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Inhaled Isotretinoin (13-cis Retinoic Acid) Is an Effective Lung Cancer Chemopreventive Agent in A/J Mice at Low doses: A Pilot Study

Battelle Memorial Institute, Columbus, Ohio 43201 [A. R. D., I. M. G., D. P. H., L. J. S., M. E. P., A. R. I.]; The Ohio State University, Columbus, Ohio 43210 [G. D. S.]; National Cancer Institute, NIH, Bethesda, Maryland 20892 [L. M. D. L., D. W., J. L. M.]

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 µg/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 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, RAR (3.9-fold vehicle), RARß (3.3-fold), and RAR (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.

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