One of our recent publications evaluates the effects of serum proteins on the biological potency of retinoic acids. These vitamin A analogues have more reported activity than any other class of agent used for the chemoprevention of tobacco-related malignancies. The relationship between the administered dose and the resulting effect of particular doses of various retinoids has been poorly described by existing pharmacologic models. It has been long known that 13 cis-retinoic acid binds avidly to albumin. Albumin is the major serum protein. Albumin-retinoid interactions greatly decrease the effectiveness of 13 cis-retinoic acid in reducing the growth rate of lung cancer cells. This decrease in retinoid bioavailability is most likely a function of the common chemical structure shared by the major retinoids used to date for chemoprevention. We propose a pharmacologic maneuver which is successful in vitro in overcoming the retinoid neutralizing effect of serum albumin. The most important clinical lead from this work though is a fundamental reconsideration of the way in which retinoids are administered. Early lung cancer which is the target of chemoprevention exists only in the tracheobronchial tree. This is the target tissue of cigarette smoke which is responsible for causing most of the cancers in this area. If the airway is effective as a conduit for the carcinogen, it may also be the most effective way of directing retinoids to the affected early lung cancer cells. The beneficial effect of retinoids on cancer cell growth is a direct drug/cancer cell interaction. Aerosolizing retinoids into the airway instead of giving them orally can result in better bioavailability of the chemoprevention agent while potentially causing less frequent side effects. We have collaborated with a group that has prepared several formulations of retinoids that would be appropriate for aerosol delivery to the respiratory system. We are now in the process of evaluating the potency and toxicity of these formulations prior to initiating clinical trials.
