Tumor-Bearing Nude Mice OVCAR-3 Growth Factor and Malignant Ascites Formation in Albendazole: a Potent Inhibitor of Vascular Endothelial

Abstract

Purpose:Angiogenesis and vesselhyperpermeability are the two factors leading to the formation of ascites.Vascular endothelial growth factor (VEGF) plays a pivotal role in malignant ascites formation.Wehave recently shown that albendazole inhibits peritoneal growth of human colorectal cancer cells (HT-29).The present study was designed to find out if albendazole can suppress ascites formation in ascites-producing peritoneal carcinomatosis. Experimental design: Female nude mice bearing peritoneal tumors of human ovarian cancer cells (OVCAR-3) were treated with albendazole. Following i.p. inoculation and ascites development, micewere given i.p. albendazole (150mg/kg) or the vehicle 3weekly for 4 weeks. Results:Whereas vehicle-treated mice developed overt ascites requiring repeated aspiration, ascites formation in the albendazole-treated mice was markedly suppressed. As a result of this, 7 of10mice from the control grouphad tobe euthanizedbefore the course of treatment wasover. Suppressed ascites production and reduced tumor vascularity observed was a result of dramatic reduction in tumor VEGF production as revealed by profoundly lower VEGF ascites fluid and plasma levels. In vitro, incubation of SKOV-3 cells with various concentrations of albendazole led to significant dose-dependent inhibition of VEGF secretion. Examination of floating tumor cells collected from the peritoneal wash revealed profound down-regulation of VEGF mRNA in albendazole-treatedmice. Conclusions:These findings suggest for the first time that in nude mice bearing OVCAR-3 peritoneal tumors, by inhibiting VEGF production, albendazole abolishes tumor angiogenesis and ascites formation. The formation of malignant ascites in patients with advancedstage cancer is a difficult problem to manage in clinical oncology (1). It is an important cause of morbidity and mortality in patients with peritoneal carcinomatosis arising from colorectal, gastric, pancreatic, endometrial, and ovarian cancers (2). Ovarian carcinoma is characterized by rapid growth of solid i.p. tumors and production of large volumes of ascites. Although malignant progression of this disease is often predominantly confined to the peritoneal cavity (3), two thirds of patients already have advanced disease when diagnosed, and rapidly accumulating ascitic fluid is associated with poor prognosis (4). Both tumor size and the accumulation of ascites are inversely associated with survival (5). Among women with stage III or IV epithelial ovarian carcinoma, development of ascites correlates with a significantly decreased 5-year survival rate (5% with ascites versus 45% without ascites; ref. 6). Despite advances in surgical cytoreduction and cytotoxic chemotherapy, the prognosis for patients with ovarian cancer remains poor (7). Current therapeutic treatment of patients with advanced ovarian cancer associates cytoreductive surgery and chemotherapy, the combination of paclitaxel and a platinum salt being considered as the standard chemotherapy for advanced ovarian cancer (8). During the most part of its natural course, ovarian cancer remains confined to the peritoneal cavity. This offers the possibility to administer cytotoxic agents directly into the peritoneal cavity, providing high concentrations of the drug at the site of tumor for a longer period of time and ideally low systemic toxicity (9, 10). Albendazole, a benzimidazole carbamate anthelmintic drug, has been in clinical use for almost three decades. As an oral anthelmintic, its efficacy and safety has been well established (11). The primary mode of action of albendazole in susceptible parasites has been described as binding to htubulin and leading to inhibition of microtubule polymerization (12, 13). Our interest in benzimidazole carbamates dates back to the 1980s when the drug was tested for hydatid disease (14). Mechanisms described for benzimidazole carbamate anthelmintic activity rekindled our interest in these compounds as possible anticancer agents. Through our studies, we were able to show that in cell culture, several Cancer Therapy: Preclinical Authors’ Affiliation: Cancer Research Laboratories, Department of Surgery, St. George Hospital, University of New SouthWales, Sydney, New SouthWales, Australia Received 6/2/05; revised11/11/05; accepted12/21/05. 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 with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints:David LawsonMorris, Department of Surgery, St. George Hospital, Kogarah, Sydney, New SouthWales 2217, Australia. Phone: 61-2-93502070; Fax: 61-2-9350-3997; E-mail: david.morris@unsw.edu.au. F2006 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-05-1181 www.aacrjournals.org Clin Cancer Res 2006;12(6) March15, 2006 1928 American Association for Cancer Research Copyright © 2006 on October 13, 2011 clincancerres.aacrjournals.org Downloaded from DOI:10.1158/1078-0432.CCR-05-1181

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@inproceedings{Pourgholami2006TumorBearingNM, title={Tumor-Bearing Nude Mice OVCAR-3 Growth Factor and Malignant Ascites Formation in Albendazole: a Potent Inhibitor of Vascular Endothelial}, author={Mohammad Hossein Pourgholami and Zhao Yan Cai and Ying Lu and M H Pourgholami and Zhaoyan Cai and Ying and David LawsonMorris}, year={2006} }