PRECLINICAL EFFICACY EVALUATION OF POTENTIAL CHEMOPREVENTIVE AGENTS IN ANIMAL CARCINOGENESIS MODELS - METHODS AND RESULTS FROM THE NCI CHEMOPREVENTION DRUG DEVELOPMENT PROGRAM

In the NCI, Chemoprevention Branch drug development program, potential chemopreventive agents are evaluated for efficacy against chemical ca rcinogen-induced tumors in animal models. This paper summarizes the re sults of 144 agents in 352 tests using various animal efficacy models. Of these results, 146 were positive, representing 85 different agents . The target organs selected for the animals model are representative of high-incidence human cancers. The assays include inhibition of tumo rs induced by MNU in hamster trachea, DEN in hamster lung, AOM in rat colon (including inhibition of AOM-induced aberrant crypts), MAM in mo use colon, DMBA and MNU in rat mammary glands, DMBA promoted by TPA in mouse skin, and OH-BBN in mouse bladder. The agents tested may be cla ssified into various pharmacological and chemical structural categorie s that are relevant to their chemopreventive potential. These categori es include antiestrogens, antiinflammatories (e.g., NSAIDs), antioxida nts, arachidonic acid metabolism inhibitors, GST and GSH enhancers, OD C inhibitors, protein kinase C inhibitors, retinoids and carotenoids, organosulfur compounds, calcium compounds, vitamin D-3 and analogs, an d phenolic compounds (e.g., flavonoids). The various categories of com pounds have different spectra of efficacy in animal models. In hamster lung, GSH-enhancing agents and antioxidants appear to have high poten tial for inhibiting carcinogenesis. In the colon, NSAIDs and other ant iinflammatory agents appear particularly promising. Likewise, NSAIDs a re very active in mouse bladder. In rat mammary glands, retinoids and antiestrogens (as would be expected) are efficacious. Several of the c hemicals evaluated also appear to be promising chemopreventive agents based on their activity in several of the animal models. Particularly, the ODC inhibitor DFMO was active in the colon, mammary glands, and b ladder models, while the dithiolthione, oltipraz, was efficacious in a ll the models listed above (i.e., lung, colon, mammary glands, skin, a nd bladder). (C) 1994 Wiley-Liss, Inc.