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SYNERGISTIC INHIBITION OF TUMOR GROWTH AND METASTASIS BY COMBINED TREATMENT WITH TNP-470 AND GEMCITABINE IN A HUMAN BLADDER CANCER KOTCC-1 MODEL

2004; Lippincott Williams & Wilkins; Volume: 172; Issue: 4 Part 1 Linguagem: Inglês

10.1097/01.ju.0000133653.74536.43

1527-3792

Mototsugu Muramaki, Hideaki Miyake, Isao Hara, Gaku Kawabata, Sadao Kamidono,

Angiogenesis and VEGF in Cancer

No AccessJournal of UrologyInvestigative Urology1 Oct 2004SYNERGISTIC INHIBITION OF TUMOR GROWTH AND METASTASIS BY COMBINED TREATMENT WITH TNP-470 AND GEMCITABINE IN A HUMAN BLADDER CANCER KOTCC-1 MODEL MOTOTSUGU MURAMAKI, HIDEAKI MIYAKE, ISAO HARA, GAKU KAWABATA, and SADAO KAMIDONO MOTOTSUGU MURAMAKIMOTOTSUGU MURAMAKI , HIDEAKI MIYAKEHIDEAKI MIYAKE , ISAO HARAISAO HARA , GAKU KAWABATAGAKU KAWABATA , and SADAO KAMIDONOSADAO KAMIDONO View All Author Informationhttps://doi.org/10.1097/01.ju.0000133653.74536.43AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: TNP-470 (O-(chloroacetylcarbamoyl)fumagillol) is a potent inhibitor of angiogenesis that was reported to enhance synergistically the antitumor effects of cytotoxic agents. We evaluated the effectiveness of combined treatment with TNP-470 and gemcitabine in vitro and in vivo using highly metastatic human bladder cancer KoTCC-1 cells. Materials and Methods: The in vitro growth inhibitory and apoptotic effects of gemcitabine and/or TNP-470 on KoTCC-1 cells were assessed using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and TUNEL staining, respectively. We then evaluated the combined effect of gemcitabine and TNP-470 therapy after subcutaneous and orthotopic injection of KoTCC-1 cells into athymic nude mice. Established tumors were analyzed by TUNEL staining and immunohistochemical staining of CD31 to quantify microvessel density. Results: In vitro TNP-470 enhanced the cytotoxic effect of gemcitabine on KoTCC-1 cells, decreasing its IC50 by more than 50%. This combined treatment significantly induced apoptosis compared with treatment with either agent alone. In vivo combined treatment with TNP-470 and gemcitabine significantly decreased tumor growth after subcutaneous and orthotopic injection into athymic nude mice and significantly decreased the incidence of lymph node metastasis after arthotopic injection compared with either agent alone. Immunohistochemical analysis of the subcutaneous tumor after each treatment demonstrated that gemcitabine administration significantly induced apoptotic cell death. In contrast, a significant decrease in microvessel density was observed after TNP-470 treatment. Conclusions: These findings demonstrate that TNP-470 and gemcitabine act synergistically to inhibit tumor growth and metastasis by enhancing apoptosis and suppressing angiogenesis. References 1 : Multimodality therapy for the treatment of muscle-invasive bladder cancer. Semin Urol Oncol2000; 18: 313. 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Google Scholar From the Division of Urology, Department of Organ Therapeutics, Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe and Department of Urology, Hyogo Medical Center for Adults, Akashi, Japan© 2004 by American Urological Association, Inc.FiguresReferencesRelatedDetails Volume 172Issue 4 Part 1October 2004Page: 1485-1489 Advertisement Copyright & Permissions© 2004 by American Urological Association, Inc.KeywordsO-(chloroacetylcarbamoyl)fumagillolgemcitabinebladderbladder neoplasmsMetricsAuthor Information MOTOTSUGU MURAMAKI More articles by this author HIDEAKI MIYAKE More articles by this author ISAO HARA More articles by this author GAKU KAWABATA More articles by this author SADAO KAMIDONO More articles by this author Expand All Advertisement PDF downloadLoading ...