Vaccinia virus GLV-1h237 carrying a Walker A motif mutation of mouse Cdc6 protein enhances human breast tumor therapy in mouse xenografts.
Recently it was shown that recombinant vaccinia virus GLV-1h68 is a promising tool for treating different type of cancers in animal models. The goal of the present study was to enhance the oncolytic potential of GLV-1h68 without decreasing its safety. A derivative of GLV-1h68 containing the gene for a Walker A motif mutant of the essential cell cycle protein Cdc6, GLV-1h237, was engineered. The characteristics of GLV-1h237 and its efficiency in treating human breast cancer GI-101A cells were compared with that of GLV-1h236 (carrying the wild-type gene for Cdc6), GLV-1h71 (a derivative of GLV-1h68) and GLV-1h68, respectively. RT-PCR and immunoblot analyses revealed that Cdc6 is efficiently overexpressed in GLV-1h237-infected GI-101A cells. GLV-1h237 was found to have higher replication efficiency and enhanced cytotoxity than GLV-1h68 in cell culture. In the GI-101A tumor xenograft animal model, GLV-1h237 turned out to be the most potent oncolytic virus strain investigated. A single i.v. injection of GLV-1h237 resulted in enhanced anti-tumor activity compared to GLV-1h68 concomitant with a high tumor selectivity and a comparable safety profile. Thus, the strategy to combine oncolytic virotherapy with agents that interfere with host cell DNA synthesis is a promising approach for effective cancer therapy.
Department of Biochemistry, Biocenter, University of Würzburg, Würzburg, Germany.
Elisabeth
E
Hofmann
Friedrich
F
Grummt
Aladar A
AA
Szalay
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002277:Carcinoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics*; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics* / Q000502:physiology; D014616:Vaccinia virus / Q000235:genetics* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
C502132:CDC6 protein, mouse; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins