PMID- 22547150
OWN - NLM
STAT- MEDLINE
DCOM- 20130124
LR  - 20220316
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 20
IP  - 9
DP  - 2012 Sep
TI  - Design and selection of Toca 511 for clinical use: modified retroviral 
      replicating vector with improved stability and gene expression.
PG  - 1689-98
LID - 10.1038/mt.2012.83 [doi]
AB  - Retroviral replicating vectors (RRVs) are a nonlytic alternative to oncolytic 
      replicating viruses as anticancer agents, being selective both for dividing cells 
      and for cells that have defects in innate immunity and interferon responsiveness. 
      Tumor cells fit both these descriptions. Previous publications have described a 
      prototype based on an amphotropic murine leukemia virus (MLV), encoding yeast 
      cytosine deaminase (CD) that converts the prodrug 5-fluorocytosine (5-FC) to the 
      potent anticancer drug, 5-fluorouracil (5-FU) in an infected tumor. We report 
      here the selection of one lead clinical candidate based on a general design goal 
      to optimize the genetic stability of the virus and the CD activity produced by 
      the delivered transgene. Vectors were tested for titer, genetic stability, CD 
      protein and enzyme activity, ability to confer susceptibility to 5-FC, and 
      preliminary in vivo antitumor activity and stability. One vector, Toca 511, (aka 
      T5.0002) encoding an optimized CD, shows a threefold increased specific activity 
      in infected cells over infection with the prototype RRV and shows markedly higher 
      genetic stability. Animal testing demonstrated that Toca 511 replicates stably in 
      human tumor xenografts and, after 5-FC administration, causes complete regression 
      of such xenografts. Toca 511 (vocimagene amiretrorepvec) has been taken forward 
      to preclinical and clinical trials.
FAU - Perez, Omar D
AU  - Perez OD
AD  - Tocagen Inc, San Diego, California 92109, USA.
FAU - Logg, Christopher R
AU  - Logg CR
FAU - Hiraoka, Kei
AU  - Hiraoka K
FAU - Diago, Oscar
AU  - Diago O
FAU - Burnett, Ryan
AU  - Burnett R
FAU - Inagaki, Akihito
AU  - Inagaki A
FAU - Jolson, Dawn
AU  - Jolson D
FAU - Amundson, Karin
AU  - Amundson K
FAU - Buckley, Taylor
AU  - Buckley T
FAU - Lohse, Dan
AU  - Lohse D
FAU - Lin, Amy
AU  - Lin A
FAU - Burrascano, Cindy
AU  - Burrascano C
FAU - Ibanez, Carlos
AU  - Ibanez C
FAU - Kasahara, Noriyuki
AU  - Kasahara N
FAU - Gruber, Harry E
AU  - Gruber HE
FAU - Jolly, Douglas J
AU  - Jolly DJ
LA  - eng
GR  - P01 CA059318/CA/NCI NIH HHS/United States
GR  - R01 CA105171/CA/NCI NIH HHS/United States
GR  - P01-CA59318/CA/NCI NIH HHS/United States
GR  - R01-CA105171/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120501
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Fungal Proteins)
RN  - 0 (Prodrugs)
RN  - D83282DT06 (Flucytosine)
RN  - EC 3.5.4.1 (Cytosine Deaminase)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
EIN - Mol Ther. 2013 Feb;21(2):494. PMID: 28160846
MH  - Animals
MH  - Antineoplastic Agents/metabolism/pharmacology
MH  - Cell Line, Tumor
MH  - Cytosine Deaminase/genetics/metabolism
MH  - Flucytosine/metabolism/pharmacology
MH  - Fluorouracil/metabolism/pharmacology
MH  - Fungal Proteins/genetics/metabolism
MH  - Gene Expression
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors
MH  - Humans
MH  - Leukemia Virus, Murine/*genetics
MH  - Mice
MH  - Neoplasm Transplantation
MH  - Neoplasms, Experimental/genetics/pathology/*therapy
MH  - Prodrugs/metabolism/pharmacology
MH  - RNA Stability
MH  - Rats
MH  - Transgenes
PMC - PMC3437576
EDAT- 2012/05/02 06:00
MHDA- 2013/01/25 06:00
PMCR- 2013/09/04
CRDT- 2012/05/02 06:00
PHST- 2012/05/02 06:00 [entrez]
PHST- 2012/05/02 06:00 [pubmed]
PHST- 2013/01/25 06:00 [medline]
PHST- 2013/09/04 00:00 [pmc-release]
AID - S1525-0016(16)32160-8 [pii]
AID - 10.1038/mt.2012.83 [doi]
PST - ppublish
SO  - Mol Ther. 2012 Sep;20(9):1689-98. doi: 10.1038/mt.2012.83. Epub 2012 May 1.