Retinal toxicity induced by small-molecule Hsp90 inhibitors in beagle dogs
-
- Kanamaru Chisako
- Research Division, Chugai Pharmaceutical Co., Ltd.
-
- Yamada Yuichiro
- Research Division, Chugai Pharmaceutical Co., Ltd.
-
- Hayashi Shuji
- Research Division, Chugai Pharmaceutical Co., Ltd.
-
- Matsushita Tomochika
- Research Division, Chugai Pharmaceutical Co., Ltd.
-
- Suda Atsushi
- Research Division, Chugai Pharmaceutical Co., Ltd.
-
- Nagayasu Miho
- Research Division, Chugai Pharmaceutical Co., Ltd.
-
- Kimura Kazuya
- Research Division, Chugai Pharmaceutical Co., Ltd.
-
- Chiba Shuichi
- Research Division, Chugai Pharmaceutical Co., Ltd.
この論文をさがす
抄録
Heat shock protein 90 (Hsp90) is a constitutively expressed molecular chaperone and plays an important role in the folding of client proteins with key regulatory roles in growth, survival, differentiation and metastasis. Because inhibition of Hsp90 degrades multiple oncogenic client proteins, it is considered to be an attractive anticancer therapy, and clinical trials of several Hsp90 inhibitors have been carried out. In the present study, two structurally distinct Hsp90 inhibitors, CH5164840 and CH5449302, were orally administered to beagle dogs to evaluate systemic toxicity. CH5164840 induced symptoms that suggest visual disorder, and ophthalmological observation and electroretinography (ERG) revealed loss of pupillary light reflex and abnormal waveforms, respectively. Histopathological examination showed changes in the photoreceptor cell layer and the outer nuclear layer of retina. On the other hand, while there were no clinical symptoms related to visual disorder, animals treated with CH5449302 showed similar abnormalities of ERG responses and histopathological changes in the photoreceptor cell layer and the outer nuclear layer of retina. The visual symptoms and abnormalities of ERG responses were noted at an earlier stage or lower dose than other toxicities in both compounds. Considering that two structurally distinct Hsp90 inhibitors induced a retinal toxicity in dogs after repeated administration, and that visual disorders were also reported in some clinical trials of Hsp90 inhibitors, it would seem highly likely that Hsp90 inhibition induces retinal toxicity. Also, our study indicated that a detailed ocular examination to evaluate the safety of Hsp90 inhibitors would be useful in both preclinical and clinical studies.
収録刊行物
-
- The Journal of Toxicological Sciences
-
The Journal of Toxicological Sciences 39 (1), 59-69, 2014
一般社団法人 日本毒性学会
- Tweet
詳細情報 詳細情報について
-
- CRID
- 1390282679880773632
-
- NII論文ID
- 130004447115
-
- NII書誌ID
- AN00002808
-
- COI
- 1:STN:280:DC%2BC2czkvFSmtw%3D%3D
-
- ISSN
- 18803989
- 03881350
-
- NDL書誌ID
- 025244054
-
- PubMed
- 24418710
-
- 本文言語コード
- en
-
- データソース種別
-
- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
-
- 抄録ライセンスフラグ
- 使用不可