In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer

Denis Evoy; Edward A. Hirschowitz; Hassan A. Naama; Xiao Kui Li; Ronald G. Crystal; John M. Daly; Michael D. Lieberman

doi:10.1006/jsre.1997.5051

In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer

Denis Evoy, Edward A. Hirschowitz, Hassan A. Naama, Xiao Kui Li, Ronald G. Crystal, John M. Daly, Michael D. Lieberman

Internal Medicine

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

Abstract

Gene therapy may allow targeted delivery of tumoricidal drugs to treat pancreatic cancer. Cytosine deaminase (CD) is a bacterial enzyme that converts the nontoxic agent 5-fluorocytosine (5FC) to the active chemotherapeutic agent 5-fluorouracil (5FU). Neoplastic cells induced to express the CD gene treated with 5FC may generate locally high concentrations of 5FU while minimizing systemic toxicity. Replication deficient adenovirus vector carrying the CD gene (AdCMV.CD) was tested for therapeutic efficacy against the murine pancreatic carcinoma cell line Pan02. Pan02 cells were infected in vitro with AdCMV.CD or null vector (Ad.Null) and were examined for expression of CD messenger RNA (mRNA) (Northern blot) and CD enzymatic function (spectrophotometry). mRNA transcripts of the CD gene increased in a dose-dependent manner after infection with AdCMV.CD. Conversion of 5FC to 5FU at a multiplicity of infection (MOI) of 20 was measured to be 51% after a 48- hr incubation. Growth inhibition was measured by MTT assay and thymidine uptake. Pan02 growth in vitro treated with AdCMV.CD and 5FC was inhibited by 80% as compared to cells treated with Ad.Null and 5FC. An in vivo model of pancreatic cancer was established by injecting 2.5 x 10⁵ PAN02 cells subcutaneously into the flanks of C57BL/6 mice. Seven days later AdCMV.CD was injected into each tumor and 5FC was administered for 10 days. Treatment of mice with AdCMV.CD and 5FC inhibited tumor growth compared to mice who received AdCMV.CD only or 5FC only. These data demonstrate the therapeutic efficacy of an enzyme prodrug strategy in experimental pancreatic cancer.

Original language	English
Pages (from-to)	226-231
Number of pages	6
Journal	Journal of Surgical Research
Volume	69
Issue number	1
DOIs	https://doi.org/10.1006/jsre.1997.5051
State	Published - Apr 1997

Bibliographical note

Funding Information:
1 Supported by a grant from The American Cancer Society Clinical Career Development Award: 96±49. These studies were supported, in part, by the National Institutes of Health/National Heart, Lung and Blood Institute P01 Hl51746±03, Cystic Fibrosis Foundation, Bethesda, MD; Will Rogers Memorial Fund, White Plains, NY; and GenVec, Inc., Rockville, MD.

ASJC Scopus subject areas

Surgery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1006/jsre.1997.5051

Cite this

@article{f22a4a46704c49e7b2b63b655319a512,

title = "In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer",

abstract = "Gene therapy may allow targeted delivery of tumoricidal drugs to treat pancreatic cancer. Cytosine deaminase (CD) is a bacterial enzyme that converts the nontoxic agent 5-fluorocytosine (5FC) to the active chemotherapeutic agent 5-fluorouracil (5FU). Neoplastic cells induced to express the CD gene treated with 5FC may generate locally high concentrations of 5FU while minimizing systemic toxicity. Replication deficient adenovirus vector carrying the CD gene (AdCMV.CD) was tested for therapeutic efficacy against the murine pancreatic carcinoma cell line Pan02. Pan02 cells were infected in vitro with AdCMV.CD or null vector (Ad.Null) and were examined for expression of CD messenger RNA (mRNA) (Northern blot) and CD enzymatic function (spectrophotometry). mRNA transcripts of the CD gene increased in a dose-dependent manner after infection with AdCMV.CD. Conversion of 5FC to 5FU at a multiplicity of infection (MOI) of 20 was measured to be 51% after a 48- hr incubation. Growth inhibition was measured by MTT assay and thymidine uptake. Pan02 growth in vitro treated with AdCMV.CD and 5FC was inhibited by 80% as compared to cells treated with Ad.Null and 5FC. An in vivo model of pancreatic cancer was established by injecting 2.5 x 105 PAN02 cells subcutaneously into the flanks of C57BL/6 mice. Seven days later AdCMV.CD was injected into each tumor and 5FC was administered for 10 days. Treatment of mice with AdCMV.CD and 5FC inhibited tumor growth compared to mice who received AdCMV.CD only or 5FC only. These data demonstrate the therapeutic efficacy of an enzyme prodrug strategy in experimental pancreatic cancer.",

author = "Denis Evoy and Hirschowitz, {Edward A.} and Naama, {Hassan A.} and Li, {Xiao Kui} and Crystal, {Ronald G.} and Daly, {John M.} and Lieberman, {Michael D.}",

note = "Funding Information: 1 Supported by a grant from The American Cancer Society Clinical Career Development Award: 96±49. These studies were supported, in part, by the National Institutes of Health/National Heart, Lung and Blood Institute P01 Hl51746±03, Cystic Fibrosis Foundation, Bethesda, MD; Will Rogers Memorial Fund, White Plains, NY; and GenVec, Inc., Rockville, MD.",

year = "1997",

month = apr,

doi = "10.1006/jsre.1997.5051",

language = "English",

volume = "69",

pages = "226--231",

number = "1",

}

TY - JOUR

T1 - In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer

AU - Evoy, Denis

AU - Hirschowitz, Edward A.

