Modulation of drug cytotoxicity by Iressa (ZD1839) in pancreatic cancer cell lines.
High expression of the epidermal growth factor receptor (EGFR) family confers a growth advantage on malignant cells in various tumor types. Most pancreatic cancers express EGFR, which seems to play an important role in the acquisition of aggressive clinical behaviour and in tumor invasion. Iressa (ZD1839), a quinazoline tyrosine kinase inhibitor selective for the EGF receptor, has shown good anti-tumor activity in both preclinical and clinical studies. Using two pancreatic cancer cell lines that express different EGFR and ErbB-2 levels, we analyzed the activity of Iressa and evaluated its modulation effect on four conventional cytotoxic drugs: gemcitabine, oxaliplatin, docetaxel and SN38. Iressa was tested at scalar doses up to the plasma peak level concentration and showed a similar weak cytostatic effect in both cell lines. Conversely, an additive or weak synergistic effect was observed when the drug was administered simultaneously with or following cytotoxic drugs. Our data show that Iressa has only a weak activity at doses within the plasmatic peak concentration and that its effect is independent of EGFR and p42/p44 expression and phosphorylation levels. This is in agreement with recent literature data that attribute an essential role to a specific EGFR mutation in mediating response to Iressa. This mutation was absent in both pancreatic cell lines tested.
Rosetti
M
M
Istituto Oncologico Romagnolo, Morgagni-Pierantoni Hospital, Forlì, Italy.
Tesei
A
A
Ulivi
P
P
Fabbri
F
F
Vannini
I
I
Brigliadori
G
G
Granato
A M
AM
Amadori
D
D
Zoli
W
W
D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000187:drug effects; D000077156:Gefitinib; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011799:Quinazolines / Q000097:blood / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D000077156:Gefitinib