Local and systemic inhibition of lung tumor growth after nanoparticle-mediated mda-7/IL-24 gene delivery
Local and systemic inhibition of lung tumor growth after nanoparticle-mediated mda-7/IL-24 gene delivery
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DOI：
10.1089/dna.2004.23.850
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发表时间：
2004-12-01
影响因子：
3.1
通讯作者：
Chada, S
中科院分区：
文献类型：
--
作者：
Ramesh, R;Ito, I;Chada, S
人黑色素瘤分化相关基因-7（mda-7），又称白细胞介素-24（IL-24），是一个具有肿瘤抑制、抗血管生成和细胞因子特性的新基因。体外腺病毒介导的人mda-7/IL-24基因（Ad-mda-7）的基因转移导致人癌细胞的普遍生长抑制，对正常细胞的毒性最小。肿瘤内给药的Ad-mda-7肺肿瘤异种移植物的结果通过诱导细胞凋亡和抗血管生成机制的生长抑制。虽然这些结果是令人鼓舞的，这种方法的一个局限性是，其局部的临床应用-全身递送腺病毒治疗播散性癌症是不可行的，目前。适合全身应用的替代方法是非病毒基因递送。我们最近证明，DOTAP：胆固醇（DOTAP：Chol）纳米粒子有效地将肿瘤抑制基因传递到原发性和播散性肺肿瘤。因此，在本研究中，我们评估了纳米颗粒介导的人mda-7/IL-24基因在体内向原发性和播散性肺肿瘤的递送。我们证明DOTAP：Chol有效地将mda-7/IL-24基因递送到人肺肿瘤异种移植物，从而抑制肿瘤生长。在原发性（P=0.001）和转移性肺肿瘤（P=0.02）中均观察到生长抑制作用。此外，在mda-7/IL-24治疗的肿瘤中，肿瘤血管化减少。最后，在用DOTAP：Chol-mda-7纳米颗粒处理的鼠同系肿瘤中，生长也被抑制（P=0.01）。这是第一份证明（1）mda-7/IL-24在肺癌中的全身治疗作用和（2）人mda-7在同基因癌症模型中的抗肿瘤作用的报告。我们的研究结果对于开发mda-7/IL-24治疗原发性和播散性癌症非常重要。
The human melanoma differentiation associated gene-7 (mda-7), also known as interleukin-24 (IL-24), is a novel gene with tumor suppressor, antiangiogenic, and cytokine properties. In vitro adenovirus-mediated gene transfer of the human mda-7/IL-24 gene (Ad-mda-7) results in ubiquitous growth suppression of human cancer cells with minimal toxicity to normal cells. Intratumoral administration of Ad-mda-7 to lung tumor xenografts results in growth suppression via induction of apoptosis and antiangiogenic mechanisms. Although these results are encouraging, one limitation of this approach is that its locoregional clinical application-systemic delivery of adenoviruses for treatment of disseminated cancer is not feasible at the present time. An alternative approach that is suitable for systemic application is non-viral gene delivery. We recently demonstrated that DOTAP:cholesterol (DOTAP: Chol) nanoparticles effectively deliver tumor suppressor genes to primary and disseminated lung tumors. In the present study, therefore, we evaluated nanoparticle-mediated delivery of the human mda-7/IL-24 gene to primary and disseminated lung tumors in vivo. We demonstrate that DOTAP:Chol efficiently delivers the mda-7/IL-24 gene to human lung tumor xenografts, resulting in suppression of tumor growth. Growth-inhibitory effects were observed in both primary (P=0.001) and metastatic lung tumors (P=0.02). Furthermore, tumor vascularization was reduced in mda-7/IL-24-treated tumors. Finally, growth was also inhibited in murine syngenic tumors treated with DOTAP:Chol-mda-7 nanoparticles (P=0.01). This is the first report demonstrating (1) systemic therapeutic effects of mda-7/IL-24 in lung cancer, and (2) antitumor effects of human mda-7 in syngeneic cancer models. Our findings are important for the development of mda-7/IL-24 treatments for primary and disseminated cancers.