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

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

Research output: Contribution to journalArticle

64 Citations (Scopus)

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 languageEnglish
Pages (from-to)226-231
Number of pages6
JournalJournal of Surgical Research
Volume69
Issue number1
DOIs
Publication statusPublished - 1 Jan 1997
Externally publishedYes

Fingerprint

Cytosine Deaminase
Pancreatic Neoplasms
Flucytosine
Genes
Therapeutics
Fluorouracil
Growth
Messenger RNA
Spectrophotometry
Prodrugs
Enzymes
Infection
Inbred C57BL Mouse

ASJC Scopus subject areas

  • Surgery

Cite this

Evoy, D., Hirschowitz, E. A., Naama, H. A., Li, X. K., Crystal, R., Daly, J. M., & Lieberman, M. D. (1997). In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer. Journal of Surgical Research, 69(1), 226-231. https://doi.org/10.1006/jsre.1997.5051

In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer. / Evoy, Denis; Hirschowitz, Edward A.; Naama, Hassan A.; Li, Xiao Kui; Crystal, Ronald; Daly, John M.; Lieberman, Michael D.

In: Journal of Surgical Research, Vol. 69, No. 1, 01.01.1997, p. 226-231.

Research output: Contribution to journalArticle

Evoy, D, Hirschowitz, EA, Naama, HA, Li, XK, Crystal, R, Daly, JM & Lieberman, MD 1997, 'In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer', Journal of Surgical Research, vol. 69, no. 1, pp. 226-231. https://doi.org/10.1006/jsre.1997.5051
Evoy, Denis ; Hirschowitz, Edward A. ; Naama, Hassan A. ; Li, Xiao Kui ; Crystal, Ronald ; Daly, John M. ; Lieberman, Michael D. / In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer. In: Journal of Surgical Research. 1997 ; Vol. 69, No. 1. pp. 226-231.
@article{8a4ea068aac649ecbc8dc65a87a824a7,
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 Ronald Crystal and Daly, {John M.} and Lieberman, {Michael D.}",
year = "1997",
month = "1",
day = "1",
doi = "10.1006/jsre.1997.5051",
language = "English",
volume = "69",
pages = "226--231",
journal = "Journal of Surgical Research",
issn = "0022-4804",
publisher = "Academic Press Inc.",
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

AU - Daly, John M.

AU - Lieberman, Michael D.

PY - 1997/1/1

Y1 - 1997/1/1

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

VL - 69

SP - 226

EP - 231

JO - Journal of Surgical Research

JF - Journal of Surgical Research

SN - 0022-4804

IS - 1

ER -