Abstract：
BACKGROUND:Azacitidine as an effective epigenetic therapeutic agent has not been used as an aerosol form to treat lung cancer patients. We aerosolized clinical grade azacitidine (Aza), optimized the formulation, and studied its pharmacokinetics and toxicity in mice. METHODS:Extrusion-precipitation method and DNA methyltransferase inhibition rate were used to measure the aerodynamic size and aerosolized Aza activity. In the single dose pharmacokinetic study, Aza concentrations in peripheral blood and lungs were measured by LC-MS method. In the multiple-dose toxicity studies, histo-pathological evaluation was used to determine the organ and bone marrow toxicities. RESULTS:In pharmacokinetic study, aerosolized Aza was found to deposit mainly into the lung with very little drug detected in the circulation. In contrast, intravenously injected (IV) Aza resulted in a high Aza concentration in the peripheral blood, with trace amounts of drug in the lung, and it was associated with significant myelosuppression. No significant myelosuppression, pulmonary toxicity, hepatotoxicity, or nephrotoxicity were observed at a daily dose of 2.5 mg/m(2) for 7 days. Reversible lung inflammation was found in mice treated with 7.5 mg/m(2) aerosolized Aza at 3 but not 6 weeks after treatment. CONCLUSIONS:Aerosol Aza aerodynamic size favors deposition of the drug to the human lower airways. The aerosol process do not compromise the drug activity. Aerosolized Aza has higher lung deposition and much less systemic toxicity than IV drug. The safe starting dose for clinical phase I trials should be 2.5 mg/m(2) for 5 to 7 days.
journal_name
Clin Lung Cancerjournal_title
Clinical lung cancerauthors
Qiu X,Liang Y,Sellers RS,Perez-Soler R,Zou Ydoi
10.1016/j.cllc.2015.09.005subject
Has Abstractpub_date
2016-05-01 00:00:00pages
214-222.e1issue
3eissn
1525-7304issn
1938-0690pii
S1525-7304(15)00237-5journal_volume
17pub_type
杂志文章abstract：:Lung cancer continues to be the leading cause of cancer-related death in the United States. Small-cell lung cancer constitutes 15%-20% of all cases of lung cancer. It is a chemosensitive disease with an overall response rate of 70%-90% in first-line treatment. However, the majority of patients relapse, and further tre...
journal_title：Clinical lung cancer
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pub_type： 杂志文章,评审
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journal_title：Clinical lung cancer
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pub_type： 临床试验,杂志文章,随机对照试验
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pub_type： 杂志文章
doi：10.1016/j.cllc.2016.11.005
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journal_title：Clinical lung cancer
pub_type： 杂志文章
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pub_type： 杂志文章,meta分析
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pub_type： 杂志文章,评审
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pub_type： 杂志文章
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pub_type： 杂志文章,评审
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pub_type： 杂志文章
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更新日期：2001-08-01 00:00:00
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journal_title：Clinical lung cancer
pub_type： 杂志文章
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pub_type： 杂志文章,评审
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pub_type： 杂志文章
doi：10.3816/clc.2002.s.003
更新日期：2002-03-01 00:00:00
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journal_title：Clinical lung cancer
pub_type： 杂志文章
doi：10.1016/j.cllc.2014.10.003
更新日期：2015-03-01 00:00:00
