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Novel Cytosine Deaminase Fusion Gene Enhances the Effect of Radiation on Breast Cancer in Bone by Reducing Tumor Burden, Osteolysis, and Skeletal Fracture

Authors' Affiliation: Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, Minnesota

Requests for reprints: Denis R. Clohisy, Department of Orthopaedic Surgery, University of Minnesota, 420 Delaware Street Southeast, MMC 806, Minneapolis, MN 55455. Phone: 612-626-9934; Fax: 612-624-0944; E-mail: clohi001{at}umn.edu.

Background: Painful breast carcinoma metastases in bone are a common manifestation of malignant disease. Eradication of these tumors can be evasive, and as a result, skeletal morbidity increases with disease progression.

Experimental Design: The treatment potential of cytosine deaminase (CD) gene therapy combined with radiation treatment was evaluated in vitro and in vivo using a 4T1 murine breast carcinoma model. 4T1 carcinoma cells were transduced with a fusion gene encoding the extracellular and transmembrane domains of the human nerve growth factor receptor and the cytoplasmic portion of the yeast CD gene (NGFR-CD_y).

Results and Conclusions: CD-expressing tumor cells (4TCD_y) were highly sensitive to treatment by 5-fluorocytosine prodrug (P < 0.0001). 5-Fluorocytosine treatment of 4TCD_y, but not 4T1 cells, enhanced the effects of radiation in vitro (P < 0.0001). 5-Fluorocytosine prodrug treatment also increased the therapeutic potential of radiation in vivo. Mice with 4TCD_y intrafemoral tumors showed increased effectiveness of radiation based on improved reductions in tumor size, reductions in tumorigenic osteolysis, and a decrease in skeletal fractures (P < 0.01).

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