|Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
The IC50 values against gefitinib was 0.028, 0.32, 0.078, and 0.091 μ M respectively for HER2 over-expressing cell lines GLM-1, GLM-2, GLM-4, and NIC-N87 established from gastric cancer liver metastases whereas they were >10 μ M in other gastric cancer cell lines. Gefitinib also exhibited eminent antiproliferative effect against GLM-1 xenografts in vivo. Gefitinib induced apoptosis in HER2 over-expressing cells at a dose of 1 μ M. LY294002, a blocker of the PI3K pathway, also induced apoptosis whereas U016 did not, and proliferation of HER2 over-expressing cells are considered to be mediated mainly through the PI3K pathway. In GLM-1, the phosphorylation of Erkl/2 was induced by ligand stimulation, but gefitinib was found to prevent this phosphorylation. Constitutive phosphorylation of Akt without ligand stimulation was observed in all cell lines, but this autophosphorylation was blocked by gefitinib only in HER2 over-expressing cell lines.
GLM-1R, a gefitinib resistant clone of GLM-1 li
neage, was created by exposure to low dose gefitinib. The IC50 value of GLM-1R was 1.82μ M and was 65-fold that of parental GLM-1. Constitutive phosphorylation of Akt was observed in the absence of ligand stimulation in GLM-1R to the extent observed in the parental cell line, but phosphorylation of Shc and Erkl/2 was more prominent in the resistant clone, suggesting that signal transduction through the MAPK pathway compensates for the blockage of PI3K pathway by gefitinib, thus conferring drug resistance.
Collagen gel droplet chemosensitivity test was performed with 30 fresh surgically resected specimens to test for sensitivity against gefitinib. Of three specimens found sensitive, all three were not stained for EGFR whereas two were strongly stained for HER2. In addition, of four patients with hepatic metastases, two stained positive for HER2 and were sensitive against gefitinib. Thus, a specific subgroup of gastric cancer that expresses HER2, has propensity towards liver metastasis, and is vulnerable to a treatment with gefitinib does exist. Less