ZD1839 ('Iressa'), a specific oral epidermal growth factor receptor-tyrosine kinase inhibitor, potentiates radiotherapy in a human colorectal cancer xenograft model.
The effect of ZD1839 ('Iressa'), a specific inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor, on the radiation response of human tumour cells (LoVo colorectal carcinoma) was evaluated in vitro and in vivo. ZD1839 (0.5 microM, incubated days 1-5) significantly increased the anti-proliferative effect of fractionated radiation treatment (2 Gy day(-1), days 1-3) on LoVo cells grown in vitro (P=0.002). ZD1839 combined with either single or fractionated radiotherapy in mice bearing LoVo tumour xenografts, also produced a highly significant increase in tumour growth inhibition (P< or = 0.001) when compared to treatment with either modality alone. The radio-potentiating effect of ZD1839 was more apparent when radiation was administered in a fractionated protocol. This phenomenon may be attributed to an anti proliferative effect of ZD1839 on tumour cell re-population between radiotherapy fractions. These data suggest radiotherapy with adjuvant ZD1839 could enhance treatment response. Clinical investigation of ZD1839 in combination with radiotherapy is therefore warranted.
Williams
K J
KJ
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK. Kaye.Williams@man.ac.uk
Telfer
B A
BA
Stratford
I J
IJ
Wedge
S R
SR
D000818:Animals; D002277:Carcinoma / Q000473:pathology* / Q000532:radiotherapy; D002455:Cell Division; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000473:pathology* / Q000532:radiotherapy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000077156:Gefitinib; D006801:Humans; D051379:Mice; D011799:Quinazolines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D004791:Enzyme Inhibitors; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D000077156:Gefitinib