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The Study for Interferon beta-1a-based Anti-cancer Therapeutics : 인터페론 베타 기반 항암 치료법 연구

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Authors

김태은

Advisor
신영기
Major
약학대학 약학과
Issue Date
2017-02
Publisher
서울대학교 대학원
Keywords
recombinant human interferon beta-1aR27Tanti-cancerresistancecFLIPtrastuzumabfusion protein
Description
학위논문 (박사)-- 서울대학교 대학원 : 약학과 병태생리학 전공, 2017. 2. 신영기.
Abstract
Interferon beta (IFN beta) has recently emerged as an anti-cancer drug owing to its ability to preferentially induce apoptosis in cancer cells. However, IFN beta resistance, the low stability and systemic toxicity of its derivative agents limit its use in treating cancer. Previously a glycoengineered version of recombinant human IFN beta-1a, termed R27T was developed which has two N-glycosylation sites: one at the 80th amino acid (original site) and one at the 25th amino acid (additional site). Compared to the parent molecule, R27T exhibited superior stability, solubility, productivity, and pharmacokinetic properties without any loss of biological activity and change in receptor-binding affinity. However, R27T alone, like its parental molecule, still has significant issues with resistance and toxicity.
In this study, I first examined the anti-cancer efficacy of R27T in various cancer cells. I found that its decreased ability to induce anti-proliferation and apoptosis in resistant cells was due to an upregulation of cellular FLICE-like inhibitory protein (cFLIP), which impairs caspase activation. I thus investigated whether inhibition of cFLIP could facilitate R27T-induced caspase activation. Toward this end, I evaluated the abilities of a cFLIP small interfering RNA (siRNA) or 4,5,6,7-tetrabromobenzotriazole [TBB, a casein kinase-2 (CK-2) inhibitor] to enhance the anti-cancer effects of R27T in vitro and in vivo.
To support the further application of R27T, I developed a fusion protein in which R27T was fused to the C-terminus of the heavy chain of a trastuzumab, an anti-ERBB-2 antibody and assessed its potential for treating ERBB-2+ gastric cancer. R27T fused protein exhibited a higher expression level in CHO cells compared with that of the parental IFN beta-1a fused protein. The fusion protein induced IFN signaling in gastric cancer cells exhibiting direct anti-cancer efficacy. Moreover, I have verified the antibody-dependent cellular cytotoxicity and complement dependent cytotoxicity using fusion protein in gastric cancer cells.
Language
English
URI
https://hdl.handle.net/10371/120152
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