AU - Naama, Hassan A.

AU - Li, Xiao Kui

AU - Crystal, Ronald G.

AU - Daly, John M.

AU - Lieberman, Michael D.

N1 - Funding Information: 1 Supported by a grant from The American Cancer Society Clinical Career Development Award: 96±49. These studies were supported, in part, by the National Institutes of Health/National Heart, Lung and Blood Institute P01 Hl51746±03, Cystic Fibrosis Foundation, Bethesda, MD; Will Rogers Memorial Fund, White Plains, NY; and GenVec, Inc., Rockville, MD.

PY - 1997/4

Y1 - 1997/4

N2 - Gene therapy may allow targeted delivery of tumoricidal drugs to treat pancreatic cancer. Cytosine deaminase (CD) is a bacterial enzyme that converts the nontoxic agent 5-fluorocytosine (5FC) to the active chemotherapeutic agent 5-fluorouracil (5FU). Neoplastic cells induced to express the CD gene treated with 5FC may generate locally high concentrations of 5FU while minimizing systemic toxicity. Replication deficient adenovirus vector carrying the CD gene (AdCMV.CD) was tested for therapeutic efficacy against the murine pancreatic carcinoma cell line Pan02. Pan02 cells were infected in vitro with AdCMV.CD or null vector (Ad.Null) and were examined for expression of CD messenger RNA (mRNA) (Northern blot) and CD enzymatic function (spectrophotometry). mRNA transcripts of the CD gene increased in a dose-dependent manner after infection with AdCMV.CD. Conversion of 5FC to 5FU at a multiplicity of infection (MOI) of 20 was measured to be 51% after a 48- hr incubation. Growth inhibition was measured by MTT assay and thymidine uptake. Pan02 growth in vitro treated with AdCMV.CD and 5FC was inhibited by 80% as compared to cells treated with Ad.Null and 5FC. An in vivo model of pancreatic cancer was established by injecting 2.5 x 105 PAN02 cells subcutaneously into the flanks of C57BL/6 mice. Seven days later AdCMV.CD was injected into each tumor and 5FC was administered for 10 days. Treatment of mice with AdCMV.CD and 5FC inhibited tumor growth compared to mice who received AdCMV.CD only or 5FC only. These data demonstrate the therapeutic efficacy of an enzyme prodrug strategy in experimental pancreatic cancer.

AB - Gene therapy may allow targeted delivery of tumoricidal drugs to treat pancreatic cancer. Cytosine deaminase (CD) is a bacterial enzyme that converts the nontoxic agent 5-fluorocytosine (5FC) to the active chemotherapeutic agent 5-fluorouracil (5FU). Neoplastic cells induced to express the CD gene treated with 5FC may generate locally high concentrations of 5FU while minimizing systemic toxicity. Replication deficient adenovirus vector carrying the CD gene (AdCMV.CD) was tested for therapeutic efficacy against the murine pancreatic carcinoma cell line Pan02. Pan02 cells were infected in vitro with AdCMV.CD or null vector (Ad.Null) and were examined for expression of CD messenger RNA (mRNA) (Northern blot) and CD enzymatic function (spectrophotometry). mRNA transcripts of the CD gene increased in a dose-dependent manner after infection with AdCMV.CD. Conversion of 5FC to 5FU at a multiplicity of infection (MOI) of 20 was measured to be 51% after a 48- hr incubation. Growth inhibition was measured by MTT assay and thymidine uptake. Pan02 growth in vitro treated with AdCMV.CD and 5FC was inhibited by 80% as compared to cells treated with Ad.Null and 5FC. An in vivo model of pancreatic cancer was established by injecting 2.5 x 105 PAN02 cells subcutaneously into the flanks of C57BL/6 mice. Seven days later AdCMV.CD was injected into each tumor and 5FC was administered for 10 days. Treatment of mice with AdCMV.CD and 5FC inhibited tumor growth compared to mice who received AdCMV.CD only or 5FC only. These data demonstrate the therapeutic efficacy of an enzyme prodrug strategy in experimental pancreatic cancer.

UR - http://www.scopus.com/inward/record.url?scp=0031127632&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031127632&partnerID=8YFLogxK

U2 - 10.1006/jsre.1997.5051

DO - 10.1006/jsre.1997.5051

M3 - Article

C2 - 9202675

AN - SCOPUS:0031127632

SN - 0022-4804

VL - 69

SP - 226

EP - 231

JO - Journal of Surgical Research

JF - Journal of Surgical Research

IS - 1

ER -

In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this