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.
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/Ad3CRAd 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.
Authors: Kelly J Shields; Kostas Verdelis; Michael J Passineau; Erin M Faight; Lee Zourelias; Changgong Wu; Rong Chong; Raymond L Benza Journal: Pulm Circ Date: 2016-12 Impact factor: 3.017
Authors: Leonard Armstrong; Julia Davydova; Eric Brown; Joohee Han; Masato Yamamoto; Selwyn M Vickers Journal: Surgery Date: 2012-04-11 Impact factor: 3.982
Authors: Christopher J LaRocca; Joohee Han; Tatyana Gavrikova; Leonard Armstrong; Amanda R Oliveira; Ryan Shanley; Selwyn M Vickers; Masato Yamamoto; Julia Davydova Journal: Surgery Date: 2015-02-27 Impact factor: 3.982