Retroviral vector-mediated transfer of an antisense cyclin G1 construct inhibits osteosarcoma tumor growth in nude mice
Retroviral vector-mediated transfer of an antisense cyclin G1 construct inhibits osteosarcoma tumor growth in nude mice
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DOI：
10.1089/hum.1997.8.14-1667
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发表时间：
1997-09-20
影响因子：
4.2
通讯作者：
Gordon, EM
中科院分区：
文献类型：
--
作者：
Chen, DS;Zhu, NL;Gordon, EM
转移性骨肉瘤是基因治疗的潜在靶点，因为常规治疗仅是姑息性的，而转移性疾病总是致命的。在人骨肉瘤细胞中经常观察到细胞周期蛋白G1（CYCG 1）基因的过表达，并且发现其持续表达对其生存至关重要。我们报道了细胞周期蛋白G1蛋白表达的下调在人MG-63骨肉瘤细胞中诱导细胞生长抑制和细胞杀伤作用（Skotzko等，Cancer Research，1995），在此，我们在致瘤性MNNG/HOS细胞系中扩展了这些发现，并报道了当将反义细胞周期蛋白G1逆转录病毒载体作为浓缩的高滴度载体上清液直接递送到无胸腺裸鼠中快速生长的皮下肿瘤中时，反义细胞周期蛋白G1载体处理的肿瘤的组织切片显示有丝分裂指数降低和残留肿瘤内基质形成增加。此外，残留肿瘤细胞的细胞周期动力学的原位分析揭示了细胞周期的S期和G2/M期的细胞数量减少，同时伴随着G1期细胞的积累。总之，这些研究证实了高滴度反义细胞周期蛋白G1逆转录病毒载体在骨肉瘤动物模型中的体内功效。
Metastatic osteosarcoma is a potential target for gene therapy, because conventional therapies are only palliative and metastatic disease is invariably fatal, Overexpression of the cyclin G1 (CYCG1) gene is frequently observed in human osteosarcoma cells, and its continued expression is found to be essential for their survival, Previously, we reported that down-regulation of cyclin G1 protein expression induced cytostatic and cytocidal effects in human MG-63 osteosarcoma cells (Skotzko et al., Cancer Research, 1995), Here, we extend these findings in a tumorigenic MNNG/HOS cell line and report on the effective inhibition of tumor growth in vivo by an antisense cyclin G1 retroviral vector when delivered as concentrated high titer vector supernatants directly into rapidly growing subcutaneous tumors in athymic nude mice, Histologic sections from the antisense cyclin G1 vector-treated tumors showed decreased mitotic indices and increased stroma formation within the residual tumors, Furthermore, in situ analysis of the cell-cycle kinetics of residual tumor cells revealed a decrease in the number of cells in S and G2/M phases of the cell cycle concomittant with an accumulation of cells in the G1 phase, Taken together, these studies demonstrate in vivo efficacy of a high-titer antisense cyclin G1 retroviral vector in an animal model of osteosarcoma.