This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Huynh, H. Articles by Soo, K. C. Search for Related Content PubMed PubMed Citation Articles by Huynh, H. Articles by Soo, K. C.

Research Articles: Therapeutics, Targets, and Development

Bevacizumab and rapamycin inhibit tumor growth in peritoneal model of human ovarian cancer

¹ Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre; ² Department of General Surgery, Singapore General Hospital, Singapore, Singapore

Requests for reprints: Hung Huynh, Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore 169610, Singapore. Phone: 65-436-8347; Fax: 65-226-5694. E-mail: cmrhth{at}nccs.com.sg

Abstract

Ovarian cancer is the leading cause of death from gynecologic cancer. Often, the disease has spread beyond the ovary to involve the peritoneal cavity and causes ascites. Whereas mammalian target of rapamycin (mTOR) functions to regulate protein translation, cell cycle progression, and metastasis, vascular endothelial growth factor promotes tumor angiogenesis, ascites formation, and metastasis in ovarian cancer. In this study, an i.p. model of human ovarian cancer was used to determine the antitumor activity of rapamycin, bevacizumab, and rapamycin plus bevacizumab (BEV/RAPA). We report that administration of rapamycin, bevacizumab, and BEV/RAPA in mice bearing peritoneal OV-90 ovarian carcinoma resulted in 74.6%, 82.4%, and 93.3% reduction in i.p. tumor burden, respectively. BEV/RAPA-induced reduction in microvessel density and inhibition of cell proliferation were associated with significant reduction in hypoxia-inducible factor-1 and cyclin D1 and inactivation of downstream targets of mTOR, p70S6 kinase, S6R, and 4E-binding protein 1. BEV/RAPA treatment was not only able to prolong life of i.p. mice but also more effective than rapamycin and bevacizumab to prevent the development of peritoneal carcinomatosis in adjuvant setting and reverse ascites accumulation in heavy peritoneal disease. Our data indicate that simultaneous inhibition of the vascular endothelial growth factor receptor and mTOR pathways with BEV/RAPA or their analogues may represent a novel approach for prevention of metastasis, recurrence, and treatment of ovarian cancer. [Mol Cancer Ther 2007;6(11):2959–66]

Grant support: National Medical Research Council of Singapore grant NMRC/0887/2004 (H. Huynh).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Supplementary materials for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 4/ 4/07; revised 7/22/07; accepted 9/17/07.