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A Third-Generation Bisphosphonate, Minodronic Acid (YM529), Augments the Interferon /ß-Mediated Inhibition of Renal Cell Cancer Cell Growth Both In vitro and In vivo

Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan

Requests for reprints: Takeshi Yuasa, Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-3630; Fax: 81-75-751-3631; E-mail: yuasa{at}kuhp.kyoto-u.ac.jp.

Purpose: Minodronic acid (YM529) is a third-generation nitrogen-containing bisphosphonate. Here, we have investigated the therapeutic efficacy of YM529 against renal cell cancer (RCC) alone or in combination with IFN both in vitro and in vivo.

Experimental Design: One murine and eight human RCC cell lines were used for the in vitro studies and were subjected to a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Western blotting. Luciferase-labeled murine RCC cells (RENCA^Luc) were transplanted into the s.c. tissue or the renal subcapsule of syngeneic BALB/c mice. These mice were treated with YM529 and/or murine IFN and the growth of the cancer cells was monitored by an in vivo imaging system.

Results: YM529 inhibited the growth of RCC cells in a dose- and time-dependent manner and enhanced the growth inhibitory potential of IFN in vitro. In the in vivo mouse models, YM529 did not markedly inhibit the RCC cell growth on its own but it augmented the anticancer effect of IFN (P < 0.05). The YM529-treated mice (with or without IFN) did not alter the / T-lymphocyte numbers. The various treatment regimens were also not associated with any adverse effects. However, YM529 combined with IFN reduced the serum vascular endothelial growth factor levels.

Conclusions: Our study suggests that YM529 may be a potent anticancer agent for RCC. The efficacy and safety of IFN plus YM529 as a therapy for RCC should be verified by early-phase clinical trials.

Key Words: renal cell cancer • bisphosphonate • minodronic acid • interferon • VEGF