Wattenberg L W, Wiedmann T S, Estensen R D, Zimmerman C L, Steele V E, Kelloff G J
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455-0315, USA.
Cancer Res. 1997 Dec 15;57(24):5489-92.
This investigation is part of a continuing effort to develop effective chemoprevention for carcinogenesis of the lung. The present study explores the use of aerosol administrations for this purpose. The agent selected for initial study was the synthetic glucocorticoid budesonide. This selection was based on previous work in which budesonide added to the diet was found to inhibit pulmonary adenoma formation in female A/J mice. However, high dose levels were required, i.e., of the order of 300 microg/kg, of body weight [L. W. Wattenberg and R. D. Estensen, Carcinogenesis (Lond.), 18: 2015-2017, 1997]. For aerosol administration of budesonide, a nose-only technique has been developed that entails nebulization of the compound dissolved in ethanol and subsequent stripping off of the solvent (less than 3 microl ethanol/liter of air remaining at the site of inhalation). The budesonide particles produced by the apparatus had a mass median aerodynamic diameter of less than 1 microm. An experiment has been carried out in which the inhibitory effects of aerosolized budesonide, given for 1 min six times a week, were studied. Concentrations of budesonide of 26, 81, and 148 microg/liter of air (calculated doses of 23, 72, and 126 microg/kg of body weight) were used. The aerosols were started 1 week after three oral administrations of benzo(a)pyrene (2 mg/20 g of body weight) to female A/J mice. All three doses of budesonide resulted in more than 80% inhibition of pulmonary tumor formation compared to the aerosol control and 90% or greater compared to mice not exposed to aerosol. The difference in inhibition is due to the aerosol procedure itself, which produces a reduction in tumor formation. A decrease in splenic weight (evidence of a systemic effect) occurred at all doses of budesonide. To the best of our knowledge, this is the first published effort at the use of aerosol administration to prevent neoplasia of the respiratory tract. The results of the present study show that administration of a potential chemopreventive agent by aerosol at a low dose can inhibit the occurrence of pulmonary carcinogenesis in female A/J mice.
本研究是为开发有效的肺癌化学预防方法而持续努力的一部分。本研究探讨了为此目的使用气雾剂给药的方法。最初研究选用的药物是合成糖皮质激素布地奈德。这一选择是基于先前的研究工作，在该研究中发现，将布地奈德添加到饮食中可抑制雌性A/J小鼠的肺腺瘤形成。然而，需要高剂量水平，即体重约300微克/千克[L. W. 瓦滕伯格和R. D. 埃斯滕森，《癌变（伦敦）》，18: 2015 - 2017，1997]。对于布地奈德的气雾剂给药，已开发出一种仅经鼻给药技术，该技术需要将溶解在乙醇中的化合物雾化，随后去除溶剂（吸入部位每升空气中残留的乙醇少于3微升）。该装置产生的布地奈德颗粒的质量中值空气动力学直径小于1微米。已进行了一项实验，研究了每周六次、每次给药1分钟的雾化布地奈德的抑制作用。使用的布地奈德浓度为每升空气26、81和148微克（计算剂量分别为体重23、72和126微克/千克）。在对雌性A/J小鼠进行三次口服苯并(a)芘（2毫克/20克体重）给药1周后开始给予气雾剂。与气雾剂对照组相比，所有三种剂量的布地奈德均导致肺肿瘤形成的抑制率超过80%，与未接触气雾剂的小鼠相比，抑制率达到90%或更高。抑制作用的差异是由于气雾剂给药程序本身导致肿瘤形成减少。所有剂量的布地奈德均导致脾脏重量减轻（全身效应的证据）。据我们所知，这是首次发表的使用气雾剂给药预防呼吸道肿瘤形成的研究。本研究结果表明，以低剂量通过气雾剂给药一种潜在的化学预防剂可抑制雌性A/J小鼠肺肿瘤的发生。
