title: Novel cytosine deaminase fusion gene enhances the effect of radiation on breast cancer in bone by reducing tumor burden, osteolysis, and skeletal fracture.
abstract: 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.
  
  
  METHODS
  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)).
  
  
  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).
authors.affiliation: Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Goblirsch
authors.forename: Pawel
authors.initials: P
authors.lastname: Zwolak
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Ramnaraine
authors.forename: Weihong
authors.initials: W
authors.lastname: Pan
authors.forename: Christine
authors.initials: C
authors.lastname: Lynch
authors.forename: Parham
authors.initials: P
authors.lastname: Alaei
authors.forename: Denis R
authors.initials: DR
authors.lastname: Clohisy
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000532:radiotherapy* / Q000556:secondary; D002277:Carcinoma / Q000473:pathology* / Q000532:radiotherapy; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005437:Flucytosine / Q000494:pharmacology*; D050723:Fractures, Bone / Q000209:etiology / Q000517:prevention & control; D005819:Genetic Markers; D015316:Genetic Therapy; D015674:Mammary Neoplasms, Animal / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D010014:Osteolysis / Q000209:etiology / Q000517:prevention & control; D010146:Pain / Q000209:etiology / Q000517:prevention & control; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D011897:Random Allocation; D020800:Receptor, Nerve Growth Factor / Q000235:genetics*; D014161:Transduction, Genetic; D016896:Treatment Outcome
chemical_list: D000963:Antimetabolites; D005819:Genetic Markers; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; D020800:Receptor, Nerve Growth Factor; D005437:Flucytosine; D043525:Cytosine Deaminase