Study for the development of molecular therapy targeting the signal transduction pathway through epidermal growth factor receptor

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Treatment with gefitinib increased the efficacy of the cisplatin-induced inhibition in the intraabdominal dissemination and production of ascites in athymic nude mice inoculated intraperitoneally with cisplatin-resistant Caov-3cells. Immunofluorescent reactivity for phosphorylated EGFR in tumors treated with gefitinib alone and combination of cisplatin + gefitinib was clearly reduced compared with that in tumors treated with vehicle and cisplatin alone. Similar Results were found for the phosphorylation of ERK and Akt.We next investigated the expression of DNA-PK by immunofluorescent staining with anti-DNA-PK antibody. Treatment with cisplatin significantly increased the expression of DNA-PK in nuclei compared with that in tumors treated with vehicle. Treatment with combination of cisplatin + gefitinib significantly reduced the expression of DNA-PK compared with treatment with cisplatin alone. These results suggested that inhibition of DNA repair by gefitinib enhanced the efficacy of cisplatin.Moreover, we investigated the effects of platinum-based chemotherapy on the signaling cascades and apoptosis before and after chemotherapy in patients with ovarian cancers using specimens obtained during surgical procedures. The increase in ERK phosphorylation was more consistent than that of Akt. Increases in apoptotic marker expression were observed in all patients exposed to chemotherapy. Activation of ERK by chemotherapy may be associated with apoptosis of tumor cells in patients with ovarian cancers.