Abstract
746
Topical delivery of non-steroidal anti-inflammatory drugs through the oral mucosa has been used for oral cancer chemoprevention. Local permeability of these agents is one of the major concerns. Here we propose an approach to predict the permeability of topically applied agents for oral cancer chemoprevention. There are two routes of drug transport into the oral mucosa, paracellular and transcellular, with the paracellular route being the major one. Absorption of the topically applied agents into the oral mucosa is a process of passive diffusion. In theory, the total flux through the oral mucosa (Jmax) can be estimated by adding the transcellular flux (JTC) and the paracellular flux (JPC). To target the Cox-2 enzyme in oral epithelial cells, it is desirable to maximize the theoretical activity index, the ratio of JTC to IC50 of a Cox-2 inhibitor (JTC/IC50-Cox-2). Since we are unable to calculate JTC of a drug in oral mucosa, skin Jmax was calculated with aqueous solubility and logP, which are predicted by the ACD Suite (Version 8.0, Advanced Chemical Development Inc., Toronto, Canada). Theoretical activity indices were then calculated based on the IC50 values in the literature. Among the 12 commonly used drugs, celecoxib, nimesulide and ibuprofen had the highest theoretical activity indices, and may be the agents of choice to target Cox-2 in oral epithelial cells through topical application. Based on these calculations, a long-term chemopreventive experiment using celecoxib (3% or 6%) through topical application was performed in a DMBA-induced hamster oral cancer model. Both 3% and 6% reduced the incidence of squamous cell carcinoma at the post-initiation stage. Such a cancer preventive effect was correlated with inhibition of prostaglandin E2biosynthesis. (Supported by NIH grant CA101235)
[Proc Amer Assoc Cancer Res, Volume 46, 2005]