| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
Thymidine phosphorylase (TP) is expressed at higher levels in a variety of human cancers than in adjacent normal tissue. It is reported that the higher expression is associated with an increase of intratumoral microvessel density and a poor prognosis. We investigated the role of TP in human non-small cell lung cancers (NSCLC). The concentrations of TP in the tumors and the adjacent normal tissue from surgically resected specimens of 54 cases of NSCLC were measured by using an enzyme-linked immunosorbent assay. Tumor specimens were also examined immunohistochemically. TP concentrations in the tumors were 169 ± 18 Unit/mg protein (mean ± SD), whereas those in normal tissue were 43 ± 4 Unit/mg protein (mean ± SD) consistent with TP staining patterns. There was no correlation between TP expression and microvessel density. Among clinicopathological factors examined, the concentrations of TP but not TP immunoreactivity correlated with tumor differentiation in lung adenocarcinoma. Although a
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specific TP inhibitor (TPI) and overexpression of TP did not affect the growth of A549 lung adenocarcinoma cells, Matrigel invasion assay showed that A549 transfected with TP had higher invasive potential than mock transfectant and such enhanced invasive activity was dramatically diminished by treatment with TPI. Furthermore, administration of TPI suppressed lung metastasis of TP-overexpressing A549 cells in nude mice. These results demonstrate that TP may play an important role in tumor differentiation, invasiveness, and metastasis in lung adenocarcinoma and suggest that TP could be a novel target for treatment of TP-overexpressing lung adenocarcinoma.
It has been speculated that clarithromycin (CAM), a 14-membered ring macrolide, has an antitumor effect besides antimicrobial and anti-inflammatory effects. We evaluated the effects of CAM on growth and invasiveness of A549 lung adenocarcinoma cells. Although CAM did not affect the growth of A549 cells, Matrigel invasion assay showed that the potential of invasion was diminished by CAM treatment. When analyzed by flow cytometry, CAM suppressed integrin α2 and β1 expression. Furthermore, thymidine phosphorylase (TP) expression was diminished by CAM treatment in a dose-dependent manner. A specific TP inhibitor also suppressed expression of β1. integrin in flow cytometry analysis. These results suggest that CAM may suppress invasive activity of A549 cells in part by diminishing the expression of TP, integrin α2, and integrin β1, which may be a downstream signal of TP pathway, and that CAM could be useful for the treatment of lung adenocarcinoma. Less
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