Over one third of patients with advanced lung cancer manifest osteolytic bone metastases, and the bone destruction is mediated by the osteoclasts. Bone metastases cause devastating complications, including pathologic fractures and hypercalcemia, and severely harm the quality of life of the patients. Therefore, the prevention and treatment of osteolytic bone metastases are clinically important for management of lung cancer patients. Recently, we have found that reveromycin A (RM-A), an acidic compound with three carboxylic groups, inhibits bone resorption through inducing apoptosis specifically in osteoclasts in vitro and in vivo. Here, we studied the effect of RM-A on osteolytic bone metastasis of human small cell lung cancer (SBC-5) cells injected intravenously into natural killer cell-depleted SCID mice. Daily administration of RM-A (1-2 mg/kg sc twice daily or 10 mg/kg ip daily) inhibited the formation of bone metastasis in a dose-dependent manner, while the same treatment had no significant effect on the metastasis to visceral organs (lung, liver and adrenal). Histological analyses revealed that the number of osteoclasts in bone lesions was lower in RM-A-treated mice, compared with control mice. In addition, in hypercalcemic model, single administration of RM-A (80 mg/kg iv) significantly suppressed the rise of serum calcium level induced by PTH(1-34) in thyroparathyroidectomized (TPTX) rats. These findings raise the possibility that RM-A may be of use as a therapeutic agent against osteolytic bone metastases.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]