Enhancement of gemcitabine-induced apoptosis by restoration of p53 function in human pancreatic tumors.
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.
Cascalló
Manel
M
Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.
Calbó
Joaquim
J
Capellà
Gabriel
G
Fillat
Cristina
C
Pastor-Anglada
Marçal
M
Mazo
Adela
A
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003124:Colorimetry; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004334:Drug Administration Schedule; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000494:pharmacology; D001616:beta-Galactosidase / Q000097:blood; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; D001616:beta-Galactosidase; D000093542:Gemcitabine