title: Vaccinia virus-mediated expression of human erythropoietin in tumors enhances virotherapy and alleviates cancer-related anemia in mice.
abstract: Recombinant human erythropoietin (rhEPO), a glycoprotein hormone regulating red blood cell (RBC) formation, is used for the treatment of cancer-related anemia. The effect of rhEPO on tumor growth, however, remains controversial. Here, we report the construction and characterization of the recombinant vaccinia virus (VACV) GLV-1h210, expressing hEPO. GLV-1h210 was shown to replicate in and kill A549 lung cancer cells in culture efficiently. In mice bearing A549 lung cancer xenografts, treatment with a single intravenous dose of GLV-1h210 resulted in tumor-specific production and secretion of functional hEPO, which exerted an effect on RBC progenitors and precursors in the mouse bone marrow, leading to a significant increase in the number of RBCs and in the level of hemoglobin. Furthermore, virally expressed hEPO, but not exogenously added rhEPO, enhanced virus-mediated green fluorescent protein (GFP) expression in tumors and subsequently accelerated tumor regression when compared with the treatment with the parental virus GLV-1h68 or GLV-1h209 that expressed a nonfunctional hEPO protein. Moreover, intratumorally expressed hEPO caused enlarged tumoral microvessels, likely facilitating virus spreading. Taken together, VACV-mediated intratumorally expressed hEPO not only enhanced oncolytic virotherapy but also simultaneously alleviated cancer-related anemia.
authors.affiliation: Department of Biochemistry, Rudolph Virchow Center for Experimental Biomedicine, and Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Duong H
authors.initials: DH
authors.lastname: Nguyen
authors.forename: Nanhai G
authors.initials: NG
authors.lastname: Chen
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ha T
authors.initials: HT
authors.lastname: Le
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Aguilar
authors.forename: Yong A
authors.initials: YA
authors.lastname: Yu
authors.forename: Joseph
authors.initials: J
authors.lastname: Cappello
authors.forename: Aladar A
authors.initials: AA
authors.lastname: Szalay
mesh_terms: D000740:Anemia / Q000150:complications / Q000628:therapy*; D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D006801:Humans; D008114:Liver Neoplasms, Experimental; D008175:Lung Neoplasms / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000378:metabolism; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: C554270:EPO protein, human; D011994:Recombinant Proteins; C485184:enhanced green fluorescent protein; D004921:Erythropoietin; D049452:Green Fluorescent Proteins