Reduction of intestinal neoplasia with adenomatous polyposis coli gene replacement and COX-2 inhibition is additive

John Lew, Yuee Guo, Richard K. Kim, Lisa Vargish, Fabrizio Michelassi, Richard B. Arenas

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Mutations of the adenomatous polyposis coli (APC) gene are implicated early in colorectal tumorigenesis. Restoration of normal APC expression through gene therapy may prevent or reduce intestinal neoplasia. Furthermore, the relationship between colorectal tumors and increased cyclooxygenase-2 (COX-2) activity provides a rationale for the use of selective COX-2 inhibitors such as rofecoxib (Vioxx) to prevent the formation of polyps. This study was performed to determine the effects of liposome-mediated APC gene therapy and a selective COX-2 inhibitor on intestinal neoplasia in vivo. Five-week-old Min mice weaned on a 30% high-fat diet were randomized to receive no treatment (control), APC only, Vioxx only, and APC/Vioxx. APC-treated mice received a plasmid containing the human APC cDNA (pCMV-APC) mixed with a liposome preparation that was administered biweekly. Vioxx was administered at 200 ppm in the high-fat rodent chow. The control mice were treated similarly with a plasmid construct lacking the APC gene. Confirmation of exogenous APC gene expression was determined by Western blot analysis. After 2 months, there was a 54% and 70% reduction in the total number of intestinal polyps after APC and Vioxx treatment, respectively. Combined APC/Vioxx therapy reduced polyp formation by 87%. The reduction of intestinal neoplasia by APC gene replacement and COX-2 inhibition suggests their separate roles in intestinal tumorigenesis. Each modality, both individually and together, may prove therapeutic and therefore contribute to new strategies in the prevention and treatment of colorectal cancer.

Original languageEnglish
Pages (from-to)563-568
Number of pages6
JournalJournal of Gastrointestinal Surgery
Volume6
Issue number4
DOIs
StatePublished - Dec 1 2002
Externally publishedYes

Fingerprint

APC Genes
Adenomatous Polyposis Coli
Cyclooxygenase 2
Neoplasms
Cyclooxygenase 2 Inhibitors
Polyps
Liposomes
Genetic Therapy
Colorectal Neoplasms
Carcinogenesis
Plasmids
Intestinal Polyps
Therapeutics
High Fat Diet
rofecoxib
Rodentia
Complementary DNA
Western Blotting
Fats
Gene Expression

Keywords

  • Adenomatous polyposis coligene
  • Colorectal polyps
  • Cyclooxygenase-2 inhibition
  • Gene therapy

ASJC Scopus subject areas

  • Surgery

Cite this

Reduction of intestinal neoplasia with adenomatous polyposis coli gene replacement and COX-2 inhibition is additive. / Lew, John; Guo, Yuee; Kim, Richard K.; Vargish, Lisa; Michelassi, Fabrizio; Arenas, Richard B.

In: Journal of Gastrointestinal Surgery, Vol. 6, No. 4, 01.12.2002, p. 563-568.

Research output: Contribution to journalArticle

Lew, John ; Guo, Yuee ; Kim, Richard K. ; Vargish, Lisa ; Michelassi, Fabrizio ; Arenas, Richard B. / Reduction of intestinal neoplasia with adenomatous polyposis coli gene replacement and COX-2 inhibition is additive. In: Journal of Gastrointestinal Surgery. 2002 ; Vol. 6, No. 4. pp. 563-568.
@article{33e3153a4e3d4274909d8b306fac2747,
title = "Reduction of intestinal neoplasia with adenomatous polyposis coli gene replacement and COX-2 inhibition is additive",
abstract = "Mutations of the adenomatous polyposis coli (APC) gene are implicated early in colorectal tumorigenesis. Restoration of normal APC expression through gene therapy may prevent or reduce intestinal neoplasia. Furthermore, the relationship between colorectal tumors and increased cyclooxygenase-2 (COX-2) activity provides a rationale for the use of selective COX-2 inhibitors such as rofecoxib (Vioxx) to prevent the formation of polyps. This study was performed to determine the effects of liposome-mediated APC gene therapy and a selective COX-2 inhibitor on intestinal neoplasia in vivo. Five-week-old Min mice weaned on a 30{\%} high-fat diet were randomized to receive no treatment (control), APC only, Vioxx only, and APC/Vioxx. APC-treated mice received a plasmid containing the human APC cDNA (pCMV-APC) mixed with a liposome preparation that was administered biweekly. Vioxx was administered at 200 ppm in the high-fat rodent chow. The control mice were treated similarly with a plasmid construct lacking the APC gene. Confirmation of exogenous APC gene expression was determined by Western blot analysis. After 2 months, there was a 54{\%} and 70{\%} reduction in the total number of intestinal polyps after APC and Vioxx treatment, respectively. Combined APC/Vioxx therapy reduced polyp formation by 87{\%}. The reduction of intestinal neoplasia by APC gene replacement and COX-2 inhibition suggests their separate roles in intestinal tumorigenesis. Each modality, both individually and together, may prove therapeutic and therefore contribute to new strategies in the prevention and treatment of colorectal cancer.",
keywords = "Adenomatous polyposis coligene, Colorectal polyps, Cyclooxygenase-2 inhibition, Gene therapy",
author = "John Lew and Yuee Guo and Kim, {Richard K.} and Lisa Vargish and Fabrizio Michelassi and Arenas, {Richard B.}",
year = "2002",
month = "12",
day = "1",
doi = "10.1016/S1091-255X(01)00042-7",
language = "English",
volume = "6",
pages = "563--568",
journal = "Journal of Gastrointestinal Surgery",
issn = "1091-255X",
publisher = "Springer New York",
number = "4",

