Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth.
BACKGROUND
Co-expression of the epidermal growth factor receptor (EGFR) and of ErbB-2 is found in a subset of primary human breast cancer.


METHODS
The antiproliferative effects of anti-EGFR and anti-ErbB-2 agents were evaluated using a monolayer assay. The effects of these agents on the activation of EGFR, ErbB-2, AKT and p42/p44 MAP kinases (MAPK) were investigated by western blot analysis.


RESULTS
We found that both ZD1839 (Iressa), a specific EGFR tyrosine kinase inhibitor, and trastuzumab (Herceptin) (TRA), a humanized anti-ErbB-2 monoclonal antibody, were able to inhibit the growth of SK-Br-3 and BT-474 breast carcinoma cells, which express both EGFR and ErbB-2. Treatment of breast carcinoma cells with a combination of ZD1839 and TRA resulted in a synergistic inhibitory effect. Treatment of SK-Br-3 cells with ZD1839 produced a significant, dose-dependent reduction of the tyrosine phosphorylation of both EGFR and ErbB-2. Phosphorylation of MAPK and AKT were significantly reduced in SK-Br-3 cells following treatment with ZD1839, whereas treatment with TRA produced a reduction of AKT but not MAPK phosphorylation. Finally, treatment with ZD1839, but not with TRA, produced a significant increase in fragmented DNA in breast carcinoma cells. However, a more pronounced increase in the levels of fragmented DNA was observed following combined treatment with ZD1839 and TRA.


CONCLUSIONS
These data suggest that combined treatment with drugs that target EGFR and ErbB-2 might result in an efficient inhibition of tumor growth in those breast carcinoma patients whose tumors co-express both receptors.
Normanno
N
N
Oncologia Sperimentale D, Istituto Tumori Milano, Milan, Italy. nicnorm@yahoo.com
Campiglio
M
M
De
Luca A
LA
Somenzi
G
G
Maiello
M
M
Ciardiello
F
F
Gianni
L
L
Salomon
D S
DS
Menard
S
S
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004273:DNA, Neoplasm; D066246:ErbB Receptors; D000077156:Gefitinib; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C494918:AKT1 protein, human