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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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99mTc-Ethylenedicysteine-C225

99mTc-EC-C225
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: December 29, 2011.

Chemical name:99mTc-Ethylenedicysteine-C225
Abbreviated name:99mTc-EC-C225
Synonym:99mTc-EC-cetuximab
Agent category:Chimeric monoclonal antibody
Target:Epidermal growth factor receptor (EGFR, HER1)
Target category:Receptor
Method of detection:Single photon emission computed tomography (SPECT)
Source of signal:99mTc
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about EGFR.

Background

[PubMed]

Epidermal growth factor (EGF) is a 53-amino acid cytokine (6.2 kDa) secreted by ectodermic cells, monocytes, kidneys and duodenal glands (1). EGF stimulates growth of epidermal and epithelial cells. EGF receptor (EGFR) is a transmembrane protein with an intracellular tyrosine kinase present on most cells. EGFR is overexpressed on many solid tumor cells such as breast, non-small-cell lung, head and neck, and colon cancer (2-4). The high level of EGFR expression on cancer cells is associated with a poor prognosis (5-7). Inhibition of EGF receptor functions by C225 (also known as centuximab), an anti-EGFR chimeric monoclonal antibody, has been shown to inhibit tumor angiogenesis, growth and metastasis (8, 9). 99mTc-EC-C225 was developed as a single photon emission computed tomography (SPECT) tracer for imaging EGFR expression on solid tumors (10, 11).

Synthesis

[PubMed]

l,l-Ethylenedicysteine (EC) was conjugated to C225-NH2 using sulfo-N-hydroxysulfosuccinimide (10) to form EC-C225, which was purified by G-25 column chromatography. A radiochemical purity of 100% was achieved, as measured by high-performance liquid chromatography (HPLC) analysis. The specific activity was calculated to be about 74 MBq/μmol (2 Ci/μmol) before in vivo injection to rats.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Three human breast cancer lines (A431 - high EGFR expression, MDA231 - medium, and MDA453 - low) with different EGFR levels were used to study the integrity of EC-C225. Western immunoblotting and immunoprecipitation studies showed that there were no differences between EC-C225 and C225 in binding to EGFR in these three cell lines (10). EC-C225 induced apoptosis in DiFi cells to the same extent as C225. There was a 4% uptake of 99mTc-EC-C225 (0.074 MBq, 2 μCi) by A431 cells at the end of 2 h incubation. There was only a marginal uptake by MDA231 cells.

Animal Studies

Rodents

[PubMed]

Rats bearing mammary adenocarcinoma 13762 NF received intravenous injections of 0.74 MBq/rat (20 μCi/rat) of 99mTc-EC-C225 or 99mTc-EC (10). The organs with the major uptake of 99mTc-EC-C225 were the kidneys (14.8% injected dose/g (ID/g)) and liver (0.72% ID/g) at 2 h. The tumor had an uptake of 0.31% ID/g versus 0.12% ID/g for 99mTc-EC. A tumor/muscle ratio of about 8 was estimated for 99mTc-EC-C225 as compared with 4 for 99mTc-EC. Pretreatment (30 min before tracer injection) of tumor-bearing rats with 100-fold excess of unlabeled C225 decreased the 99mTc-EC-C225 tumor/muscle ratio to about 4 (background) at 2 h after injection of the tracer.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

Human dosimetry of 99mTc-EC-C225 was determined from blood samples and SPECT images in 6 patients with head and neck carcinoma after intravenous injection of 925 MBq (25 mCi) (11). High uptake in the kidneys, spleen, liver, and gallbladder was observed. The effective dose equivalent was estimated to be 0.006 mSv/MBq (22 mrem/mCi). The organ that received the highest dose was the kidneys (0.0274 mGy/MBq or 0.1014 rad/mCi), followed by the spleen (0.0214 mGy/MBq or 0.0793 rad/mCi), liver (0.0157 mGy/MBq or 0.058 rad/mCi), and gallbladder (0.0059 mGy/MBq or 0.0219 rad/mCi).

NIH Support

CA16672, P01 CA06294

References

1.
Carpenter G., Cohen S. Epidermal growth factor. J Biol Chem. 1990;265(14):7709–12. [PubMed: 2186024]
2.
Grunwald V., Hidalgo M. Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst. 2003;95(12):851–67. [PubMed: 12813169]
3.
Mendelsohn J. Anti-epidermal growth factor receptor monoclonal antibodies as potential anti-cancer agents. J Steroid Biochem Mol Biol. 1990;37(6):889–92. [PubMed: 2285602]
4.
Yasui W., Sumiyoshi H., Hata J., Kameda T., Ochiai A., Ito H., Tahara E. Expression of epidermal growth factor receptor in human gastric and colonic carcinomas. Cancer Res. 1988;48(1):137–41. [PubMed: 2446740]
5.
Ang K.K., Berkey B.A., Tu X., Zhang H.Z., Katz R., Hammond E.H., Fu K.K., Milas L. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62(24):7350–6. [PubMed: 12499279]
6.
Costa S., Stamm H., Almendral A., Ludwig H., Wyss R., Fabbro D., Ernst A., Takahashi A., Eppenberger U. Predictive value of EGF receptor in breast cancer. Lancet. 1988;2(8622):1258. [PubMed: 2903994]
7.
Ethier S.P. Growth factor synthesis and human breast cancer progression. J Natl Cancer Inst. 1995;87(13):964–73. [PubMed: 7629883]
8.
Fan Z., Masui H., Altas I., Mendelsohn J. Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res. 1993;53(18):4322–8. [PubMed: 8364927]
9.
Kim E.S., Khuri F.R., Herbst R.S. Epidermal growth factor receptor biology (IMC-C225). Curr Opin Oncol. 2001;13(6):506–13. [PubMed: 11673692]
10.
Schechter N.R., Yang D.J., Azhdarinia A., Kohanim S., Wendt R., Oh C.S., Hu M., Yu D.F., Bryant J., Ang K.K., Forster K.M., Kim E.E., Podoloff D.A. Assessment of epidermal growth factor receptor with 99mTc-ethylenedicysteine-C225 monoclonal antibody. Anticancer Drugs. 2003;14(1):49–56. [PubMed: 12544258]
11.
Schechter N.R., Wendt R.E., Yang D.J., Azhdarinia A., Erwin W.D., Stachowiak A.M., Broemeling L.D., Kim E.E., Cox J.D., Podoloff D.A., Ang K.K. Radiation dosimetry of 99mTc-labeled C225 in patients with squamous cell carcinoma of the head and neck. J Nucl Med. 2004;45(10):1683–7. [PubMed: 15471833]

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