LUNG CANCER CHEMOPREVENTION IN RODENT MODELS OF CHEMICAL CARCINOGENESIS

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Chemically-induced lung tumors have been widely used to identify drugs and botanically-derived agents that may be effective for chemoprevention. Chemoprevention can be defined as the use of chemo- or dietary agents to prevent tumor formation or progression. As mentioned above, chemically-induced lung tumors in the mouse share many characteristics with human lung cancer, both genetic and histological. These properties also make them a suitable model to use for chemoprevention. Administration of a test compound can begin anywhere from pre-initiation to late in the tumorigenesis process . Because the stages of lung tumor progression are well characterized in chemically induced mouse lung tumors, the efficacy of chemo- or dietary agents can be determined at each step in the tumorigenic process, an important consideration for translating findings into humans..

Because of its susceptible nature, the most common pre-clinical chemoprevention model for the lung is the A/J strain mouse. The cigarette smoke carcinogens B(a)P and NNK have been the most widely used and are typically administered by i.p. injection, although other carcinogens such as urethane and vinyl carbamate and other routes of administration such as oral gavage have been used. The types of chemoprevention schedules used can be divided into three general categories: 1) complete, where the agent is administered beginning before carcinogen administration and continues throughout the experiment; 2) initiation, where the agent is administered from just before carcinogen administration and is terminated within a few weeks of initiation, and 3) progression, where treatment is begun after carcinogen administration and continued until experiment termination. Obviously, there are many variations of experimental design that will depend on the goals of the investigators.

To date, over 200 pre-clinical studies of lung cancer chemoprevention have been published and it is beyond the scope of this brief review to begin to discuss them all. An ideal chemoprevention agent will combine efficacy with a very favorable safety profile. Because chemoprevention agents would be administered to patients essentially free of overt disease, the presence of even relatively mild effects could limit the usefulness of a compound due to low levels of patient compliance as well as concerns over patient welfare. This is a major reason why many chemoprevention studies have focused on using botanically derived agents, sometimes referred to as neutraceuticals. These include both complex mixtures isolated from a given plant type (e.g. tea polyphenol fractions or freeze dried berries) and purified compounds that are thought to be the main active ingredients present in these preparations. The compound (-)-epigallocatechin gallate (EGCG) is generally considered to be the most potent polyphenolic compound in green tea extracts. However, chemoprevention with purified EGCG has not yielded as large of an effect as the complex mixture (60). The use of complex mixtures may provide higher degrees of efficacy or alternatively improve stability and bioavailability.

The timing of administration of a chemopreventive agent is of great importance when testing a new compound. To be useful in humans, a chemoprevention agent must effectively block or slow the progression of pre-cancerous lesions to cancerous ones. In many early studies, the administration of a chemopreventive agent began prior to initiation with the carcinogen. This raises the possibility that the effect of the agent is on expression of metabolic enzymes, agent uptake or agent excretion rather then effects on tumor progression per se.  Endpoints such as incidence, multiplicity and tumor size are frequently measured. In addition, the pathology and histopathology of lesions is frequently investigated. The detection and localization of cells expressing a particular protein in lung tumors can provide clues as to molecular mechanisms of the agent and has the potential for identifying biomarkers.

Several notable limitations for testing chemoprevention agents in mouse models exist. As mentioned above, beginning treatment prior to initiation of carcinogenesis has the potential to cause changes in tumor formation that are based on alterations in carcinogen metabolism. Notable differences in key metabolic enzymes such as cytochrome p450s exist between mice and humans and could ultimately affect the disposition of the carcinogen. This is another reason to avoid starting chemoprevention prior to initiation of carcinogenesis. The metabolic differences between rodents and humans can of course also have effects on the metabolism and ultimate excretion of preventive agents. The route of administration of a chemoprevention agent can also have a major effect on the bioavailability of that agent. Ideally, pharmacokinetic /phamacodynamic studies should be performed in conjunction with initial characterization of a chemoprentive agent.