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2008:
Ramírez Pedro J; Vickers Selwyn M; Ono Hidetaka A; Davydova Julia; Takayama Koichi; Thompson Timothy C; Curiel David T; Bland Kirby I; Yamamoto Masato
Optimization of conditionally replicative adenovirus for pancreatic cancer and its evaluation in an orthotopic murine xenograft model.
American journal of surgery 2008;
195(
4):.
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.
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