}

TY - JOUR

T1 - Reduction of intestinal neoplasia with adenomatous polyposis coli gene replacement and COX-2 inhibition is additive

AU - Lew, John

AU - Guo, Yuee

AU - Kim, Richard K.

AU - Vargish, Lisa

AU - Michelassi, Fabrizio

AU - Arenas, Richard B.

PY - 2002/12/1

Y1 - 2002/12/1

N2 - Mutations of the adenomatous polyposis coli (APC) gene are implicated early in colorectal tumorigenesis. Restoration of normal APC expression through gene therapy may prevent or reduce intestinal neoplasia. Furthermore, the relationship between colorectal tumors and increased cyclooxygenase-2 (COX-2) activity provides a rationale for the use of selective COX-2 inhibitors such as rofecoxib (Vioxx) to prevent the formation of polyps. This study was performed to determine the effects of liposome-mediated APC gene therapy and a selective COX-2 inhibitor on intestinal neoplasia in vivo. Five-week-old Min mice weaned on a 30% high-fat diet were randomized to receive no treatment (control), APC only, Vioxx only, and APC/Vioxx. APC-treated mice received a plasmid containing the human APC cDNA (pCMV-APC) mixed with a liposome preparation that was administered biweekly. Vioxx was administered at 200 ppm in the high-fat rodent chow. The control mice were treated similarly with a plasmid construct lacking the APC gene. Confirmation of exogenous APC gene expression was determined by Western blot analysis. After 2 months, there was a 54% and 70% reduction in the total number of intestinal polyps after APC and Vioxx treatment, respectively. Combined APC/Vioxx therapy reduced polyp formation by 87%. The reduction of intestinal neoplasia by APC gene replacement and COX-2 inhibition suggests their separate roles in intestinal tumorigenesis. Each modality, both individually and together, may prove therapeutic and therefore contribute to new strategies in the prevention and treatment of colorectal cancer.

AB - Mutations of the adenomatous polyposis coli (APC) gene are implicated early in colorectal tumorigenesis. Restoration of normal APC expression through gene therapy may prevent or reduce intestinal neoplasia. Furthermore, the relationship between colorectal tumors and increased cyclooxygenase-2 (COX-2) activity provides a rationale for the use of selective COX-2 inhibitors such as rofecoxib (Vioxx) to prevent the formation of polyps. This study was performed to determine the effects of liposome-mediated APC gene therapy and a selective COX-2 inhibitor on intestinal neoplasia in vivo. Five-week-old Min mice weaned on a 30% high-fat diet were randomized to receive no treatment (control), APC only, Vioxx only, and APC/Vioxx. APC-treated mice received a plasmid containing the human APC cDNA (pCMV-APC) mixed with a liposome preparation that was administered biweekly. Vioxx was administered at 200 ppm in the high-fat rodent chow. The control mice were treated similarly with a plasmid construct lacking the APC gene. Confirmation of exogenous APC gene expression was determined by Western blot analysis. After 2 months, there was a 54% and 70% reduction in the total number of intestinal polyps after APC and Vioxx treatment, respectively. Combined APC/Vioxx therapy reduced polyp formation by 87%. The reduction of intestinal neoplasia by APC gene replacement and COX-2 inhibition suggests their separate roles in intestinal tumorigenesis. Each modality, both individually and together, may prove therapeutic and therefore contribute to new strategies in the prevention and treatment of colorectal cancer.

KW - Adenomatous polyposis coligene

KW - Colorectal polyps

KW - Cyclooxygenase-2 inhibition

KW - Gene therapy

UR - http://www.scopus.com/inward/record.url?scp=0037960862&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037960862&partnerID=8YFLogxK

U2 - 10.1016/S1091-255X(01)00042-7

DO - 10.1016/S1091-255X(01)00042-7

M3 - Article

VL - 6

SP - 563

EP - 568

JO - Journal of Gastrointestinal Surgery

JF - Journal of Gastrointestinal Surgery

SN - 1091-255X

IS - 4

ER -