Inhaled isotretinoin (13-cis retinoic acid) is an effective lung cancer chemopreventive agent in A/J mice at low doses: A pilot study

In previously treated head-and-neck cancer patients, p.o. administered isot retinoin (13-cis retinoic acid) reduced the occurrence of second aerodigest ive tumors, including lung tumors, but side effects made chronic therapy pr oblematic. We reasoned that inhaled isotretinoin might provide sufficient d rug 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 s ingle i.p. doses of urethane, a common experimental lung carcinogen, or ben zo[a]pyrene (BaP) or 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK), p utative major carcinogens in tobacco smoke. The following day, exposures to isotretinoin aerosols for 45 min daily at 1.3, 20.7, or 481 mu g/l were in itiated. After 2 weeks, the high dose caused severe toxicity on the snout s kin, necessitating a reduction of dose frequency to twice a week. As a prec aution, the mid dose was reduced to three exposures per week. The weekly to tal 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 repo rted 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 showe d 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 similar to 12 weeks, when both these and the high-dose mice began los ing weight. The low-dose mice had nonsignificant reductions of 30% (P < 0.1 3) and 16% (P < 0.30) for BaP- and NNK-treated mice, respectively without a ny evidence of side effects. For BaP- and NNK-treated mice, numbers of hype rplastic areas directly correlated to dose level and inversely to tumor num ber, suggesting arrested progression. Inhaled mid-dose isotretinoin caused up-regulation of lung tissue nuclear retinoic acid receptors (RARs) relativ e to vehicle-exposed mice, RAR alpha (3.9-fold vehicle), RAR beta (3.3-fold ), and RAR gamma (3.7-fold), suggesting that these receptors may be useful biomarkers of retinoid activity in this system. The encouraging results fro m this pilot study suggest that inhaled isotretinoin merits evaluation in p eople at high risk for lung cancer.