title: Measles vaccine strains for virotherapy of non-small-cell lung carcinoma.
abstract: BACKGROUND
  Oncolytic virus therapy is a promising therapy for numerous tumor types. Edmonston-strain measles virus (MV) has been tested in clinical trials for ovarian cancer, glioma, and myeloma. Therefore, the antitumor activity of MV against non-small-cell lung cancer (NSCLC) was assessed.
  
  
  METHODS
  Human NSCLC cells and immortalized lung epithelial cell lines, Beas2B, were infected with either MV-producing green fluorescent protein or MV-producing carcinoembryonic antigen. Cells were assessed for viability, induction of apoptosis by caspase and poly-ADP ribose polymerase cleavage, and for viral transgene production. The dependency of MV entry on CD46 and nectin-4 were determined using blocking antibodies. The role of host translational activity on viral replication was assessed by overexpression of eIF4E and translation inhibition. Antitumor activity was assessed by measuring treated NSCLC xenografts from flanks of nude mice.
  
  
  RESULTS
  MV infection of NSCLC cells results in potent cell killing in most of the cell lines compared with immortalized Beas2B cells and induces apoptosis. MV infection was prevented by blocking of CD46, however independent of nectin-4 blockade. Tumor weights are diminished after intratumoral injections of MV-producing carcinoembryonic antigen in one of two cell lines and result in detectable viral transgene in serum of mice.
  
  
  CONCLUSIONS
  These data indicate that MV is oncolytic for human NSCLC and this was independent of nectin-4 expression. Dysregulated protein translational machinery may play a role in determining tumor tropism in NSCLC. MV combined with gemcitabine could be explored further as chemovirotherapy for NSCLC.
authors.affiliation: *Division of Hematology, Oncology, and Transplantation, University of Minnesota Medical School, Minneapolis; and †Department of Molecular Medicine, Mayo Clinic Medical Center, Rochester, MN.
authors.forename: Manish R
authors.initials: MR
authors.lastname: Patel
authors.forename: Blake A
authors.initials: BA
authors.lastname: Jacobson
authors.forename: Holly
authors.initials: H
authors.lastname: Belgum
authors.forename: Ahmad
authors.initials: A
authors.lastname: Raza
authors.forename: Ahad
authors.initials: A
authors.lastname: Sadiq
authors.forename: Jeremy
authors.initials: J
authors.lastname: Drees
authors.forename: Hengbing
authors.initials: H
authors.lastname: Wang
authors.forename: Joseph
authors.initials: J
authors.lastname: Jay-Dixon
authors.forename: Ryan
authors.initials: R
authors.lastname: Etchison
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Federspiel
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Russell
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kratzke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D002272:Carcinoembryonic Antigen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004847:Epithelial Cells / Q000821:virology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D008168:Lung; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008458:Measles Vaccine; D008459:Measles virus / Q000235:genetics / Q000502:physiology*; D051916:Membrane Cofactor Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D050130:Oncolytic Virotherapy; D010750:Phosphoproteins / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D047368:Tumor Burden; D014779:Virus Replication; D000093542:Gemcitabine; D000075983:Nectins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D003841:Deoxycytidine; D039561:Eukaryotic Initiation Factor-4E; D049452:Green Fluorescent Proteins; D006835:Hydrazones; D008458:Measles Vaccine; D051916:Membrane Cofactor Protein; D010750:Phosphoproteins; D020123:Sirolimus; D013844:Thiazoles; D000093542:Gemcitabine; C517852:4EGI-1 compound; C497857:CD46 protein, human; C087000:EIF4EBP1 protein, human; C442228:NECTIN4 protein, human; D000075983:Nectins