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Properties of Bisphosphonates in the 13762 Rat Mammary Carcinoma Model of Tumor-Induced Bone Resorption

¹ Lilly Research Laboratories, Indianapolis, Indiana;
² St. Vincent’s Institute of Medical Research, Melbourne, Fitzroy, Australia;
³ Genzyme Corporation, Framingham, Massachusetts; and
⁴ Curagen Corporation, Branford, Connecticut

Bone metastasis from primary tumors is a clinically important complication of neoplastic progression. The role of parathyroid hormone-related protein (PTHrP) and transforming growth factor (TGF)-ß1 in this process has been clearly established. The current study describes an in vivo model of 13762 rat mammary carcinoma tumor cell-induced osteolysis in which PTHrP and TGF-ß1 expression is observed. Exposure of in vitro-cultured 13762 cells to doxorubicin, cis-platinum, carboplatin, methotrexate, 5-fluorouracil, paclitaxel, alendronate, risedronate, or pamidronate for 72 h resulted in varying effects on cell proliferation (IC₅₀ values of 0.005, 0.4, 1.9, >40, 17.9, 0.003, >40, >40, and 33.6 µM, respectively). Tumor cells were implanted into the intramedullary space of the proximal tibia of rats, and the time course of tumor progression was evaluated using radiographic and microcomputed tomography scanning techniques. Trabecular bone mineral density, cortical bone mineral density, and whole bone mineral density were measured (in mg/cm³). In untreated animals, radiographic evidence of osteolysis was evident 7 days after implantation. Trabecular bone mineral density and whole bone mineral density were significantly decreased by 21 days after implantation (48% and 26%, respectively). Bisphosphonates showed broad protective activity against tumor-driven osteolysis, Immunohistochemical evaluation of s.c. and intratibially implanted cells demonstrated the expression of PTHrP and TGF-ß1. The results of this study demonstrate the ability of 13762 rat mammary carcinoma cells to elicit a measurable osteolysis and that bisphosphonates inhibit the tumor-induced bone resorption in this model.

Commentary

Antitumor Activity of Bisphosphonates

Matthew R. Smith
Clin. Cancer Res. 2003 9: 5433-5434. [Full Text] [PDF]

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