PMID- 17245354
OWN - NLM
STAT- MEDLINE
DCOM- 20070925
LR  - 20190608
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 15
IP  - 5
DP  - 2007 May
TI  - Rapamycin-regulated control of antiangiogenic tumor therapy following 
      rAAV-mediated gene transfer.
PG  - 912-20
AB  - Regulated gene expression may be required for the clinical development of certain 
      gene therapies. Several approaches have been developed that allow pharmacologic 
      control of transgene expression, including the dimerizer-regulated 
      transcriptional system in which rapamycin or its analogs function as 
      transcriptional inducers. These compounds can also act as direct antitumor agents 
      via inhibition of mammalian target of rapamycin (mTOR). We describe the 
      development of an optimized recombinant adeno-associated virus (AAV) expression 
      cassette that allows dimerizer-regulated gene expression from a single vector in 
      vitro and in vivo. After demonstrating multiple cycles of rapamycin-dependent 
      transgene induction following a single administration of an AAV vector in vivo, 
      application of this regulated AAV gene expression system to the pharmacologic 
      control of antiangiogenic therapy was evaluated in preclinical tumor models. 
      Dimerizer-regulated vectors were constructed encoding a soluble inhibitor of the 
      vascular endothelial growth factor (VEGF) pathway. In two subcutaneous models of 
      glioblastoma, regulated expression of the VEGF inhibitor via recombinant 
      AAV-mediated gene transfer, in combination with rapamycin, was shown to decrease 
      tumor growth rate significantly. The dual properties of rapamycin--as a 
      transcriptional inducer and mTOR inhibitor--are exploited in combination with an 
      AAV-encoded antiangiogenic agent to provide a novel approach for the treatment of 
      malignant diseases.
FAU - Nguyen, Minh
AU  - Nguyen M
AD  - Cell Genesys Inc., South San Francisco, California, USA. minhn@cellgenesys.com
FAU - Huan-Tu, Guang
AU  - Huan-Tu G
FAU - Gonzalez-Edick, Melissa
AU  - Gonzalez-Edick M
FAU - Rivera, Victor M
AU  - Rivera VM
FAU - Clackson, Tim
AU  - Clackson T
FAU - Jooss, Karin U
AU  - Jooss KU
FAU - Harding, Thomas C
AU  - Harding TC
LA  - eng
PT  - Journal Article
DEP - 20070123
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Prealbumin)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 86090-08-6 (Angiostatins)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Angiostatins/genetics/metabolism
MH  - Animals
MH  - Blotting, Western
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Dependovirus/*genetics
MH  - Disease Models, Animal
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Gene Expression Regulation/drug effects
MH  - Gene Transfer Techniques
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/genetics
MH  - Glioblastoma/genetics/metabolism/therapy
MH  - Humans
MH  - Immunosuppressive Agents/pharmacology
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasms/blood supply/genetics/*therapy
MH  - Prealbumin/genetics
MH  - Promoter Regions, Genetic/genetics
MH  - Receptors, Vascular Endothelial Growth Factor/genetics/metabolism
MH  - Sirolimus/*pharmacology
MH  - Vascular Endothelial Growth Factor A/antagonists & inhibitors
MH  - Xenograft Model Antitumor Assays
EDAT- 2007/01/25 09:00
MHDA- 2007/09/26 09:00
CRDT- 2007/01/25 09:00
PHST- 2007/01/25 09:00 [pubmed]
PHST- 2007/09/26 09:00 [medline]
PHST- 2007/01/25 09:00 [entrez]
AID - S1525-0016(16)31642-2 [pii]
AID - 10.1038/mt.sj.6300079 [doi]
PST - ppublish
SO  - Mol Ther. 2007 May;15(5):912-20. doi: 10.1038/mt.sj.6300079. Epub 2007 Jan 23.