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Combined Therapy with a New Bisphosphonate, Minodronate (YM529), and Chemotherapy for Multiple Organ Metastases of Small Cell Lung Cancer Cells in Severe Combined Immunodeficient Mice

Departments of Internal Medicine and Molecular Therapeutics [S. Y., H. Z., M. H., T. M., H. G., S. S.] and Environmental and Molecular Pathology [H. U.], Course of Bioregulation and Medical Oncology, University of Tokushima School of Medicine, Tokushima, Japan

Purpose: Lung cancer in the advanced stage frequently metastasizes to multiple organs, including the liver, lungs, lymph nodes, and bone. Bisphosphonates have been widely used to treat osteolytic bone metastasis in the past years; however, many studies have implicated that a single use of bisphosphonates could not prolong the survival of patients. In the present study, using a multiple-organ metastasis model of human lung cancer cells, we examined the effect of combined therapy with a new bisphosphonate (YM529) and etoposide (VP-16).

Experimental Design: Human small cell lung cancer (SBC-5) cells i.v. inoculated into natural killer cell-depleted severe combined immunodeficient mice metastasized to multiple organs, including the lungs, liver, kidneys, lymph nodes, and bone. SBC-5-bearing mice were treated with YM529 and/or VP-16 and sacrificed 5 weeks after tumor cell inoculation. Bone metastasis was assessed by X-ray photographs, and visceral metastasis was evaluated macroscopically. The number of osteoclasts in the bone lesions was examined by tartrate-resistant acid phosphatase staining.

Results: Monotherapy with YM529 suppressed the production of bone metastases, but not visceral metastasis. Histological analyses revealed that the number of osteoclasts in bone lesions was lower in YM526-treated mice, compared with control mice. VP-16 inhibited both bone metastasis and visceral (lung and liver) metastasis. However, neither YM529 alone nor VP-16 alone significantly prolonged the survival of SBC-5-bearing mice. Combined use of YM529 and VP-16 further inhibited the production of bone metastasis and significantly prolonged survival.

Conclusions: Combined therapy with bisphosphonate and chemotherapy may be useful for small cell lung cancer patients with multiple organ metastases including bone metastasis.

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