Dahl A R, Grossi I M, Houchens D P, Scovell L J, Placke M E, Imondi A R, Stoner G D, De Luca L M, Wang D, Mulshine J L
Battelle Memorial Institute, Columbus, Ohio 43201, USA.
Clin Cancer Res. 2000 Aug;6(8):3015-24.
In previously treated head-and-neck cancer patients, p.o. administered isotretinoin (13-cis retinoic acid) reduced the occurrence of second aerodigestive tumors, including lung tumors, but side effects made chronic therapy problematic. We reasoned that inhaled isotretinoin might provide sufficient drug to the target cells for efficacy while avoiding systemic toxicity, and we proceeded with the pilot study reported here. Male A/J mice were given single i.p. doses of urethane, a common experimental lung carcinogen, or benzo[a]pyrene (BaP) or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), putative major carcinogens in tobacco smoke. The following day, exposures to isotretinoin aerosols for 45 min daily at 1.3, 20.7, or 481 microg/l were initiated. After 2 weeks, the high dose caused severe toxicity on the snout skin, necessitating a reduction of dose frequency to twice a week. As a precaution, the mid dose was reduced to three exposures per week. The weekly total deposited doses after the dose frequency reductions were calculated to be 0.24, 1.6, and 24.9 mg/kg for the low, mid, and high doses, of which 16% was estimated to be deposited in the lungs. The weekly deposited pulmonary drug doses were calculated to be 0.01, 0.07, and 1.1% of a previously reported ineffective oral dose in urethane-treated A/J mice. After 10-16 weeks, mice were sacrificed to count areas of pulmonary hyperplasia and adenomas. For all carcinogens, the mice exposed to the high isotretinoin dose showed reductions of tumor multiplicity ranging from 56 to 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.
在先前接受过治疗的头颈癌患者中，口服异维甲酸（13 - 顺式维甲酸）可降低包括肺癌在内的第二原发气消化道肿瘤的发生率，但副作用使长期治疗存在问题。我们推测吸入异维甲酸可能为靶细胞提供足够药物以发挥疗效，同时避免全身毒性，于是开展了此处报道的初步研究。给雄性A/J小鼠腹腔注射单剂量的氨基甲酸乙酯（一种常见的实验性肺癌致癌物）、苯并[a]芘（BaP）或4 -（甲基亚硝胺基）-1 -（3 - 吡啶基）-1 - 丁酮（NNK，烟草烟雾中的主要致癌物）。次日，开始每天暴露于浓度为1.3、20.7或481微克/升的异维甲酸气雾剂中45分钟。2周后，高剂量组导致鼻端皮肤出现严重毒性，因此将给药频率减至每周两次。作为预防措施，中剂量组减至每周给药三次。给药频率降低后，低、中、高剂量组每周的总沉积剂量经计算分别为0.24、1.6和24.9毫克/千克，其中估计16%沉积在肺部。经计算，每周肺部沉积的药物剂量分别为先前报道的在氨基甲酸乙酯处理的A/J小鼠中无效口服剂量的0.01%、0.07%和1.1%。10 - 16周后，处死小鼠以计数肺部增生和腺瘤区域。对于所有致癌物，暴露于高剂量异维甲酸的小鼠肿瘤发生率降低了56%至80%（P < 0.005）。中剂量组在BaP和NNK处理的小鼠中分别使肿瘤发生率降低了67%和88%（P < 0.005），并且在约12周前耐受性良好，之后这些小鼠和高剂量组小鼠均开始体重减轻。低剂量组在BaP和NNK处理的小鼠中分别使肿瘤发生率非显著降低了30%（P < 0.13）和16%（P < 0.30），且未出现任何副作用迹象。对于BaP和NNK处理的小鼠，增生区域数量与剂量水平直接相关，与肿瘤数量呈负相关，表明进展受阻。与暴露于赋形剂的小鼠相比，吸入中剂量异维甲酸使肺组织核维甲酸受体（RARs）上调，RARα（是赋形剂组的3.9倍）、RARβ（3.3倍）和RARγ（3.7倍），这表明这些受体可能是该系统中类视黄醇活性的有用生物标志物。这项初步研究的令人鼓舞的结果表明，吸入异维甲酸值得在肺癌高危人群中进行评估。
