Goblirsch Michael, Zwolak Pawel, Ramnaraine Margaret L, Pan Weihong, Lynch Christine, Alaei Parham, Clohisy Denis R
Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Clin Cancer Res. 2006 May 15;12(10):3168-76. doi: 10.1158/1078-0432.CCR-05-2729.
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.
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)).
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).
乳腺癌骨转移疼痛是恶性疾病的常见表现。根除这些肿瘤可能具有挑战性，因此，随着疾病进展，骨骼发病率会增加。
使用4T1小鼠乳腺癌模型在体外和体内评估胞嘧啶脱氨酶（CD）基因治疗联合放射治疗的治疗潜力。用编码人神经生长因子受体的细胞外和跨膜结构域以及酵母CD基因（NGFR-CD(y)）的细胞质部分的融合基因转导4T1癌细胞。
表达CD的肿瘤细胞（4TCD(y)）对5-氟胞嘧啶前药治疗高度敏感（P < 0.0001）。5-氟胞嘧啶处理4TCD(y)细胞而非4T1细胞，可增强体外放射治疗效果（P < 0.0001）。5-氟胞嘧啶前药治疗还增加了体内放射治疗的潜力。患有4TCD(y)股内肿瘤的小鼠基于肿瘤大小改善性缩小、致瘤性骨溶解减少和骨骼骨折减少，显示出放射治疗效果增强（P < 0.01）。
