Abstract. The epidermal growth factor receptor (EGFR) is a member of the EGFR family of receptors. EGFR and other members of the EGFR family have been shown to play significant roles in human cancer cell proliferation and therefore present important molecular targets for the treatment of cancer. The purpose of this study was to examine the effect of the pan-erbB tyrosine kinase inhibitor CI-1033 against esophageal squamous cell carcinoma in vitro and in vivo. We selected 4 human esophageal squamous cell carcinoma cell lines (TT, TE2, TE6, and TE10), and determined their expression of EGFR and HER2. We examined the ability of CI-1033 to inhibit cell growth in vitro and in vivo. EGFR and HER2 were overexpressed in all 4 esophageal cancer cells. We found that CI-1033 could inhibit the growth of esophageal cancer cell lines in a dose-dependent manner with the inhibition of phosphorylation of both MAPK and AKT. The oral administration of CI-1033 exerted a significant antitumor effect on esophageal cancer tumors in athymic nude mice. Our results suggest that CI-1033 effectively inhibits the growth of esophageal squamous cell carcinoma which co-expresses both EGFR and HER2 with the inhibition of phosphorylation of both MAPK and AKT. Furthermore, in vivo animal studies of CI-1033 suggest that CI-1033 holds significant clinical potential in esophageal cancer.
Abstract. The ERBB proteins are cell membrane tyrosine kinase receptors. Among these receptors, ERBB1 (EGFR or HER1) and ERBB2 (HER2/Neu) have been reported to be the most important in terms of the development and progression of squamous cell carcinoma of the esophagus (SCC). Thus, targeting of ERBB1 and ERBB2 may become a promising strategy to treat SCC. In the present study, we examined ERBB1 and ERBB2 expression of SCC cell lines (TT, TE2, TE6 and TE10) and tumor samples. In addition, we evaluated the effect of the anti-ERBB1 antibody cetuximab and the anti-ERBB2 antibody trastuzumab for SCC in vitro and in vivo. Biological activities (receptor downregul ation, the phosphorylation of MAPK and AKT) induced by the two agents were also investigated. Immunohistochemistry of SCC samples showed that ERBB1 was detected in 84%, while ERBB2 was detected in 30%. RT-PCR analysis revealed that ERBB1 and ERBB2 mRNA were detectable in all four cell lines. MTT cell proliferation analysis showed that cetuximab, but not trastuzumab, inhibited growth in each of the SCC cell lines in a dose-dependent manner. Further, cetuximab and trastuzumab used together produced stronger inhibition of growth compared to cetuximab alone. Cetuximab downregulated ERBB1, but not ERBB2, at the TE6 cell surface. However, neither ERBB1 nor ERBB2 showed any downregul ation by trastuzumab at the TE6 cell surface. Cetuximab, not but trastuzumab, inhibited the phosphorylation of MAPK and Akt. When administered in combination, the two agents inhibited Akt phosphorylation to a greater degree compared to treatment with cetuximab alone. In the in vivo study, cetuximab, but not trastuzumab, significantly inhibited the TT tumors. Additionally, the combination of cetuximab with trastuzumab induced a synergistic inhibitory antitumor effect in the TT tumors. In conclusion, combination of cetuximab and trastuzumab revealed a synergistic antitumor effect for SCC in vitro and in vivo. The antitumor effect may be induced by the inhibition of the phosphorylation of Akt. These findings suggest that combination therapy including cetuximab and trastuzumab may be a promising strategy to treat SCC.
A 60-year-old man was refferred to our hospital with complaints of abdominal fullness, diarrhea and massive ascites. Puncture of the ascites detected chylous ascites. Abdominal computed tomography (CT) scans showed considerable thickness and calcification of the mesentery. High levels of CA125 and sIL-2r were detected in the ascites. Laparotomy was performed for diagnosis, and showed massive chylous ascites and sclerotic, as well as allowing us to shorten the mesentery. We resected a short segment of the ileum with the thickening mesentery. Histopathological findings showed mesenteric panniculitis. Treatment with steroids temporarily improved the symptoms of diarrhea and ascites ; however, the number of ascites eventually increased. Five months after operation, he suffered from perforative peritonitis and treated with surgery, after which the ascites disappeared and CA125 levels were normalized.
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