Development of Immunogene therapy using IL-6 for Pancreatic Cancer

使用 IL-6 治疗胰腺癌的免疫基因疗法的开发

• 批准号: 10557106
• 负责人: SUGIURA Hiroshi
• 金额: $ 7.81万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557106/
• 关键词: Pancreatic Cancer; IL-6; Gene Therapy; Immunogene Therapy

Production of interleukin-6 (IL-6) by human pancreatic carcinoma cells inversely correlates with potentials for blood-borne metastasis to the liver in nude mice. IL-6 cDNA was transfected to PCI-43, one of our cultured pancreatic carcinoma cell lines that does not produce IL-6 and generates numerous metastases to the liver. An IL-6 high-producer clone (PCI-43h) generated few metastases; IL-6 production thus has a direct effect on metastasis, whereas other transfectants (PCI-43l and PCI-43n), which are IL-6 low-, and IL-6 non-producers, respectively, did generate metastases. Tumor-reactive IgG, which mediated antibody-dependent cellular cytotoxicity (ADCC) in vitro, was detected in sera from recipient nude mice inoculated with PCI-43h but not in sera from mice given PCI-43l, PCI-43n or parent PCI-43. In addition, we tested the efficacy of N116Y in blocking the in vivo growth of pancreatic cancer cells using an adenoviral vector. Direct injection of the AdCEA-N116Y in which N116Y expression is driven by the CEA promoter, into the spleen in nude mice suppressed their growth of liver metastases significantly.

人胰腺癌细胞产生的白介素6(IL-6)与裸鼠肝脏血行转移的潜能呈负相关。将IL-6基因转移到我们培养的胰腺癌细胞系之一的pCI-43中，该细胞不产生IL-6，并产生大量的肝脏转移。IL-6高表达克隆(pCI-43h)产生的转移较少；因此，IL-6的产生对转移有直接影响，而其他转染体(pCI-43l和pCI-43n)分别是IL-6低产生和IL-6非产生，确实产生转移。在接种组裸鼠的血清中检测到肿瘤反应性的免疫球蛋白G，而在接种组、接种组和亲本接种组的血清中未检测到肿瘤反应性的免疫球蛋白。此外，我们用腺病毒载体检测了N116Y对胰腺癌细胞体内生长的阻断作用。将由CEA启动子驱动表达N116Y的AdCEA-N116Y直接注射到裸鼠的脾内，可显著抑制其肝转移瘤的生长。

项目成果

Toshiya Nishibe: "Expanded Polytetrafluoroethylene Grafts for Portal Vein Replacement : Use of Omentum Wrap to Promote Graft Healing"Surgery Today Jpn J Surg. 27. 149-153 (1998)

Toshiya Nishibe：“用于门静脉置换的膨胀聚四氟乙烯移植物：使用大网膜包裹促进移植物愈合”Surgery Today Jpn J Surg。

Nagino M.: "Segmental Liver Resections for Hilar Cholangiocarcinoma." Hepato-Gastroenterology. 45. 7-13 (1998)

Nagino M.：“肝门部胆管癌的分段肝切除术。”

Takeuchi M: "The dominant negative H-ras mutant, N116Y, suppresses growth of metastatic human pancreatic cancer cells in the liver of nude mice."Gene Ther. (in press).

Takeuchi M：“显性失活 H-ras 突变体 N116Y 可抑制裸鼠肝脏中转移性人类胰腺癌细胞的生长。”Gene Ther。

Naoto Senmaru: "SUPPRESSION OF Erk ACTIVATION AND IN VIVO GROWTH IN ESOPHAGEAL CANCER CELLS BY THE DOMINANT NEGATIVE Ras MUTANT, N116Y." International Journal of Cancer. 78. 366-371 (1998)

Naoto Senmaru：“显性阴性 Ras 突变体 N116Y 抑制食管癌细胞的 Erk 激活和体内生长。”

Katsunori Saito: "INTERLEUKlN-6 PRODUCED BY PANCREATIC CARCINOMA CELLS ENHANCES HUMORAL IMMUNE RESPONSES AGAINST TUMOR CELLS : A POSSIBLE EVENT IN TUMOR REGRESSION."International Journal of Cancer. 75. 284-289 (1998)

Katsunori Saito：“胰腺癌细胞产生的 INTERLEUKlN-6 增强了针对肿瘤细胞的体液免疫反应：肿瘤消退中的一个可能事件。”国际癌症杂志。