Basic Research
Copyright ©The Author(s) 2004. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 15, 2004; 10(24): 3583-3589
Published online Dec 15, 2004. doi: 10.3748/wjg.v10.i24.3583
The effect of adenovirus expressing wild-type p53 on 5-fluorouracil chemosensitivity is related to p53 status in pancreatic cancer cell lines
Sven Eisold, Michael Linnebacher, Eduard Ryschich, Dalibor Antolovic, Ulf Hinz, Ernst Klar, Jan Schmidt
Sven Eisold, Ernst Klar, Department of General Surgery, Thoracic and Vascular Surgery, University of Rostock, Schillingallee 35, D-18057 Rostock, Germany
Eduard Ryschich, Dalibor Antolovic, Ulf Hinz, Jan Schmidt, Department of General Surgery, University of Heidelberg, INF, D-69120 Heidelberg, Germany
Michael Linnebacher, Molecular Pathology, University of Heidelberg, INF, D-68120 Heidelberg, Germany
Author contributions: All authors contributed equally to the work.
Correspondence to: Sven Eisold, Department of General Surgery, Thoracic and Vascular Surgery, University of Rostock, Schillingallee 35, D-18057 Rostock, Germany. sven.eisold@med.uni-rostock.de
Telephone: +49-381-4946001 Fax: +49-381-4946002
Received: April 15, 2004
Revised: May 28, 2004
Accepted: June 7, 2004
Published online: December 15, 2004
Abstract

AIM: There are conflicting data about p53 function on cellular sensitivity to the cytotoxic action of 5-fluorouracil (5-FU). Therefore the objective of this study was to determine the combined effects of adenovirus-mediated wild-type (wt) p53 gene transfer and 5-FU chemotherapy on pancreatic cancer cells with different p53 gene status.

METHODS: Human pancreatic cancer cell lines Capan-1p53mut, Capan-2p53wt, FAMPACp53mut, PANC1p53mut, and rat pancreatic cancer cell lines ASp53wt and DSL6Ap53null were used for in vitro studies. Following infection with different ratios of Ad-p53-particles (MOI) in combination with 5-FU, proliferation of tumor cells and apoptosis were quantified by cell proliferation assay (WST-1) and FACS (PI-staining). In addition, DSL6A syngeneic pancreatic tumor cells were inoculated subcutaneously in to Lewis rats for in vivo studies. Tumor size, apoptosis (TUNEL) and survival were determined.

RESULTS: Ad-p53 gene transfer combined with 5-FU significantly inhibited tumor cell proliferation and substantially enhanced apoptosis in all four cell lines with an alteration in the p53 gene compared to those two cell lines containing wt-p53. in vivo experiments showed the most effective tumor regression in animals treated with Ad-p53 plus 5-FU. Both in vitro and in vivo analyses revealed that a sublethal dose of Ad-p53 augmented the apoptotic response induced by 5-FU.

CONCLUSION: Our results suggest that Ad-p53 may synergistically enhance 5-FU-chemosensitivity most strikingly in pancreatic cancer cells lacking p53 function. These findings illustrate that the anticancer efficacy of this combination treatment is dependent on the p53 gene status of the target tumor cells.

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