Inhibition of Bone Metastasis by Intrapulmonary Administration of Zoledronate, a Nitrogen-Containing Bisphosphonate

Hidemasa Katsumi1, Yuji Kanamoto1, Kentaro Fukui1, Tomohiro Hasei1, Tetsushi Watanabe1, Toshiyasu Sakane1, Makiya Nishikawa2, Hiroyuki Yasui1, and Akira Yamamoto1

1Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan 2Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan hkatsumi@mb.kyoto-phu.ac.jp

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ABSTRACT SUMMARY
To evaluate whether the lung is a promising alternative route of zoledronate administration, a nitrogen-containing bisphosphonate, for the treatment of bone metastasis, we examined the therapeutic effects of zoledronate after its intrapulmonary administration on tumor metastasis in a bone metastasis mouse model. At 14 days after tumor inoculation, an intrapulmonary administration of zoledronate at one day before tumor inoculation effectively reduced the number of tumor cells in the bone to a level similar to that achieved with intravenous injection. Inoculation of the tumor cells increased the expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule-1 (VCAM)-1 and matrix metalloproteinase (MMP)-9 in the bone, which was inhibited by zoledronate. An intrapulmonary administration of zoledronate at 7 days after tumor inoculation also reduced the number of the tumor cells in the bone. Furthermore, an intrapulmonary administration of zoledronate did not induce renal damage, which was clearly observed in mice receiving an intravenous injection of zoledronate. These results indicate that the lung is a promising alternative route of zoledronate administration for the treatment of bone metastasis.

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