• Mika Fukutome, Katsuya Maebayashi, Sachiko Nasu, Kaori Seki, and Norio Mitsuhashi.
• Department of Radiology, Tokyo Women's Medical University, School of Medicine, Tokyo, Japan. fukutome@rad.twmu.ac.jp
• Int. J. Radiat. Oncol. Biol. Phys. 2006 Oct 1; 66 (2): 528-36.

PurposeThe aims of this study were twofold: (1) to examine the effects of dual inhibition of 2 members of the HER family, the epidermoid growth factor receptor (EGFR) and HER2/neu, by gefitinib (ZD1839) and trastuzumab on radiosensitivity; and (2) to explore the molecular mechanism of radiosensitization especially focusing on the survival signal transduction pathways by using A431 human vulvar squamous carcinoma cells expressing EGFR and HER2/neu.Methods And MaterialsThe effects of inhibitors on the radiation-induced activation of EGFR and/or HER2/neu, and the intracellular proteins that are involved in their downstream signaling, were quantified by the Western blot. Radiosensitizing effects by the blockage of EGFR and/or HER2/neu were determined by a clonogenic assay.ResultsRadiation-induced activation of the EGFR and HER2/neu was inhibited with ZD1839 and/or trastuzumab. ZD1839 also inhibited the radiation-induced phosphorylation of HER2/neu. Radiation in combination with the HER family inhibitors inhibited the activation of Akt and MEK1/2, the downstream survival signaling of the HER family. ZD1839 enhanced radiosensitivity with a dose-modifying factor (DMF) (SF3) of 1.45 and trastuzumab did so with a DMF (SF3) of 1.11. Simultaneous blockade of EGFR and HER2/neu induced a synergistic radiosensitizing effect with a DMF (SF3) of 2.29.ConclusionsThe present data suggest that a dual EGFR and HER2/neu targeting may have potential for radiosensitization in tumors in which both of these pathways are active.

45 keywords...

hide…