Engineered measles virus as a novel oncolytic therapy against prostate cancer.
BACKGROUND
No curative therapy is currently available for locally advanced or metastatic prostate cancer. Oncolytic viruses represent a novel class of therapeutic agents that demonstrates no cross-resistance with existing approaches and can therefore be combined with conventional treatment modalities. Measles virus strains deriving from the Edmonston (MV-Edm) vaccine strain have shown considerable oncolytic activity against a variety of solid tumers and hematologic malignancies. In this study, we investigated the antitumor potential of recombinant MV-Edm derivatives as novel oncolytic agents against prostate cancer.


METHODS
The susceptibility of prostate cancer cell lines (PC-3, DU-145, and LNCaP) to measles virus infection was demonstrated using an MV-Edm derivative expressing green fluorescent protein (GFP). MV-Edm replication in prostate cancer cell lines was assessed by one step viral growth curves. The oncolytic effect of an MV-Edm strain engineered to express the human carcinoembryonic antigen (CEA) was demonstrated in vitro by MTT assays and in vivo in subcutaneous PC-3 xenografts. CEA levels were quantitated in cell supernatants and mouse serum samples.


RESULTS
Recombinant MV-Edm strains can effectively infect, replicate in and kill prostate cancer cells. Intratumoral administration of MV-CEA at a total dose of 6 x 10(6) TCID50 resulted in statistically significant tumor growth delay (P = 0.004) and prolongation of survival (P = 0.001) in a subcutaneous PC-3 xenograft model. Viral growth kinetics paralleled CEA production.


CONCLUSIONS
MV-CEA has potent antitumor activity against prostate cancer cell lines and xenografts. Viral gene expression during treatment can be determined by monitoring of CEA levels in the serum; the latter could allow dose optimization and tailoring of individualized treatment protocols.
Msaouel
Pavlos
P
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Iankov
Ianko D
ID
Allen
Cory
C
Morris
John C
JC
von Messling
Veronika
V
Cattaneo
Roberto
R
Koutsilieris
Michael
M
Russell
Stephen J
SJ
Galanis
Evanthia
E
D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005434:Flow Cytometry; D005818:Genetic Engineering / Q000379:methods; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007275:Injections, Intravenous; D008156:Luciferases / Q000235:genetics; D008297:Male; D008458:Measles Vaccine / Q000235:genetics*; 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 / Q000379:methods*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
C497857:CD46 protein, human; D008458:Measles Vaccine; D051916:Membrane Cofactor Protein; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D008156:Luciferases