Cigarette smoke-induced preneoplastic lung lesions in guinea pigs fed a diet high in ascorbic acid

Proc Amer Assoc Cancer Res, Volume 45, 2004 782 Lung cancer is the third most common cancer in the U.S., and is the leading cause of cancer death. There are, so far, no effective screening procedures and the cancer has a very high metastatic potential. While cigarette smoking is the most significant cause of lung cancer, more than 50% of new lung cancer cases develop in those smokers who have quit. There is, therefore, an urgent need for new methods of treatment as well as for effective chemopreventive agents for this disease. One serious obstacle to the development of chemopreventive agents for cigarette smoke-induced lung cancer is the lack of realistic animal laboratory models. We have been using the guinea pig in studies to assess the effects of natural antioxidants, such as ascorbic acid, on pulmonary damage due to reactive oxygen and nitrogen species derived from inhaled cigarette smoke. The guinea pig provides a more suitable experimental model for this purpose than other species, such as the mouse, rat, hamster or ferret, which have been used in the past for smoking studies, because the guinea pig, like the human, requires an exogenous source of ascorbic acid. This is not true of the other species, which biosynthesize ascorbic acid according to need. In a 28 day study involving cigarette smoke inhalation by male Hartley guinea pigs twice a day, seven days a week, we found that this treatment induced putative preneoplastic lesions in the lungs. These included hyperplasias, dysplasias and squamous cell metaplasias in the epithelia of bronchi and bronchiolae, and were in every way similar to those found in the lungs of human smokers. No lesions were found in guinea pigs that served as “sham-smoked” controls (i.e., placed in clean inhalation devices without cigarettes, but otherwise treated exactly as the experimental guinea pigs). Because the lesions appeared in the relatively short time of 28 days of cigarette smoke inhalation, it is reasonable to expect that a longer exposure time will lead to the development of frank lung tumors as in the human. To date, this has not been satisfactorily achieved with any animal model. While the appearance of these lesions in the short time span of 28 days was surprising, even more surprising was the fact that most of them occurred in the lungs of guinea pigs consuming a diet high (4000 ppm) rather than low (50 ppm) in ascorbic acid. While some contribution of vitamin E, which was also a variable in this study, cannot be excluded, it would appear that consumption of a diet high in the antioxidant ascorbic acid may facilitate rather than protect from cigarette smoke-induced lung lesions in the guinea pig model. This study was supported by NCI Grant 5 P01 CA 70972.