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International Journal of Gynecological Cancer:
doi: 10.1097/IGC.0b013e31829d2d51
Ovarian Cancer

Alterations of Hypoxia-Induced Factor Signaling Pathway Due to Mammalian Target of Rapamycin (mTOR) Suppression in Ovarian Clear Cell Adenocarcinoma: In Vivo and in Vitro Explorations for Clinical Trial

Hirasawa, Takeshi MD, PhD*; Miyazawa, Masaki PhD*; Yasuda, Masanori MD, PhD; Shida, Masako MD*; Ikeda, Masae MD, PhD*; Kajiwara, Hiroshi MD, PhD; Matsui, Naruaki PhD; Fujita, Mariko PhD§; Muramatsu, Toshinari MD, PhD*; Mikami, Mikio MD, PhD*

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Abstract

Objectives: Before setting into the clinical trial using a combination of mammalian target of rapamycin (mTOR) inhibitors (rapamycin and everolimus) and other anticancer drugs, this study was conducted to confirm the efficacy of the new therapeutic strategy for ovarian clear cell adenocarcinoma (CCA), which targeted mTOR–hypoxia-induced factor (HIF) signal transduction system.

Materials and Methods: Using the cultured cells of CCA and animal models, alteration of mTOR-HIF cofactors and cell proliferation under the mTOR inhibitor–treated condition were analyzed.

Results: Mammalian target of rapamycin–HIF cofactors were inhibited dependent on concentration by mTOR inhibitor, resulting in suppression of the cultured CCA proliferation. However, von Hippel-Lindau was up-regulated at the messenger RNA level. In the nude mice with subcutaneously implanted CCA cells, apoptosis and necrosis were detected especially around the center of the tumors in the mTOR inhibitor–treated group more conspicuously than in the nontreated group. In the assessment of combination therapy with other antitumor agents, a combined treatment with mTOR inhibitor and chemotherapeutic agents caused a significant decrease in tumor size compared to the chemotherapeutic agents–only group.

Conclusions: Treatment by mTOR inhibitor is expected to down-regulate the cell proliferation of the CCA as a new therapeutic strategy.

© 2013 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.

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