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Institut National de la Santé et de la Recherche Médicale Research Unit 403, Pavillon F [S. B., S. M., P. D. D., P. C.], Service d'Anatomopathologie [L. F.], and Pavillon V [B. C.], Hôpital Edouard Herriot, 69437 Lyon, France; and Procter & Gamble Pharmaceuticals, Mason, Ohio [F. H. E.].
The molecular mechanisms by which tumor cells induce osteolytic metastases are likely to involve tumor cell adhesion to bone as well as the release of soluble mediators from tumor cells that stimulate osteoclast-mediated bone resorption. Bisphosphonates (BPs) are powerful inhibitors of the osteoclast activity and are, therefore, used in the treatment of cancer-associated osteolytic metastases. Here, we investigated the effect of BPs on breast and prostate carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. BP pretreatment of tumor cells inhibited tumor cell adhesion to unmineralized and mineralized osteoblastic extracellular matrices in a dose-dependent manner. In contrast, BP did not affect adhesion of normal cells (fibroblasts) to extracellular matrices. The order of potency for four BPs in inhibiting tumor cell adhesion to extracellular matrices was found to be: ibandronate > NE-10244 (antiresorptive active pyridinium analogue of risedronate) > pamidronate > clodronate. BP did not affect [3H]thymidine incorporation by tumor cells, as assessed by a mitogenesis assay, indicating that BP did not exert any cytotoxic effect at concentrations used to inhibit tumor cell adhesion. NE-58051, the inactive pyridylpropylidene analogue of risedronate, had no inhibitory effect on tumor cell adhesion compared to that observed with its active counterpart NE-10244, suggesting that the mechanism of action of BP on tumor cells involved a stereospecific recognition step. Although integrins mediate cell-matrix interactions, BP recognition by tumor cells did not modulate cell surface integrin expression. In conclusion, our results provide evidence for a direct cellular effect of BP in preventing tumor cell adhesion to bone, suggesting that BPs may be useful agents for the prophylactic treatment of patients with cancer that is known to preferentially metastasize to bone.
1 This study was supported by grants from the Institut National de la Santé et de la Recherche Médicele (INSERM; to P. C.), Rhône-Poulenc RORER Laboratories (to P. C.), and the Association pour la Recherche sur Les Tumeurs de la Prostate (to P. C.).
2 To whom requests for reprints should be addressed, at INSERM Research Unit 403, Pavillon F, Hôpital Edouard Herriott, Place d'Arsonval, 69437 Lyon Cédex 03, France.
Received 9/ 6/96. Accepted 7/30/97.
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