Mechanistic analysis and comparison of viral fusogenic membrane proteins for their synergistic effects on chemotherapy.
Previously we demonstrated that the expression of fusogenic membrane proteins (FMG) of measles virus (MV-H/F) can synergistically enhance chemotherapy. In this study, we used median-effect analysis to evaluate whether the expression of respiratory syncytial virus (RSV-F), as well as vesicular stomatitis virus (VSV-G) can also synergistically enhance chemotherapy. Furthermore we elucidated by western blot analysis some molecular pathways that might be responsible for this effect. We showed in colorectal cancer cell lines that the expression of MV-H/F, but also of RSV-F, as well as VSV-G can synergistically enhance p53-independent clinically relevant chemotherapy (FOLFOX) over most of the cytotoxic dose range. In a subcutaneous HT-29 colorectal xenograft model, we demonstrated that the administration of replication-deficient adenovirus vectors encoding MV-H/F, RSV-F or VSV-G in combination with FOLFOX significantly enhanced treatment outcome when compared to the treatment with each compound individually. The anti-neoplastic efficacy of RSV-F was somewhat better than that of MV-H/F and both were statistically significantly more efficacious than VSV-G alone or in combination with chemotherapy. Treatment efficacy was further significantly improved when the replication-deficient FMG encoding vectors were trans-complemented for replication with a replication-restricted oncolytic adenovirus to improve tumor transduction efficiency. The combination of FMG expression, chemotherapy and trans-complementing oncolytic vectors resulted in a significantly better treatment efficacy than treatment with its components as single- or double-agent therapy. Our data indicates that FMG expression (i.e., RSV-F and MV-H/F) in combination with chemotherapy and viral oncolysis warrants further investigations.
Hoffmann
Dennis
D
Ruhr-University Bochum, Institute of Microbiology and Hygiene, Department of Molecular and Medical Virology, Bochum, Germany.
Grunwald
Thomas
T
Kuate
Seraphin
S
Wildner
Oliver
O
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008561:Membrane Fusion; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000201:enzymology; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012136:Respiratory Syncytial Viruses / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D018116:Vesiculovirus / Q000235:genetics*; D014760:Viral Fusion Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D017304:Annexin A5; D009944:Organoplatinum Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D014760:Viral Fusion Proteins; D020169:Caspases; D002955:Leucovorin; D005472:Fluorouracil