Intranasal Iloprost Prevents Tumors in a Murine Lung Carcinogenesis Model.
Intranasal Iloprost Prevents Tumors in a Murine Lung Carcinogenesis Model.
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DOI：
10.1158/1940-6207.capr-21-0086
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Keith RL
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文献类型：
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作者：
Tennis MA;Smith AJ;Dwyer-Nield LD;Keith RL
使用前列环素类似物伊洛前列素进行肺癌化学预防是迄今为止最有前途的方法，用于阻止前吸烟者癌前肺病变的进展。以前的伊洛前列素临床前研究使用口服给药，但需要一项研究建模直接向靶器官给药。体内和体外研究已经确定了伊洛前列素治疗后的基因表达变化，包括E-钙粘蛋白和PPARγ增加以及COX 2和波形蛋白减少。我们使用肿瘤计数和基因表达来证明伊洛前列素鼻内给药在癌前腺瘤小鼠模型中的有效性。与未处理的尿烷对照组相比，鼻内给予伊洛前列素减少了FVB小鼠尿烷暴露后14周的腺瘤多样性。伊洛前列素鼻内给药可逆转肿瘤和全肺中的前列腺素诱导的基因表达变化。这些结果与先前的口服伊洛前列素和体外治疗人支气管上皮细胞的研究一致。该研究表明，在肺癌前病变小鼠模型中鼻内递送伊洛前列素是有效的化学预防。这将是探索伊洛前列素化学预防的机制和结果的重要工具，沿着正在进行的吸入伊洛前列素化学预防的临床试验。
Lung cancer chemoprevention with the prostacyclin analogue iloprost is the most promising approach to date for intercepting progression of premalignant lung lesions in former smokers. Previous pre-clinical studies of iloprost used oral delivery, but a study modeling delivery directly to the target organ was needed. In vivo and in vitro studies have identified gene expression changes following iloprost treatment, including increased E-cadherin and PPAR𝛄 and decreased COX2 and Vimentin. We used tumor counts and gene expression to demonstrate the effectiveness of intranasal delivery of iloprost in a murine model of premalignant adenomas. Intranasal delivery of iloprost reduced adenoma multiplicity14 weeks after urethane exposure in FVB mice compared to untreated urethane controls. Intranasal iloprost reversed urethane-induced gene expression changes in tumors and whole lung. These results correspond to previous studies of oral iloprost and in vitro treatment of human bronchial epithelial cells. This study demonstrates that intranasal delivery of iloprost in a mouse model of lung premalignant lesions is effective chemoprevention. This will be an essential tool for exploring mechanisms and outcomes of iloprost chemoprevention, along with supporting ongoing clinical trials of inhaled iloprost chemoprevention.