Optimization of conditionally replicative adenovirus for pancreatic cancer and its evaluation in an orthotopic murine xenograft model

Pedro J. Ramírez; Selwyn M. Vickers; Hidetaka A. Ono; Julia Davydova; Koichi Takayama; Timothy C. Thompson; David T. Curiel; Kirby I. Bland; Masato Yamamoto

doi:10.1016/j.amjsurg.2007.04.014

Optimization of conditionally replicative adenovirus for pancreatic cancer and its evaluation in an orthotopic murine xenograft model

Pedro J. Ramírez, Selwyn M. Vickers, Hidetaka A. Ono, Julia Davydova, Koichi Takayama, Timothy C. Thompson, David T. Curiel, Kirby I. Bland, Masato Yamamoto

Surgery

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23 Scopus citations

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.

Original language	English (US)
Pages (from-to)	481-490
Number of pages	10
Journal	American journal of surgery
Volume	195
Issue number	4
DOIs	https://doi.org/10.1016/j.amjsurg.2007.04.014
State	Published - Apr 2008

Keywords

Conditionally replicative adenovirus
Fiber modification
Gene therapy
Orthotopic cancer model
Pancreatic cancer
Tumor-specific promoter

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title = "Optimization of conditionally replicative adenovirus for pancreatic cancer and its evaluation in an orthotopic murine xenograft model",

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.",

keywords = "Conditionally replicative adenovirus, Fiber modification, Gene therapy, Orthotopic cancer model, Pancreatic cancer, Tumor-specific promoter",

author = "Ram{\'i}rez, {Pedro J.} and Vickers, {Selwyn M.} and Ono, {Hidetaka A.} and Julia Davydova and Koichi Takayama and Thompson, {Timothy C.} and Curiel, {David T.} and Bland, {Kirby I.} and Masato Yamamoto",

year = "2008",

month = apr,

doi = "10.1016/j.amjsurg.2007.04.014",

language = "English (US)",

volume = "195",

pages = "481--490",

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T1 - Optimization of conditionally replicative adenovirus for pancreatic cancer and its evaluation in an orthotopic murine xenograft model

AU - Ramírez, Pedro J.

AU - Vickers, Selwyn M.

AU - Ono, Hidetaka A.

AU - Davydova, Julia

AU - Takayama, Koichi

AU - Thompson, Timothy C.

AU - Curiel, David T.

AU - Bland, Kirby I.

AU - Yamamoto, Masato

PY - 2008/4

Y1 - 2008/4

N2 - 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.

AB - 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.

KW - Conditionally replicative adenovirus

KW - Fiber modification

KW - Gene therapy

KW - Orthotopic cancer model

KW - Pancreatic cancer

KW - Tumor-specific promoter

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Optimization of conditionally replicative adenovirus for pancreatic cancer and its evaluation in an orthotopic murine xenograft model

Abstract

Keywords

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