https://scholars.lib.ntu.edu.tw/handle/123456789/369144
Title: | 5-Fluorocytosine combined with Fcy-hEGF fusion protein targets EGFR-expressing cancer cells | Authors: | KENG-HSUEH LAN | Keywords: | 5-Fluorocytosine (5-FC); Cytosine deaminase; Epidermal growth factor (EGF); Epidermal growth factor receptor (EGFR); Fusion protein | Issue Date: | 2012 | Journal Volume: | 428 | Journal Issue: | 2 | Start page/Pages: | 292-297 | Source: | Biochemical and Biophysical Research Communications | Abstract: | Human epithelial cancers account for approximately 50% of all cancer deaths. This type of cancer is characterized by excessive activation and expression of the epidermal growth factor receptor (EGFR). The EGFR pathway is critical for cancer cell proliferation, survival, metastasis and angiogenesis. The EGF-EGFR signaling pathway has been validated as an important anticancer drug target. Increasing numbers of targeted therapies against this pathway have been either approved or are currently under development. Here, we adopted a prodrug system that uses 5-fluorocytosine (5-FC) and human EGF (hEGF) fused with yeast cytosine deaminase (Fcy) to target EGFR-overexpressing cancer cells and to convert 5-FC to a significantly more toxic chemotherapeutic, 5-fluorouracil (5-FU). We cloned and purified the Fcy-hEGF fusion protein from Pichia pastoris yeast. This fusion protein specifically binds to EGFR with a similar affinity as hEGF, approximately 10nM. Fcy-hEGF binds tightly to A431 and MDA-MB-468 cells, which overexpress EGFR, but it binds with a lower affinity to MDA-MB-231 and MCF-7, which express lower levels of EGFR. Similarly, the viability of EGFR-expressing cells was suppressed by Fcy-hEGF in the presence of increasing concentrations of 5-FC, and the IC50 values for A431 and MDA-MB-468 were approximately 10-fold lower than those of MDA-MB-231 and MCF-7. This novel prodrug system, Fcy-hEGF/5-FC, might represent a promising addition to the available class of inhibitors that specifically target EGFR-expressing cancers. ? 2012 Elsevier Inc. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-84869226738&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/369144 |
DOI: | 10.1016/j.bbrc.2012.10.050 | SDG/Keyword: | epidermal growth factor receptor; Fcy hEGF fusion protein; flucytosine; hybrid protein; unclassified drug; antineoplastic activity; article; binding affinity; cancer cell; cell strain MCF 7; cell viability; concentration response; controlled study; drug cytotoxicity; drug protein binding; drug targeting; female; gene overexpression; human; human cell; IC 50; molecular cloning; nonhuman; Pichia pastoris; priority journal; protein expression; protein purification; Carcinoma; Cell Line, Tumor; Cloning, Molecular; Cytosine Deaminase; Epidermal Growth Factor; Flucytosine; Humans; Inhibitory Concentration 50; Mitogens; Prodrugs; Receptor, Epidermal Growth Factor; Recombinant Fusion Proteins; Pichia pastoris |
Appears in Collections: | 腫瘤醫學研究所 |
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