A measles virus vaccine strain derivative as a novel oncolytic agent against breast cancer.
Breast cancer is the most common malignancy and the second leading cause of female cancer mortality in the United States. There is an urgent need for development of novel therapeutic approaches. In this study, we investigated the antitumor potential of a novel viral agent, an attenuated strain of measles virus deriving from the Edmonston vaccine lineage, genetically engineered to produce carcinoembryonic antigen (CEA) against breast cancer. CEA production as the virus replicates can serve as a marker of viral gene expression. Infection of a variety of breast cancer cell lines including MDA-MB-231, MCF7 and SkBr3 at different multiplicities of infection (MOIs) from 0.1 to 10 resulted in significant cytopathic effect consisting of extensive syncytia formation and massive cell death at 72-96 h from infection. All breast cancer lines overexpressed the measles virus receptor CD46 and supported robust viral replication, which correlated with CEA production. TUNEL assays indicated an apoptotic mechanism of syncytial death. The efficacy of this approach in vivo was examined in a subcutaneous Balb C/nude mouse model of MDA-MB-231 cells. Intravenous administration of MV-CEA at a total dose of 1.2 x 10(7) TCID50 resulted in statistically significant tumor growth delay ( p=0.005) and prolongation of survival ( p=0.001). In summary, MV-CEA has potent antitumor activity against breast cancer lines and xenografts. Monitoring marker peptide levels in the serum could serve as a low-risk method of detecting viral gene expression during treatment and could allow dose optimization and individualization of treatment. Trackable measles virus derivatives merit further exploration in breast cancer treatment.
McDonald
Cari J
CJ
Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA.
Erlichman
Charles
C
Ingle
James N
JN
Rosales
Gabriela A
GA
Allen
Cory
C
Greiner
Suzanne M
SM
Harvey
Mary E
ME
Zollman
Paula J
PJ
Russell
Stephen J
SJ
Galanis
Evanthia
E
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology*; D002522:Chlorocebus aethiops; D003588:Cytopathogenic Effect, Viral; D005260:Female; D006801:Humans; D008458:Measles Vaccine / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D008459:Measles virus / Q000235:genetics / Q000276:immunology*; D051916:Membrane Cofactor Protein / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D010051:Ovarian Neoplasms; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014709:Vero Cells; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D002272:Carcinoembryonic Antigen; D008458:Measles Vaccine; D051916:Membrane Cofactor Protein