Prevention and reversal by a non-polar arotinoid (Ro 15-0778) of 3,4-benzpyrene- and cigarette smoke condensate-induced hyperplasia and metaplasia of rodent respiratory epithelia grown in vitro

Abstract

A non-polar arotinoid, Ro 15-0778, has been investigated for its effect on carcinogen-induced changes in rodent respiratory epithelia in organ culture. In neonatal rat tracheas and fetal mouse lungs grown in vitro, 3,4-benzpyrene and cigarette smoke condensate induce an increased proliferation of epithelial cells associated with a loss of secretory activity and of ciliary function. These changes persist in the absence of carcinogens in explants transferred to control medium. Ro 15-0778 alone has no influence on the normal epithelial growth rate or normal differentiation. However, if combined with either benzpyrene or smoke condensate, the arotinoid antagonizes the carcinogen-induced hyperplasia and metaplasia. During simultaneous treatment, it prevents the increase in mitosis and the loss of secretory activity or ciliary function. In explants pretreated with benzpyrene or cigarette smoke condensate, Ro 15-0778 reverses the high proliferation rate and restores secretory differentiation and ciliary function. The compound is of experimental and clinical interest, since--in contrast to most retinoids--it lacks the signs and symptoms of the classical hypervitaminosis A syndrome. It may be justified to consider it for the treatment of early precancerous changes of the bronchial tree.