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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.

AbstractBACKGROUND:
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).
AuthorsMichael Goblirsch, Pawel Zwolak, Margaret L Ramnaraine, Weihong Pan, Christine Lynch, Parham Alaei, Denis R Clohisy
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 10 Pg. 3168-76 (May 15 2006) ISSN: 1078-0432 [Print] United States
PMID16707617 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimetabolites
  • Genetic Markers
  • Prodrugs
  • Radiation-Sensitizing Agents
  • Receptor, Nerve Growth Factor
  • Flucytosine
  • Cytosine Deaminase
Topics
  • Animals
  • Antimetabolites (pharmacology)
  • Bone Neoplasms (radiotherapy, secondary)
  • Carcinoma (pathology, radiotherapy)
  • Combined Modality Therapy
  • Cytosine Deaminase (biosynthesis, genetics, metabolism)
  • Disease Models, Animal
  • Female
  • Flucytosine (pharmacology)
  • Fractures, Bone (etiology, prevention & control)
  • Genetic Markers
  • Genetic Therapy
  • Mammary Neoplasms, Animal (pathology, radiotherapy)
  • Mice
  • Osteolysis (etiology, prevention & control)
  • Pain (etiology, prevention & control)
  • Prodrugs
  • Radiation-Sensitizing Agents (pharmacology)
  • Random Allocation
  • Receptor, Nerve Growth Factor (genetics)
  • Transduction, Genetic
  • Treatment Outcome

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