Abstract
Chemotherapy does not significantly improve prognosis in pancreatic cancer. New therapeutical approaches involving p53 gene replacement appear to be very encouraging due to the key role of p53 in the cell response to DNA damage. Here, we have evaluated the effectiveness of combining wild-type p53 (wt-p53) gene reintroduction (Ad5CMV-p53) and exposure to two genotoxic drugs, gemcitabine and cisplatin, in several human pancreatic cell lines. The efficiency of the combinations was clearly dependent upon timing, as assessed by cell survival determinations. Although wt-p53 transduction before drug treatment induced chemoresistance, p53 transduction in cells treated previously with gemcitabine increased cytotoxicity. Cell cycle profiles showed significant decreases in the percentage of cells in the S phase as a consequence of arrests provoked by the expression of exogenous p53, reducing the number of cells susceptible to the drug. The sensitivity of cells to cisplatin, which has a lower degree of S-phase specificity, was not modified as much by p53 gene replacement. In contrast, the recognition of the previous drug-induced DNA damage by the newly expressed wt-p53 elicited increases in sub-G1 populations, consistent with the annexin determinations and bax/bcl-2 ratios observed. Experiments on subcutaneous pancreatic xenografts corroborated the effectiveness of this approach in vivo. Thus, the combination of p53 transduction and chemotherapy, under a correct schedule of administration, appears to be a very promising therapy for human pancreatic cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cascalló, M., Calbó, J., Gelpí, J. et al. Modulation of drug cytotoxicity by reintroduction of wild-type p53 gene (Ad5CMV-p53) in human pancreatic cancer. Cancer Gene Ther 7, 545–556 (2000). https://doi.org/10.1038/sj.cgt.7700150
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.cgt.7700150
Keywords
This article is cited by
-
An EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms
Nature Communications (2022)
-
Redox-responsive targeted gelatin nanoparticles for delivery of combination wt-p53 expressing plasmid DNA and gemcitabine in the treatment of pancreatic cancer
BMC Cancer (2014)
-
Trichostatin A enhances the response of chemotherapeutic agents in inhibiting pancreatic cancer cell proliferation
Virchows Archiv (2006)
-
Overexpression of p73 enhances cisplatin-induced apoptosis in HeLa cells
Archives of Pharmacal Research (2006)
-
Cooperative effect of adenoviral p53 gene therapy and standard chemotherapy in ovarian cancer cells independent of the endogenous p53 status
Cancer Gene Therapy (2004)