Sequence-dependent antiproliferative effects of cytotoxic drugs and epidermal growth factor receptor inhibitors.
BACKGROUND
Epidermal growth factor receptor (EGFR) inhibitors are in clinical development in cancer treatment. Preclinical studies have shown potential antitumor efficacy of these agents in combination with chemotherapy or with radiotherapy. However, controversial results have been obtained in different clinical trials.


METHODS
The effects on proliferation, cell cycle distribution and induction of apoptosis of three different anti-EGFR agents (gefitinib, ZD6474, cetuximab) were evaluated in different sequences of combination with either a platinum derivative (cisplatin, carboplatin, oxaliplatin) or a taxane (docetaxel, paclitaxel) in KYSE30 cells, a model of a human cancer cell line with a functional EGFR autocrine pathway.


RESULTS
The combination of a cytotoxic drug with an EGFR inhibitor caused different antiproliferative effects on KYSE30 cancer cells depending on the treatment schedule. An antagonistic effect was observed when treatment with each EGFR inhibitor was done before chemotherapy. In contrast, a synergistic antiproliferative activity was obtained when chemotherapy was followed by treatment with EGFR antagonists. This effect was accompanied by potentiation of apoptosis and arrest of the surviving cancer cells in the G(2)/M phases of the cell cycle.


CONCLUSIONS
This study provides a rationale for the evaluation of a potentially synergistic sequence of cytotoxic drugs and EGFR inhibitors in a clinical setting.
Morelli
M P
MP
Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale F. Magrassi e A. Lanzara, Seconda Università degli Studi di Napoli, Napoli, Italy.
Cascone
T
T
Troiani
T
T
De Vita
F
F
Orditura
M
M
Laus
G
G
Eckhardt
S G
SG
Pepe
S
S
Tortora
G
G
Ciardiello
F
F
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D000068818:Cetuximab; D002945:Cisplatin / Q000627:therapeutic use; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D000077156:Gefitinib; D006801:Humans; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D043823:Taxoids / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010880:Piperidines; D011799:Quinazolines; D043823:Taxoids; D000077150:Oxaliplatin; D000077143:Docetaxel; D016190:Carboplatin; D066246:ErbB Receptors; D017239:Paclitaxel; D000068818:Cetuximab; D002945:Cisplatin; D000077156:Gefitinib; C452423:vandetanib