Dissertation
Dissertation > Medicine, health > Oncology > General issues > Tumor Therapy

The Insulin-like Growth Factor Receptor-I (IGF-IR) is a Potent Target for Cancer Therapy

Author LiuShiGuo
Tutor DaiWuXing;LiZongHai
School Huazhong University of Science and Technology
Course Biochemistry and Molecular Biology
Keywords IGF-IR AS [S] ODN Chemotherapy SCCHN Apoptosis Insulin-like growth factor receptor Lentiviral vectors Hybridoma Monoclonal antibodies 4F2 HCC Adriamycin
CLC R730.5
Type PhD thesis
Year 2010
Downloads 123
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Insulin-like growth factor receptor type I (Insulin-like growth factor-Ⅰ receptor, IGF-IR) is a transmembrane tyrosine kinase receptor cell surface, play an important function in cell proliferation, differentiation, apoptosis and metastasis. IGF-IR overexpression in many tumors, including breast cancer, lung cancer, cervical cancer, Wilms' tumor. Another study found that low expression of IGF-IR in normal liver cells, and high expression in hepatocellular carcinoma (Hepatocellular carcinoma, HCC). The activation of the IGF-IR signal is one of the important reasons for HCC resistant to many chemotherapy drugs in the treatment of HCC. Accordingly, in the course of the treatment of HCC, IGF-IR is a potential therapeutic target. Has developed a lot of small molecules for the intracellular region of IGF-IR tyrosine kinase inhibitors, but due to the IGF-IR intracellular zone having a high homology with IR, this small molecule inhibitors of application prospects challenge. Recently developed many specific monoclonal antibody against the IGF-IR, these antibodies do pre-clinical studies for many tumor cells, but the anti-IGF-IR monoclonal antibody treatment effect on HCC has not conducted a comprehensive study reported . In this study, screening by hybridoma technique for the IGF-IR monoclonal antibody 4F2, 4F2 inhibited combination of ligands of IGF-I / II and receptor of IGF-IR, but can not inhibit the combination of insulin to its receptor IR; CCK- 8 detected 4F2 inhibited HCC cell proliferation inhibitory effect than when used alone is more obvious when with doxorubicin; 4F2 can inhibit the phosphorylation of the IGF-IR and the substrates of IRS-1, and inhibit IGF- IR activation of downstream signaling pathways. Cause downregulation of the IGF-IR in 4F2 role in tumor cells after 48 hours; 4F2 and doxorubicin alone caused apoptosis, when the combination enhances the rate of apoptosis by proapoptotic molecules The expression of anti-apoptotic molecules detected further confirmed; treatment in vivo results show that the 4F2 when used alone, the effect is not obvious, but when its doxorubicin enhances the inhibitory effect of doxorubicin. In the world of head and neck cancer (squamous cell carcinomas of the head and neck, SCCHN) is the tenth most popular kinds of cancer. Although current therapies have greatly increased in the past 10 years, the 5-year survival rate is still very low. Therefore, especially for poorly differentiated SCCHN, found new and effective molecular targeted therapy methods and its molecular mechanism of action is very important therapeutic approach. IGF-IR in cancer therapy is a new potential targets. Previous studies have proved that in SCCHN IGF-IR over-expression, and the activation of the IGF-IR signal enhancement of the head and neck cancer cell proliferation, migration. But so far, through the IGF-IR antisense nucleotide, alone or with the effect of chemotherapy drugs on SCCHN combination therapy there has not been reported, the present study attempts by the decrease of the expression of the IGF-IR to observe the passage of IGF-IR inhibition whether the enhanced sensitivity of chemotherapy drugs SCCHN. IGF-IR of the phosphorothioate antisense oligonucleotide (phosphorothioate antisense oligonucleotides, AS [S] ODN) lowered the expression of the IGF-IR, inhibiting the proliferation of the TU159 and 183A cells, weakening the IGF-IR phosphorylation of its downstream signaling pathway. AS [S] ODN enhanced the inhibitory effect of the chemotherapy drugs the TU159 and 183A cells, enhanced apoptosis induced by the chemotherapy drug doxorubicin. The body was found, AS [S] ODN enhanced doxorubicin TU159 tumor inhibition.

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