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Intravesical Chemotherapy of High-Grade Bladder Cancer with HTI-286, A Synthetic Analogue of the Marine Sponge Product Hemiasterlin

Authors' Affiliations: ¹ The Prostate Centre at Vancouver General Hospital, Departments of ² Urologic Sciences and ³ Earth and Ocean Sciences, University of British Columbia, Vancouver, British Columbia, Canada and ⁴ Centre de Recherche en Cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, Quebec, Canada

Requests for reprints: Alan I. So, Department of Urologic Sciences, 2775 Laurel Street, Level 6, Vancouver, BC, V5Z 1M9, Canada. Phone: 604-875-5006; Fax: 604-875-5654; E-mail: alan.so{at}ubc.ca.

Purpose: HTI-286 is a fully synthetic analogue of the natural tripeptide hemiasterlin that inhibits tubulin polymerization and has strong cytotoxic potential. In this study, we evaluate the inhibitory effects of HTI-286 on human bladder cancer growth, both in vitro and as an intravesical agent in an orthotopic murine model.

Experimental Design: Various bladder cancer cell lines were treated with HTI-286 and mitomycin C (MMC) in vitro. Human KU-7 bladder tumor cells that stably express firefly luciferase were inoculated in female nude mice by intravesical instillation and quantified using bioluminescence imaging. Mice with established KU-7-luc tumors were given HTI-286 or MMC intravesically twice a week for 2 h. Pharmacokinetic data was obtained using high-performance liquid chromatography–mass spectrometry analyses.

Results: In vitro, HTI-286 was a potent inhibitor of proliferation in all tested cell lines and induced marked increases in apoptosis of KU-7-luc cells even after brief exposure. In vivo, HTI-286 significantly delayed cancer growth of bladder tumors in a dose-dependent fashion. HTI-286, at a concentration of 0.2 mg/mL, had comparable strong cytotoxicity as 2.0 mg/mL of MMC. The estimated systemic bioavailability of intravesically given HTI-286 was 1.5% to 2.1% of the initial dose.

Conclusions: Intravesical HTI-286 instillation therapy showed promising antitumor activity and minimal toxicity in an orthotopic mouse model of high-grade bladder cancer. These findings provide preclinical proof-of-principle for HTI-286 as an intravesical therapy for nonmuscle-invasive bladder cancer and warrant further evaluation of efficacy and safety in early-phase clinical trials.

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