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¹ Equipe de recherche INSERM E 03-37 Oncogenèse des Tumeurs Respiratoires et Urogénitales, Faculté de Médecine, Créteil, France; ² Service d'Histologie et de Biologie Tumorale, Hôpital Tenon, Paris, France; and ³ NicOx S.A., Sophia-Antipolis, France

Requests for Reprints: Dominique K. Chopin, Equipe de recherche INSERM E 03-37 Oncogenèse des Tumeurs Respiratoires et Urogénitales, Faculté de Médecine, 8, Rue du Général Sarrail, 94010 Créteil Cedex, France. Phone: 33-1-49-81-35-51; Fax: 33-1-49-81-35-52. E-mail: chopin{at}univ-paris12.fr

Non-steroidal anti-inflammatory drugs (NSAIDs) are potent antitumoral agents but their side effects limit their clinical use. A novel class of drugs, nitric oxide-donating NSAIDs (NO-NSAIDs), was found to be safer and more active than classical NSAIDs. This study explored the effect of the NO-donating sulindac derivative, NCX 1102, on three human urothelial epithelial carcinoma cell lines (T24, 647V, and 1207) and primary cultures of normal urothelial cells. Cytotoxicity, antiproliferative effect, cell cycle alterations, morphological changes, and apoptosis were investigated after treatment with NCX 1102 in comparison with the native molecule. After treatment, there was a cytotoxic effect (with IC₅₀ at 48 h of 23.1 µM on 647V, 19.4 µM on T24, and 14.5 µM on 1207) and an antiproliferative effect on all three cell lines with NCX 1102 but not with sulindac. No effect was detected on normal urothelial cells. Flow cytometric analysis showed a differential NCX 1102-induced accumulation of cells in various phases of the cell cycle, depending on cell line and concentration. NCX 1102 induced an occurrence of multinucleated cells in all cell lines and mitotic arrest in 647V and 1207. NCX 1102-treated T24 and 647V cell lines showed a significant difference of apoptotic cell amount when compared to controls. Our results demonstrated a greater antiproliferative potency of NCX 1102 compared to its parent molecule sulindac, and suggested that this new NO-NSAID may have therapeutic impact in the management of bladder cancer.

Key Words: Cellular responses to anticancer drugs • NO-NSAID • genitourinary cancers • bladder • antiproliferation • cell death

Grant support: INSERM, Faculté de Médecine de Créteil, Université Paris 12 Val de Marne, Association Claude Bernard, Association Certus.

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 7/31/03; revised 10/22/03; accepted 12/12/03.