Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
Bend Research Inc., Bend, OR, USA.
Br J Cancer. 2020 Apr;122(8):1194-1204. doi: 10.1038/s41416-020-0765-2. Epub 2020 Feb 27.
Epigenetic therapy through demethylation of 5-methylcytosine has been largely ineffective in treating lung cancer, most likely due to poor tissue distribution with oral or subcutaneous delivery of drugs such as 5-azacytidine (5AZA). An inhalable, stable dry powder formulation of 5AZA was developed.
Pharmacokinetics of inhaled dry powder and aqueous formulations of 5AZA were compared to an injected formulation. Efficacy studies and effect of therapy on the epigenome were conducted in an orthotopic rat lung cancer model for inhaled formulations.
Inhaled dry powder 5AZA showed superior pharmacokinetic properties in lung, liver, brain and blood compared to the injected formulation and for all tissues except lung compared to an inhaled aqueous formulation. Only dry powder 5AZA was detected in brain (~4-h half-life). Inhaled dry powder was superior to inhaled aqueous 5AZA in reducing tumour burden 70-95%. Superiority of inhaled 5AZA dry powder was linked to effectively reprogramming the cancer genome through demethylation and gene expression changes in cancer signalling and immune pathways.
These findings could lead to widespread use of this drug as the first inhaled dry powder therapeutic for treating local and metastatic lung cancer, for adjuvant therapy, and in combination with immunotherapy to improve patient survival.
通过 5-甲基胞嘧啶去甲基化的表观遗传疗法在治疗肺癌方面效果甚微，这很可能是由于口服或皮下给予 5-氮杂胞苷（5AZA）等药物时组织分布不佳所致。我们开发了一种可吸入的、稳定的 5AZA 干粉制剂。
比较了吸入干粉和水性 5AZA 制剂与注射制剂的药代动力学。在原位大鼠肺癌模型中进行了疗效研究和治疗对表观基因组的影响。
与注射制剂相比，吸入干粉 5AZA 在肺部、肝脏、大脑和血液中的药代动力学特性均优于注射制剂，除肺部外，所有组织的药代动力学特性均优于吸入水性制剂。只有干粉 5AZA 可在大脑中检测到（~4 小时半衰期）。与吸入水性 5AZA 相比，吸入干粉可使肿瘤负担降低 70-95%。吸入 5AZA 干粉的优越性与通过去甲基化和癌症信号转导及免疫途径中的基因表达变化有效重编程癌症基因组有关。
这些发现可能会导致广泛使用这种药物作为第一种治疗局部和转移性肺癌的可吸入干粉治疗药物，用于辅助治疗，并与免疫疗法联合使用，以提高患者的生存率。
