Enhancement of Gemcitabine-Induced Apoptosis by Restoration of p53 Function in Human Pancreatic Tumors

Vol. 68, No. 2-3, 2005

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Laboratory Investigation

Enhancement of Gemcitabine-Induced Apoptosis by Restoration of p53 Function in Human Pancreatic Tumors
Manel Cascalló^a,b, Joaquim Calbó^a, Gabriel Capellà^b, Cristina Fillat^c, Marçal Pastor-Anglada^a, Adela Mazo^a

^aDepartment of Biochemistry and Molecular Biology, University of Barcelona,
^bLaboratori de Recerca Translacional, Institut Català d'Oncologia,
^cCentre de Regulació Genòmica, Barcelona, Spain

Address of Corresponding Author

Oncology 2005;68:179-189 (DOI: 10.1159/000086772)

Key Words

Gemcitabine
Apoptosis
p53
Pancreatic cancer

Abstract

Human pancreatic adenocarcinomas are highly resistant to conventional treatment modalities, specially to chemotherapy. Among the genes that modulate apoptosis in response to cytotoxic drugs, the role of p53 has been demonstrated to be of paramount importance. Moreover, p53 is mutated in close to 50% of pancreatic cancer, which renders attractive the reintroduction of this gene as a way to enhance the action of chemotherapeutics. In this paper, gemcitabine, the most effective drug for the treatment of pancreatic tumors, has been selected to develop a new combination approach in vivo based on an administration schedule previously optimized in vitro. In a human xenograft model, the sequential administration of gemcitabine and p53 resulted in potent tumor growth inhibition. Statistical differences were observed with respect to the growth of tumors receiving only gemcitabine or p53. Moreover, the chemosensitization observed in tumors treated with the combination gemcitabine-p53 correlated with differential histological features such as important increases in intratumoral fibrosis and apoptotic levels, when compared with unimodal treatments. Taken together, our data indicate that reintroduction of p53 function in human pancreatic tumors in vivo allows to restore molecular pathways improving the response to gemcitabine. It may constitute a useful step towards a better clinical treatment of patients harboring pancreatic cancer.

Author Contacts

Dr. A. Mazo
Department of Biochemistry and Molecular Biology
Diagonal 645
ES-08028 Barcelona (Spain)
Tel. +34 93 402 12 10, Fax +34 93 402 15 59, E-Mail amazo@uq.edu

Article Information

Received: December 30, 2003
Accepted after revision: June 25, 2004
Published online: July 4, 2005
Number of Print Pages : 11
Number of Figures : 6, Number of Tables : 1, Number of References : 43

Medline Abstract (ID 16006755)

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