Novel cytosine deaminase fusion gene enhances the effect of radiation on breast cancer in bone by reducing tumor burden, osteolysis, and skeletal fracture.
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).
Goblirsch
Michael
M
Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Zwolak
Pawel
P
Ramnaraine
Margaret L
ML
Pan
Weihong
W
Lynch
Christine
C
Alaei
Parham
P
Clohisy
Denis R
DR
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
D000963:Antimetabolites; D005819:Genetic Markers; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; D020800:Receptor, Nerve Growth Factor; D005437:Flucytosine; D043525:Cytosine Deaminase