Optimization of conditionally replicative adenovirus for pancreatic cancer and its evaluation in an orthotopic murine xenograft model - 20/08/11
, Hidetaka A. Ono, M.D., Ph.D. b, Julia Davydova, M.D., Ph.D. c, Koichi Takayama, M.D., Ph.D. b, Timothy C. Thompson, Ph.D. d, David T. Curiel, M.D., Ph.D. b, Kirby I. Bland, M.D. a, Masato Yamamoto, M.D., Ph.D. c
Corresponding author. Tel. +1-612-626-1999; fax: +1-612-626-0654.Abstract |
Background |
The full realization of the therapeutic potential of conditionally replicative adenoviruses (CRAds) in the field of pancreatic cancer has been hindered by limited tumor transduction and suboptimal replication control.
Methods |
We optimized infectivity enhancements and tumor-specific promoters (tsps) for pancreatic cancer. Infectivity was enhanced both by incorporating an RGD motif and by substituting the knob region with Ad serotype 3 knob (Ad5/Ad3). An optimized CRAd was tested in an orthotopic pancreatic cancer model by systemic administration.
Results |
Among a panel of 8 tsps, the 1.5-kb cyclooxygenase-2 (Cox-2L) promoter profile was most advantageous in the pancreatic cancer cell lines, whereas 4 more promoters were also promising. An infectivity-enhanced Ad5/Ad3 CRAd controlled with Cox-2L promoter was found to safely exhibit replication within a tumor in this model and was found to suppress tumor growth after systemic delivery.
Conclusions |
The infectivity-enhanced, promoter-controlled CRAd promises useful clinical applications for pancreatic cancer gene therapy.
Il testo completo di questo articolo è disponibile in PDF.Keywords : Pancreatic cancer, Gene therapy, Conditionally replicative adenovirus, Tumor-specific promoter, Fiber modification, Orthotopic cancer model
Mappa
| Supported in part by R01DK063615 (MY), P20CA101955 (SV/MY), DAMD 17-03-1-0104 (MY), R01CA94084 (MY/DTC), R56CA94084 (MY), and NIH 5 T32 CA091078 (Dr. Kirby Bland). |
Vol 195 - N° 4
P. 481-490 - aprile 2008 Ritorno al numero
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