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

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)-β1 in this process has been clearly established. The current study describes an in vivo model of 13762 ra...

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Published in:	Clinical cancer research Vol. 9; no. 15; pp. 5705 - 5713
Main Authors:	ALVAREZ, Enrique, WESTMORE, Michael, ZAMBRANO, Carmen, MA, Linda, SATO, Masahiko, MARTIN, T. John, TEICHER, Beverly A, GALBREATH, Elizabeth J, SELLS GALVIN, Rachelle J, CLAPP, Crystal L, CONSIDINE, Eileen L, SMITH, Shawn J, KEYES, Kristan, IVERSEN, Philip W, DELAFUENTE, Dawn M, SULAIMON, Shola
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-11-2003
Subjects:	Animals Antineoplastic agents Antineoplastic Agents - toxicity Biological and medical sciences Bone Resorption - etiology Bone Resorption - prevention & control Cell Division - drug effects Cell Line, Tumor Cell Survival - drug effects Chemotherapy Diphosphonates - therapeutic use Disease Progression Female Humans Mammary Neoplasms, Experimental - complications Mammary Neoplasms, Experimental - drug therapy Medical sciences Neoplasm Metastasis Osteolysis - etiology Osteolysis - prevention & control Parathyroid Hormone-Related Protein - analysis Parathyroid Hormone-Related Protein - genetics Pharmacology. Drug treatments Rats Rats, Inbred F344 Transforming Growth Factor beta - analysis Transforming Growth Factor beta - genetics Antineoplastic agent Carcinoma Rat Rodentia Resorption Diphosphonic acid derivatives Antimetastatic agent Malignant tumor Metastasis Osteolysis Bisphosphonates Mammary gland diseases Vertebrata Chemotherapy Mammalia Treatment Animal Subcutaneous administration Metastatic Mammary gland Bone
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Summary:	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)-β1 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-β1 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 (IC 50 values of 0.005, 0.4, 1.9, >40, 17.9, 0.003, >40, >40, and 33.6 μ m , 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/cm 3 ). 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-β1. 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.
ISSN:	1078-0432 1557-3265