title: Combined therapy of oncolytic adenovirus and temozolomide enhances lung cancer virotherapy in vitro and in vivo.
abstract: Oncolytic adenoviruses (OAds) are very promising for the treatment of lung cancer. However, OAd-based monotherapeutics have not been effective during clinical trials. Therefore, the effectiveness of virotherapy must be enhanced by combining OAds with other therapies. In this study, the therapeutic potential of OAd in combination with temozolomide (TMZ) was evaluated in lung cancer cells in vitro and in vivo. The combination of OAd and TMZ therapy synergistically enhanced cancer cell death; this enhanced cancer cell death may be explained via three related mechanisms: apoptosis, virus replication, and autophagy. Autophagy inhibition partially protected cancer cells from this combined therapy. This combination significantly suppressed the growth of subcutaneous H441 lung cancer xenograft tumors in athymic nude mice. In this study, we have provided an experimental rationale to test OAds in combination with TMZ in a lung cancer clinical trial.
authors.affiliation: Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: jgguti01@louisville.edu.
authors.forename: Jorge G
authors.initials: JG
authors.lastname: Gomez-Gutierrez
authors.affiliation: Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Nitz
authors.affiliation: Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Wechman
authors.affiliation: Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Riedinger
authors.affiliation: Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Elvis
authors.initials: E
authors.lastname: Martinez-Jaramillo
authors.affiliation: Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Heshan
authors.initials: H
authors.lastname: Sam Zhou
authors.affiliation: Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McMasters
mesh_terms: D000256:Adenoviridae / Q000502:physiology; D000257:Adenoviridae Infections / Q000821:virology; D017501:Adenovirus E1B Proteins / Q000235:genetics; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D008175:Lung Neoplasms / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D017501:Adenovirus E1B Proteins; D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: Adenovirus; Apoptosis; Autophagy; Cancer; Lung; Oncolytic; Temozolomide