吸入异维甲酸(13-顺式维甲酸)在A/J小鼠中是一种低剂量有效的肺癌化学预防剂:一项初步研究。
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Dahl AR, Grossi IM, houchen DP, Scovell LJ, Placke ME, Imondi AR, Stoner GD, De Luca LM, Wang D, Mulshine JL
吸入异维甲酸(13-顺式维甲酸)在A/J小鼠中是一种低剂量有效的肺癌化学预防剂:一项初步研究。
临床癌症杂志2000年8月;6(8):3015-24。
- PubMed ID
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10955779 (PubMed视图］
- 摘要
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在先前接受过治疗的头颈部癌症患者中，p.o.给予异维甲酸(13-顺式维甲酸)减少了包括肺部肿瘤在内的第二呼吸道消化系统肿瘤的发生，但副作用使慢性治疗成为问题。我们认为吸入异维甲酸可以为靶细胞提供足够的药物以获得疗效，同时避免全身毒性，因此我们进行了本文报道的先导研究。雄性A/J小鼠给予单次i.p.剂量的脲烷，一种常见的实验性肺癌致癌物，或苯并[A]芘(BaP)或4-(甲基亚硝胺)-1-(3-吡啶基)-1-丁酮(NNK)，烟草烟雾中的推定主要致癌物。第二天，开始以1.3、20.7或481微克/升的浓度每天暴露于异维甲酸气溶胶45分钟。2周后，高剂量对鼻部皮肤造成严重毒性，需要将剂量频率减少到每周两次。作为预防措施，中等剂量减少到每周三次。计算出降低剂量频率后，低、中、高剂量的每周总沉积剂量分别为0.24、1.6和24.9 mg/kg，其中估计有16%沉积在肺部。在经脲处理的a /J小鼠中，每周肺部沉积药物剂量分别为先前报道的无效口服剂量的0.01、0.07和1.1%。10-16周后，处死小鼠以计数肺增生和腺瘤面积。对于所有致癌物，暴露于高剂量异维甲酸的小鼠的肿瘤多样性减少了56%至80% (P < 0.005)。 The mid dose was associated with reductions of tumor multiplicity by 67 and 88% (P < 0.005) in BaP- and NNK-treated mice, respectively, and was tolerated until approximately 12 weeks, when both these and the high-dose mice began losing weight. The low-dose mice had nonsignificant reductions of 30% (P < 0.13) and 16% (P < 0.30) for BaP- and NNK-treated mice, respectively without any evidence of side effects. For BaP- and NNK-treated mice, numbers of hyperplastic areas directly correlated to dose level and inversely to tumor number, suggesting arrested progression. Inhaled mid-dose isotretinoin caused up-regulation of lung tissue nuclear retinoic acid receptors (RARs) relative to vehicle-exposed mice, RARalpha (3.9-fold vehicle), RARbeta (3.3-fold), and RARgamma (3.7-fold), suggesting that these receptors may be useful biomarkers of retinoid activity in this system. The encouraging results from this pilot study suggest that inhaled isotretinoin merits evaluation in people at high risk for lung cancer.