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Title: 5-Fluorocytosine combined with Fcy-hEGF fusion protein targets EGFR-expressing cancer cells

Abstract

Highlights: Black-Right-Pointing-Pointer EGFR-expressing epithelial cancers account for significant portion of cancer deaths. Black-Right-Pointing-Pointer EGF-EGFR signaling pathway is validated as an important anticancer drug target. Black-Right-Pointing-Pointer EGF and Fcy fusion protein (Fcy-hEGF) can bind to EGFR and convert 5-FC to 5-FU. Black-Right-Pointing-Pointer Fcy-hEGF combined with 5-FC preferentially inhibits EGFR-expressing cells viability. -- 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 10 nM. Fcy-hEGF binds tightly to A431 and MDA-MB-468 cells, which overexpress EGFR,more » 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 IC{sub 50} 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.« less

Authors:
 [1];  [2];  [3];  [4];  [2];  [4];  [2];  [4]
  1. Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei 100, Taiwan (China)
  2. Cancer Center, Taipei Veterans General Hospital, Taipei 112, Taiwan (China)
  3. Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China)
  4. (China)
Publication Date:
OSTI Identifier:
22210335
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 428; Journal Issue: 2; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANGIOGENESIS; ANTINEOPLASTIC DRUGS; CELL PROLIFERATION; CYTOSINE; GROWTH FACTORS; METASTASES; NEOPLASMS; RECEPTORS; THERAPY; TOXICITY; URACILS; YEASTS

Citation Formats

Lan, Keng-Hsueh, Shih, Yi-Sheng, Chang, Cheng Allen, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei 112, Taiwan, Yen, Sang-Hue, Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan, Lan, Keng-Li, E-mail: kllan@vghtpe.gov.tw, and Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan. 5-Fluorocytosine combined with Fcy-hEGF fusion protein targets EGFR-expressing cancer cells. United States: N. p., 2012. Web. doi:10.1016/J.BBRC.2012.10.050.
Lan, Keng-Hsueh, Shih, Yi-Sheng, Chang, Cheng Allen, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei 112, Taiwan, Yen, Sang-Hue, Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan, Lan, Keng-Li, E-mail: kllan@vghtpe.gov.tw, & Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan. 5-Fluorocytosine combined with Fcy-hEGF fusion protein targets EGFR-expressing cancer cells. United States. doi:10.1016/J.BBRC.2012.10.050.
Lan, Keng-Hsueh, Shih, Yi-Sheng, Chang, Cheng Allen, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei 112, Taiwan, Yen, Sang-Hue, Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan, Lan, Keng-Li, E-mail: kllan@vghtpe.gov.tw, and Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan. Fri . "5-Fluorocytosine combined with Fcy-hEGF fusion protein targets EGFR-expressing cancer cells". United States. doi:10.1016/J.BBRC.2012.10.050.
@article{osti_22210335,
title = {5-Fluorocytosine combined with Fcy-hEGF fusion protein targets EGFR-expressing cancer cells},
author = {Lan, Keng-Hsueh and Shih, Yi-Sheng and Chang, Cheng Allen and School of Biomedical Science and Engineering, National Yang-Ming University, Taipei 112, Taiwan and Yen, Sang-Hue and Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan and Lan, Keng-Li, E-mail: kllan@vghtpe.gov.tw and Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan},
abstractNote = {Highlights: Black-Right-Pointing-Pointer EGFR-expressing epithelial cancers account for significant portion of cancer deaths. Black-Right-Pointing-Pointer EGF-EGFR signaling pathway is validated as an important anticancer drug target. Black-Right-Pointing-Pointer EGF and Fcy fusion protein (Fcy-hEGF) can bind to EGFR and convert 5-FC to 5-FU. Black-Right-Pointing-Pointer Fcy-hEGF combined with 5-FC preferentially inhibits EGFR-expressing cells viability. -- 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 10 nM. 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 IC{sub 50} 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.},
doi = {10.1016/J.BBRC.2012.10.050},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 2,
volume = 428,
place = {United States},
year = {2012},
month = {11}
}