期刊
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
卷 52, 期 -, 页码 132-137出版社
ELSEVIER
DOI: 10.1016/j.ejps.2013.10.018
关键词
Claudin; Clostridium perfringens enterotoxin; Kidney; Liver; Tissue distribution
资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [21689006, 24390042]
- Health and Labor Sciences Research Grant from the Ministry of Health, Labour, and Welfare of Japan
- Takeda Science Foundation
- Nakatomi Foundation
- Adaptable and Seamless Technology Transfer Program through Target-driven R&D, Japan Science and Technology Agency
- Platform for Drug Discovery, Informatics, and Structural Life Science of the Ministry of Education, Culture, Sports, Science, and Technology, Japan
- Grants-in-Aid for Scientific Research [24390042, 21689006] Funding Source: KAKEN
We previously found that claudin (CL) is a potent target for cancer therapy using a CL-3 and -4-targeting molecule, namely the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE). Although CL-3 and -4 are expressed in various normal tissues, the safety of this CL-targeting strategy has never been investigated. Here, we evaluated the tissue distribution of C-CPE in mice. Ten minutes after intravenous injection into mice, C-CPE was distributed to the liver and kidney (24.0% and 9.5% of the injected dose, respectively). The hepatic level gradually fell to 3.2% of the injected dose by 3 h post-injection, whereas the renal C-CPE level gradually rose to 46.5% of the injected dose by 6 h post-injection and then decreased. A C-CPE mutant protein lacking the ability to bind CL accumulated in the liver to a much lesser extent (2.0% of the dose at 10 min post-injection) than did C-CPE, but its renal profile was similar to that of C-CPE. To investigate the acute toxicity of CL-targeted toxin, we intravenously administered C-CPEfused protein synthesis inhibitory factor to mice. The CL-targeted toxin dose-dependently increased the levels of serum biomarkers of liver injury, but not of kidney injury. Histological examination confirmed that injection of CL-targeted toxin injured the liver but not the kidney. These results indicate that potential adverse hepatic effects should be considered in C-CPE-based cancer therapy. (C) 2013 Elsevier B.V. All rights reserved.
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