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.
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 in vitro 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(1) and G(2)-M phases, with a decrease in the S-phase 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-PKc pathways after radiation. Tumor xenograft studies demonstrated that the combination of gefitinib and radiation caused growth inhibition and tumor regression of well-established OSCC tumors in athymic mice; tumor volume was reduced from 1,008.2 to 231.4 mm(3) in HSC2 cells (p < 0.01) and from 284.2 to 12.4 mm(3) in HSC3 cells (p < 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.
Department of Oral and Maxillofacial Surgery, Ehime University School of Medicine, 454 Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan. satoru@m.ehime-u.ac.jp
Satoru
S
Shintani
Chunnan
C
Li
Mariko
M
Mihara
Nagaaki
N
Terakado
Junya
J
Yano
Koh-ichi
K
Nakashiro
Hiroyuki
H
Hamakawa
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D002455:Cell Division / Q000187:drug effects* / Q000528:radiation effects; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D000077156:Gefitinib; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D011799:Quinazolines / Q000627:therapeutic use*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D011799:Quinazolines; D000077156:Gefitinib