| Project/Area Number |
18390220
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
YAMAMOTO Hiroyuki Sapporo Medical University, School of Medicine, Instructor (40332910)
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| Co-Investigator(Kenkyū-buntansha) |
SHINOMURA Yasuhisa Sapporo Medical University, School of Medicine, Professor (90162619)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,840,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥2,040,000)
Fiscal Year 2007: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
Fiscal Year 2006: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | insulin-like growth factor / extracellular matrix degrading enzyme / gastrointestinal cancer / microsatellite instability / IGF- 1 receptor / dominant negative / tyrosine kinase inhibitor / Akt / 細胞外基質分解酵素 / ERK / IGF-I receptor / Akt-1 / bystander効果 |
|---|
| Research Abstract |
Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal cancers. The association between the expression of IGF-IR and IGF-II ligand and prognosis was investigate in surgically resected esophageal squamous cell carcinoma (ESCC). We then assessed the therapeutic effect of blocking IGF-IR signaling using dominant negative IGF-IR (IGF-IR/dn) in ESCC in vitro. Expression of IGF-IR and IGF-II were detected in 60 and 50% of tumors, respectively, and were associated with the progression and recurrence. Patients with tumors expressing both IGF-IR and IGF-II had the worst prognosis in both single and multivariate analysis. IGF-IR/dn suppressed proliferation and motility as well as upregulating chemotherapy-induced apoptosis through blocking ligand-induced Akt activation. Detection of IGF-IR/IGF-II in ESCC may be useful for the prediction of recurrence and poor prognosis and for selecting patients for IGF-IR-targeted the
… More
rapy.
We assessed the effect of a new tyrosine kinase inhibitor of IGF-IR, NVP-AEW541 on signal transduction, proliferation, survival, and migration in gastrointestinal cancer cells. The effects of NVP-AEW541 alone and with chemotherapy were studied in vitro and in nude mouse xenografts. We also analyzed the effects of NVP-AEW541 on insulin signals and hybrid receptor formation between IGF-IR and insulin receptor. NVP-AEW541 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by IGFs, but not by insulin. NVP-AEW541 suppressed proliferation and tumorigenicity in vitro in a dose dependent manner in all cell lines. The drug inhibited tumor as a single agent and when combined with stressors, up-regulated apoptosis in a dose dependent fashion, and inhibited mobility. NVP-AEW541 augmented the effects of chemotherapy on in vitro growth and induction of apoptosis. Moreover, the combination of NVP-AEW541 and chemotherapy was highly effective against tumors in mice. Thus, NVP-AEW541 may have significant therapeutic utility in human gastrointestinal carcinomas, both alone and incombination with chemotherapy. Less
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