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¹ The Prostate Centre, Department of Surgery (Divisions of ² Urology and ³ Thoracic Surgery), and ⁴ Department of Pathology and Laboratory Medicine, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Vancouver, BC, Canada

Requests for Reprints: Martin E. Gleave, Division of Urology, Department of Surgery, University of British Columbia, D-9, 2733 Heather Street, Vancouver, BC V5Z 3J5, Canada. Phone: (604) 875-5003; Fax: (604) 875-5654. E-mail: gleave{at}interchange.ubc.ca

Introduction: Lung cancer is highly lethal and resistant to most anticancer interventions. Treatment resistance is mediated, in part, by enhanced expression of cell survival proteins that help facilitate tumor progression. Clusterin is a stress-associated cytoprotective protein up-regulated by various apoptotic triggers in many cancers and confers treatment resistance when overexpressed. The objectives in this study were to evaluate clusterin expression levels in human lung cancer tissue, and to test effects of clusterin silencing using antisense oligonucleotides (ASOs) and short interfering double-stranded RNAs (siRNAs) on chemosensitivity in human lung cancer A549 cells. Methods: Clusterin immunostaining was evaluated in a tissue microarray of 149 spotted human lung cancers. The effects of clusterin ASO or siRNA treatment on clusterin expression and chemosensitivity to paclitaxel was examined in A549 cells in vitro while the ability of clusterin ASO to chemosensitize in vivo was evaluated in immunocompromised mice bearing A549 tumors. Results: More than 80% of human non-small cell lung cancers are immunoreactive for clusterin. Clusterin ASO or siRNA decreased clusterin mRNA expression in A549 cells >75% in a dose-dependent, sequence-specific manner, and significantly enhanced chemosensitivity to paclitaxel in vitro. Characteristic apoptotic DNA laddering was observed after combined treatment with ASO plus paclitaxel, but not with either agent alone. In vivo administration of clusterin ASO, compared to mismatch control oligonucleotide, synergistically enhanced the effects of paclitaxel or gemcitibine to significantly delay A549 tumor growth. Conclusion: These findings identify clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced lung cancer.

Key Words: Clusterin • TRPM-2 • lung cancer • taxol • apoptosis • antisense • RNAi

Grant support: Grant 009002 from the National Cancer Institute of Canada, and a Training Centre Grant from the Canadian Prostate Cancer Research Initiative.

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.

Received 9/10/03; revised 11/10/03; accepted 11/13/03.