Local interferon-α gene therapy elicits systemic immunity in a syngeneic pancreatic cancer model in hamster
Local interferon-α gene therapy elicits systemic immunity in a syngeneic pancreatic cancer model in hamster
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DOI：
10.1111/j.1349-7006.2007.00408.x
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发表时间：
2007-03-01
期刊：
影响因子：
5.7
通讯作者：
Aoki, Kazunori
中科院分区：
文献类型：
--
作者：
Hara, Hidehiko;Kobayashi, Akihiko;Aoki, Kazunori
干扰素（IFN）蛋白是一种具有多效生物学功能的细胞因子，包括诱导细胞凋亡、抑制血管生成和免疫调节。我们之前利用 IFN-α 在其体内作用中未表现出跨物种活性的事实，研究了两种抗肿瘤机制。在使用人胰腺癌细胞的裸鼠皮下异种移植模型中，人IFN-α的表达有效诱导人胰腺癌细胞的细胞死亡，而小鼠IFN-α通过刺激自然杀伤细胞增强抗肿瘤免疫力。在这里，我们将研究扩展到同基因胰腺癌模型，以便可以严格评估局部IFN-α基因治疗的综合抗肿瘤活性，包括抗增殖、促凋亡、抗血管生成和免疫调节作用。当将重组仓鼠 IFN-α 腺病毒注射到叙利亚仓鼠的仓鼠胰腺癌 (PGHAM-1) 细胞同基因皮下肿瘤中时，由于细胞死亡以及 T 细胞和自然杀伤细胞介导的抗肿瘤免疫，肿瘤生长显着受到抑制。此外，在这种情况下，不仅观察到注射的皮下肿瘤的肿瘤消退，而且还观察到腹膜腔和远处部位未经治疗的肿瘤的肿瘤消退。在接受治疗的仓鼠中没有观察到明显的全身毒性。此外，在最初的肿瘤攻击后，四只治愈仓鼠中的三只拒绝了 PGHAM-1 细胞的皮下再攻击。这项研究进一步证明，局部 IFN-α 基因治疗是一种有前途的胰腺癌治疗策略，因为它具有多种抗肿瘤活性机制，并且没有明显的毒性。
The interferon (IFN) protein is a cytokine with pleiotropic biological functions that include induction of apoptosis, inhibition of angiogenesis and immunomodulation. We previously examined the two antitumor mechanisms, taking advantage of the fact that IFN-alpha did not show cross-species activity in its in vivo effect. In a nude mouse subcutaneous xenograft model using human pancreatic cancer cells, the expression of human IFN-alpha effectively induced cell death of human pancreatic cancer cells, whereas mouse IFN-alpha augmented antitumor immunity by stimulation of natural killer cells. Here, we extended our investigation to a syngeneic pancreatic cancer model, so that the integrated antitumor activity of local IFN-alpha gene therapy, including the antiproliferative, proapoptotic, antiangiogeneic and immunomodulatory effects, can be evaluated rigorously. When a recombinant hamster IFN-alpha adenovirus was injected into syngeneic subcutaneous tumors of hamster pancreatic cancer (PGHAM-1) cells in Syrian hamster, tumor growth was significantly suppressed due to cell death and T cell- and natural killer cell-mediated antitumor immunity. Moreover, in this case, tumor regression was observed not only for the injected subcutaneous tumors but also for the untreated tumors both in the peritoneal cavity and at distant sites. No significant systemic toxicity was observed in the treated hamsters. Moreover, the subcutaneous rechallenge of PGHAM-1 cells was rejected in three of four cured hamsters from the initial tumor challenge. This study further demonstrated that local IFN-alpha gene therapy is a promising therapeutic strategy for pancreatic cancer, due to its multiple mechanisms of antitumor activity and its lack of significant toxicity.