{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T22:10:48Z","timestamp":1790374248390,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2003,9,12]],"date-time":"2003-09-12T00:00:00Z","timestamp":1063324800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2003,12,20]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Molecular blockade of EGFR with either an EGFR MAb or an EGFR TKI enhances the radiosensitivity of human SCCs. In the present study, we investigated whether treatment with the EGFR TKI gefitinib (Iressa, ZD1839) improves the response to radiotherapy in the OSCC cell lines HSC2 and HSC3. We examined potential mechanisms that may contribute to the enhanced radiation response induced by gefitinib. Growth inhibition was observed <jats:italic>in vitro<\/jats:italic> with radiation or gefitinib. A cooperative antiproliferative effect was obtained when cancer cells were treated with radiation followed by gefitinib. Cells treated with a combination of radiation and gefitinib arrested in G<jats:sub>1<\/jats:sub> and G<jats:sub>2<\/jats:sub>\u2013M phases, with a decrease in the S\u2010phase population. While radiation alone did not significantly affect MEK1\/2 and p38 MAPK autophosphorylation, the combination of gefitinib and radiation completely inhibited the downstream signaling of EGFR. Results from DNA damage repair analysis in cultured OSCC cells demonstrated that gefitinib had a strong inhibitory effect on DNA\u2010PKc pathways after radiation. Tumor xenograft studies demonstrated that the combination of gefitinib and radiation caused growth inhibition and tumor regression of well\u2010established OSCC tumors in athymic mice; tumor volume was reduced from 1,008.2 to 231.4 mm<jats:sup>3<\/jats:sup> in HSC2 cells (<jats:italic>p<\/jats:italic> &lt; 0.01) and from 284.2 to 12.4 mm<jats:sup>3<\/jats:sup> in HSC3 cells (<jats:italic>p<\/jats:italic> &lt; 0.01). Immunohistochemical analysis of OSCC xenografts revealed that gefitinib caused a striking decrease in tumor cell proliferation when combined with radiotherapy. Overall, we conclude that gefitinib enhances tumor radioresponse by multiple mechanisms that may involve antiproliferative growth inhibition and effects on DNA repair after exposure to radiation. \u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.11437","type":"journal-article","created":{"date-parts":[[2004,1,24]],"date-time":"2004-01-24T23:45:04Z","timestamp":1074987904000},"page":"1030-1037","source":"Crossref","is-referenced-by-count":77,"title":["Enhancement of tumor radioresponse by combined treatment with gefitinib (Iressa, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, is accompanied by inhibition of DNA damage repair and cell growth in oral cancer"],"prefix":"10.1002","volume":"107","author":[{"given":"Satoru","family":"Shintani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunnan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko","family":"Mihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagaaki","family":"Terakado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junya","family":"Yano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koh\u2010ichi","family":"Nakashiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Hamakawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2003,9,12]]},"reference":[{"key":"e_1_2_5_2_2","first-page":"25","article-title":"Regulatory features of the epidermal growth factor receptor","volume":"5","author":"Gill GN","year":"1987","journal-title":"J Cell Physiol"},{"key":"e_1_2_5_3_2","first-page":"2703","article-title":"Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy","volume":"3","author":"Mendelsohn J","year":"1997","journal-title":"Clin Cancer Res"},{"key":"e_1_2_5_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/89.17.1271"},{"key":"e_1_2_5_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19930515)71:10<2902::AID-CNCR2820711004>3.0.CO;2-J"},{"key":"e_1_2_5_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/90.11.824"},{"key":"e_1_2_5_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/81.13.1020"},{"key":"e_1_2_5_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1991.286"},{"key":"e_1_2_5_9_2","first-page":"1935","article-title":"Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck","volume":"59","author":"Huang SM","year":"1999","journal-title":"Cancer Res"},{"key":"e_1_2_5_10_2","first-page":"2166","article-title":"Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis","volume":"6","author":"Huang SM","year":"2000","journal-title":"Clin Cancer Res"},{"key":"e_1_2_5_11_2","first-page":"701","article-title":"In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody","volume":"6","author":"Milas L","year":"2000","journal-title":"Clin Cancer Res"},{"key":"e_1_2_5_12_2","first-page":"4343","article-title":"Antitumor activity of combined treatment of human cancer cells with ionizing radiation and anti\u2010epidermal growth factor receptor monoclonal antibody C225 plus type I protein kinase A antisense oligonucleotide","volume":"6","author":"Bianco C","year":"2000","journal-title":"Clin Cancer Res"},{"key":"e_1_2_5_13_2","doi-asserted-by":"publisher","DOI":"10.1053\/sonc.2002.31521"},{"key":"e_1_2_5_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6600182"},{"key":"e_1_2_5_15_2","unstructured":"HuangS LiJ HarariPM.Modulation of radiation response and tumor\u2010induced angiogenesis following EGFR blockade by ZD1839 (Iressa) in human squamous cell carcinomas. 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