Erlotinib in combination with capecitabine (5'dFUR) in resistant pancreatic cancer cell lines.
The combination of capecitabine and the tyrosine kinase inhibitor erlotinib has recently been tested in patients with gemcitabine-refractory pancreatic tumors, with limited success. To understand this lack of efficacy, we studied the molecular effects of these agents in Capan-1 and Capan-2 human pancreatic resistant cancer cells. Erlotinib up-regulated thymidine phosphorylase (+50%) and downregulated dihydropyrimidine dehydrogenase (+55%) in a cell-dependent manner, thus suggesting that the combination should result in synergism. However, only mild additivity was achieved at best when combining both drugs, and several sequences tested even led to strong antagonism. Further experiments were performed to understand this lack of efficacy. We found that the fluoropyrimidine down-regulated EGFR expression by 30%, an unexpected finding resulting in a possible reduction in efficacy when cells were subsequently exposed to erlotinib. We also observed marked drug-induced over-expression of both cytosolic and extracellular vascular endothelial growth factor (VEGF) secretion, thus possibly triggering proliferation. These preliminary findings strongly suggest that these observations could be new mechanisms in the development of acquired drug resistance in pancreatic cancer cells.
Chefrour
M
M
Oncopharmacology Unit, Centre Antoine Lacassagne, Nice, France.
Fischel
J-L
JL
Formento
P
P
Giacometti
S
S
Ferri-Dessens
R-M
RM
Marouani
H
H
Francoual
M
M
Renée
N
N
Mercier
C
C
Milano
G
G
Ciccolini
J
J
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000069287:Capecitabine; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000096:biosynthesis; D000069347:Erlotinib Hydrochloride; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D010190:Pancreatic Neoplasms; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D013939:Thymidine Phosphorylase / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D000964:Antimetabolites, Antineoplastic; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D000069287:Capecitabine; D000069347:Erlotinib Hydrochloride; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; D066246:ErbB Receptors; D005472:Fluorouracil