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Efficacy of RAD001 (everolimus) in peritoneal dissemination of gastric cancer

Taguchi, Fumiko and Kodera, Yasuo and Yanagihara, Kazuyoshi and Tamura, Tomohide and Koizumi, Fumiaki and Imark, Esther (2010) Efficacy of RAD001 (everolimus) in peritoneal dissemination of gastric cancer. Investigational New Drugs, 29 (6). pp. 1198-1205. ISSN 0167-6997

Abstract

Peritoneal dissemination occurs frequently in patients with unresectable advanced stage gastric cancer. In this study, we tested mTOR inhibitor RAD001 (everolimus) for efficacy on peritoneal dissemination of gastric cancer.
Using the two cell lines 58As1, a highly peritoneal metastatic cell line, and its parental HSC58, a human scirrhous gastric cancer cell line, we first examined the growth inhibition activity of everolimus in vitro. Methylene blue assay demonstrated a moderate inhibitory effect on both cell lines under normal culture condition. When cells were maintained in hypoxic (1% O2) conditions, growth inhibition by everolimus was greatly reduced in HSC58, whereas the reduction was much smaller in 58As1. In western blotting, phosphorylation of mTOR, and its down-stream signaling molecules, P70S6K and 4E-BP1, were decreased under hypoxic conditions in HSC58. However, in 58As1, phospho-P70S6K and -4E-BP1 remained active state in hypoxic conditions and was suppressed by treatment with everolimus. Cell-cycle analysis showed that the hypoxia-induced G1 arrest was not manifested in 58As1 cells as compared to HSC58 cells. Separately, an in vivo orthotopic mouse model of 58As1 revealed that everolimus significantly reduces peritoneal dissemination as evaluated by quantitative photon counting method.
Taken together, our results suggest that everolimus may have activity against gastric cancer, particularly in cases with peritoneal dissemination.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/1608

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