© 2005 European Society for Medical Oncology
Invited Paper |
Sequence-dependent antiproliferative effects of cytotoxic drugs and epidermal growth factor receptor inhibitors
1 Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale F. Magrassi e A. Lanzara, Seconda Università degli Studi di Napoli, Napoli, Italy; 2 University of Colorado Health Sciences Center, Denver, CO, USA; 3 Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università degli Studi di Napoli Federico II, Napoli, Italy
* Correspondence to: Dr Fortunato Ciardiello, Cattedra di Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale ‘F. Magrassi e A. Lanzara’, Seconda Università degli Studi di Napoli, Via S. Pansini, 5 – 80 131 Naples, Italy. Tel: +39-081-5666745; Fax: +39-081-5666728; Email: fortunato.ciardiello{at}unina2.it
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.
Materials and 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 G2/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.
Key words: Cytotoxic drugs, combination therapy, epidermal growth factor receptor inhibitors, monoclonal antibodies, small molecule tyrosine kinase inhibitors
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