Bystander effect of IL-12 and P53 gene therapy in the head and neck

IL-12 和 P53 基因治疗在头颈部的旁观者效应

• 批准号: 13671792
• 负责人: TSUKUDA Mamoru
• 金额: $ 2.62万
• 依托单位: Department of Otolaryngology, Yokohama City University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671792/
• 关键词: Head and Neck Ca.; Gene Therapy; IL-12 gene; Anti-tumor effects; Mechanism; 抗血管新生阻害作用; IL-12gene

The research was mainly focused on IL-12 gene therapy. Human KB cells transfected hIL-12 gene(KB/IL-12) produced IL-12 in the culture supernatant. KB/IL-12 cells showed a strong anti-tumor potential through elevated immunity. On the other hand direct administration of mIL-12 gene to inoculated tumors with NR-S1 (murine oral carcinoma) resulted in IFN-γ production and anti-tumor effects. The mRNA expression of VEGF in NR-S1 cells transfected with mIL-12 gene decreased significantly, compared to non-treated NR-S1 cells.Furthermore, combined treatment with IL-12 gene therapy and chemotherapy, e. g. CDDP or UFT, showed a compete response in the murine model. The mechanisms of anti-tumor effects were considered to be induction of apoptosis, ant angiogenesis, immunological enhancement with the accumulation of CD8+ and CD56+ in the tumor site and synergistic effects of both treatments, especially immunological augmentation of IL-12 gene therapy on the deteriorated immunity by chemotherapy.In ELISPOT analysis, IFN-γ positive spleen cells increased in the mice group receiving IL-12 gene therapy, compared to those in the control one. This result showed Th_1 predominant condition caused by IL-12 gene therapy.In conclusion, IL-12 gene therapy not only augments local and systemic immunity and induce apoptotic change of tumor cells, but also suppresses angiogenesis of tumors, resulting in anti-tumor effects through comprehensive mechanisms.

研究主要集中在IL-12基因治疗。转染hIL-12基因的人KB细胞（KB/IL-12）培养上清产生IL-12。KB/IL-12细胞通过提高免疫力而显示出强大的抗肿瘤潜力。另一方面，将mIL-12基因直接施用到用NR-S1（小鼠口腔癌）接种的肿瘤导致IFN-γ产生和抗肿瘤作用。转染mIL-12基因的NR-S1细胞VEGF mRNA的表达较未转染的NR-S1细胞明显降低。G. CDDP或UFT在小鼠模型中显示竞争反应。IL-12基因治疗的抗肿瘤作用机制可能是诱导肿瘤细胞凋亡、抑制肿瘤血管生成、增强肿瘤局部CD_（8+）和CD_（56+）的免疫功能以及两者的协同作用，尤其是IL-12基因治疗对化疗所致免疫功能下降的免疫增强作用。IL-12基因治疗组小鼠IFN-γ阳性脾细胞数较对照组增加。结论：IL-12基因治疗不仅能增强局部和全身免疫功能，诱导肿瘤细胞凋亡，而且能抑制肿瘤血管生成，通过多种机制发挥抗肿瘤作用。

项目成果

M Tsukuda: "Induction of sparc by VEGF in human vascular endotherial cells"Biochem Biopyhs Rca Commun. 287(2). 422-426 (2001)

M Tsukuda：“人血管内皮细胞中 VEGF 诱导 sparc”Biochem Biopyhs Rca Commun。

佃 守: "21世紀耳鼻咽喉科 領域の臨床18免疫アレルギー疾患 Biological response modifier(BRM)とサイトカインによる治療"中山書店. 11 (2001)

Mamoru Tsukuda：“21世纪耳鼻喉科领域的临床18种免疫过敏性疾病。生物反应调节剂（BRM）和细胞因子的治疗”Nakayama Shoten 11（2001）。

M Tsakuda: "Reduced expression of p16 and p27 proteifls in nasopharyngeal carcinoma"Cancer Deteciori and Prevention. 25(5). 414-419 (2001)

M Tsakuda：“鼻咽癌中 p16 和 p27 蛋白的表达降低”癌症检测和预防。

佃 守: "頭頸部癌新しい治療の展開"癌と化学療法. 28(4). 464-474 (2001)

Mamoru Tsukuda：“头颈癌新疗法的开发”《癌症与化疗》28(4) (2001)。

M Tsukuda: "The inhibitory effects of TNP470 on tumour growth of head and neck carcinoma cell producing iiiterleukin-8"J Laryngol Otol. 115(10). 802-807 (2001)

M Tsukuda：“TNP470 对产生 iiiterleukin-8 的头颈癌细胞肿瘤生长的抑制作用”J Laryngol Otol。