Sequence-dependent effects of ZD1839 ('Iressa') in combination with cytotoxic treatment in human head and neck cancer.
Elevated levels of epidermal growth factor receptor in head and neck cancer have been extensively reported, and are correlated with poor prognosis. The combination of cisplatin and 5-fluorouracil is a standard treatment regimen for head and neck cancer, with radiation representing another therapeutic option. Six head and neck cancer cell lines were used to study the cytotoxic effects of combining ZD1839 ('Iressa'), a new selective epidermal growth factor receptor tyrosine kinase inhibitor, and radiation. Two of the cell lines were also used to study the combination of ZD1839 and cisplatin/5-fluorouracil. Cytotoxic effects were assessed by the MTT test. The results indicated that ZD1839 applied before radiation gave the best effects (P=0.002); an effect that was strongest in those p53-mutated cell lines that express the highest epidermal growth factor receptor levels. The effects of ZD1839 with cisplatin and/or 5-fluorouracil were sequence dependent (P<0.003), with the best results achieved when ZD1839 was applied first. For the triple combinations, ZD1839 applied before cisplatin and 5-fluorouracil resulted in a slight synergistic effect (P=0.03), although the effect was greater when ZD1839 was applied both before and during cytotoxic drug exposure. In conclusion, ZD1839 applied before radiation and before and/or during cisplatin/5-fluorouracil may improve the efficacy of treatment for head and neck cancer.
Magné
N
N
Department of Oncopharmacology, Oncopharmacology Unit, Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice Cedex 2, France.
Fischel
J L
JL
Dubreuil
A
A
Formento
P
P
Marcié
S
S
Lagrange
J-L
JL
Milano
G
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000008:administration & dosage; D000077156:Gefitinib; D016158:Genes, p53; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D011799:Quinazolines / Q000494:pharmacology*; D017978:Receptors, Growth Factor / Q000096:biosynthesis; D011975:Receptors, Mitogen / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011799:Quinazolines; D017978:Receptors, Growth Factor; D011975:Receptors, Mitogen; D040262:Receptors, Vascular Endothelial Growth Factor; D002945:Cisplatin; D000077156:Gefitinib; D005472:Fluorouracil