin
authors.forename: Asim
authors.initials: A
authors.lastname: Khwaja
authors.forename: Nalini
authors.initials: N
authors.lastname: Singh
authors.forename: Jenny
authors.initials: J
authors.lastname: McIntosh
authors.forename: Anthony
authors.initials: A
authors.lastname: Meager
authors.forename: Meenu
authors.initials: M
authors.lastname: Wadhwa
authors.forename: Christian
authors.initials: C
authors.lastname: Streck
authors.forename: Catherine
authors.initials: C
authors.lastname: Ng
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.forename: Amit C
authors.initials: AC
authors.lastname: Nathwani
mesh_terms: D000208:Acute Disease; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004353:Drug Evaluation, Preclinical; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage / Q000494:pharmacology; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology; D016899:Interferon-beta / Q000008:administration & dosage* / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D051379:Mice; D014162:Transfection; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D007370:Interferon Type I; D016898:Interferon-alpha; D016899:Interferon-beta