Gene therapy for the treatment of chondrosarcoma

软骨肉瘤的基因疗法

• 批准号: 12470306
• 负责人: UCHIDA Atsumasa
• 金额: $ 5.5万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470306/
• 关键词: chondrosarcoma; gene therapy; suicide gene; bystander effect; apoptosis; 軟部腫瘍

Gene therapy for the treatment of chondrosarcoma was studied in vitro and in vivo using cell culture and an experimental animal model developed originally. Cell culture study showed cytocidal effect of chondrosarcoma cells incorporated suicide gene (thymidine kinase gene of herpes simplex virus) by addition of anti-virus agent (Ganciclovir). The bystander effect was also confirmed with the ratio of 1:50. The bystander effect in chondrosarcoma cells seems to be caused by the presence of the structure as gap junction which was demonstrated electron microscopically. These effects were enhanced by the addition of some cytocidal cytokines TRAIL and TNF α. Cell death was caused by apoptosis.Growth of the tumor implanted into the mice subcutaneously was markedly inhibited by injection of suicide gene into the tumor and thereafter intraabdominal administration of anti-virus agent. The tumor size after administration of suicide gene and anti-virus agent was one fifth of control after 4 weeks.These results suggest that gene therapy by suicide gene is useful for the treatment of chondrosarcoma which does not have effective treatments except surgery. Improvement of survival rate in chondrosarcoma by gene therapy will contribute to those in other malignant bone and soft tissue sarcomas.

采用细胞培养和自行建立的实验动物模型，对软骨肉瘤的基因治疗进行了体内外研究。细胞培养研究表明，在抗病毒药物更昔洛韦的作用下，携带自杀基因(单纯疱疹病毒胸苷激酶基因)的软骨肉瘤细胞具有杀伤作用。旁观者效应也得到证实，比例为1：50。在软骨肉瘤细胞中的旁观者效应似乎是由于作为间隙连接的结构的存在而引起的，这在电子显微镜下得到了证实。加入一些细胞毒细胞因子TRAIL和肿瘤坏死因子α可增强上述作用。细胞死亡是由细胞凋亡引起的，移植到小鼠皮下的肿瘤通过向肿瘤内注射自杀基因，然后再经腹腔注射抗病毒药物来显著抑制肿瘤的生长。应用自杀基因和抗病毒药物治疗4周后，肿瘤体积仅为对照组的1/5，提示自杀基因治疗软骨肉瘤是一种有效的治疗方法。通过基因治疗提高软骨肉瘤的存活率，将有助于其他恶性骨和软组织肉瘤的存活率的提高。

项目成果

R Tomod, A Uchida, et al: "Telomerase Activity and human telomerase reverse transcriptase mRNA expression are correlated with clinical aggressiveness in soft tissue tumor"Cancer. 95(5). 1127-1133 (2002)

R Tomod、A Uchida 等人：“端粒酶活性和人端粒酶逆转录酶 mRNA 表达与软组织肿瘤的临床侵袭性相关”癌症。

M Seto: "Gene therapy of chondrosarcoma using retrovirus vectors encoding the herpes simplex virus thymidine kinase gene"Int J Oncology. 14. 1137-114 (1999)

M Seto：“使用编码单纯疱疹病毒胸苷激酶基因的逆转录病毒载体进行软骨肉瘤的基因治疗”Int J Oncology。

M Hasegawa, Y Doi, A Uchida: "Cell-mediated bioresorption of sintered carbonate apatite in rabbits"J Bone Joint Surg. 85(B). 142-147 (2003)

M Hasekawa、Y Doi、A Uchida：“兔子体内烧结碳酸盐磷灰石的细胞介导生物吸收”J Bone Joint Surg。

R Tomod, A Uchida, et al.: "Telomerase Activity and human telomerase reverse transcriptase mRNA expression are correlated with clinical aggressiveness in soft tissue tumor"Cancer. 95(5). 1127-1133 (2002)

R Tomod、A Uchida 等人：“端粒酶活性和人端粒酶逆转录酶 mRNA 表达与软组织肿瘤的临床侵袭性相关”癌症。

K Mori: "Cross-Talk between RANKL and FRP-1/CD98 Systems:RANKL-Mediated Osteoclastogenesis Is Suppressed by an inhibitory Anti-CD98 Heavy Chain mAb and CD98 Mediated Osteoclastogenesis Is Suppressed Ostroclastogenesis Inhibitory Factor"Cell Imm. 207. 118-

K Mori：“RANKL 和 FRP-1/CD98 系统之间的交叉对话：RANKL 介导的破骨细胞生成受到抑制性抗 CD98 重链单克隆抗体的抑制，并且 CD98 介导的破骨细胞生成受到破骨细胞生成抑制因子的抑制”Cell Imm。