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ID 106055
Title Alternative
プラジェノライドB及びその誘導体は胃癌に対して高い抗腫瘍活性を有する
Pladienolide is active on gastric cancer
Author
Sato, Momoko Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School
Kimura, Tetsuo University of Tokushima KAKEN Search Researchers
Yano, Hiromi University of Tokushima
Sannnomiya, Katsutaka University of Tokushima
Goji, Takahiro University of Tokushima KAKEN Search Researchers
Wada, Satoshi Oe Kyodo Hospital
Iwata, Masao Eisai Co., Ltd
Keywords
Apoptosis
ascites
gastric cancer
pladienolide B
RNA splicing
Content Type
Thesis or Dissertation
Description
The antitumor activity of pladienolide B, a novel splicing inhibitor, against gastric cancer is totally unknown and no predictive biomarker of pladienolide B efficacy has been reported. We investigated the antitumor activity of pladienolide B and its derivative on gastric cancer cell lines and primary cultured cancer cells from carcinomatous ascites of gastric cancer patients. The effect of pladienolide B and its derivative on six gastric cancer cell lines was investigated using a MTT assay and the mean IC50 values determined to be 1.6 ± 1.2 (range, 0.6–4.0) and 1.2 ± 1.1 (range, 0.4–3.4) nM, respectively, suggesting strong antitumor activity against gastric cancer. The mean IC50 value of pladienolide B derivative against primary cultured cells from 12 gastric cancer patients was 4.9 ± 4.7 nM, indicative of high antitumor activity. When 18 SCID mice xenografted with primary cultured cells from three patients were administered the pladienolide B derivative intraperitoneally, all tumors completely disappeared within 2 weeks after treatment. Histological examination revealed a pathological complete response for all tumors. In the xenograft tumors after treatment with pladienolide B derivative, immature mRNA were detected and apoptotic cells were observed. When the expressions of cell-cycle proteins p16 and cyclin E in biopsied gastric cancer specimens were examined using immunohisctochemistry, positivities for p16 and cyclin E were significantly and marginally higher, respectively, in the low-IC50 group compared with the high-IC50 group, suggesting the possibility that they might be useful as predictive biomarkers for pladienolide B. In conclusion, pladienolide B was very active against gastric cancer via a mechanism involving splicing impairment and apoptosis induction.
Journal Title
Cancer Science
ISSN
13497006
NCID
AA12100165
Publisher
Wiley|Japanese Cancer Association
Volume
105
Issue
1
Start Page
110
End Page
116
Published Date
2013-11-01
Remark
内容要旨・審査要旨・論文本文の公開
内容要旨・審査要旨 : LID201403051005.pdf
論文本文 : LID201405271003.pdf
本論文は, 著者Momoko Satoの学位論文として提出され, 学位審査・授与の対象となっている。
Rights
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.( https://creativecommons.org/licenses/by-nc/3.0/ )
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第2660号
Diploma Number
甲医第1186号
Granted Date
2014-01-23
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences
University Hospital