Polyamines are organic cations derived from amino acids and are found in all organisms. They are formed by the enzymatic decarboxylation of ornithine or arginine. Ornithine decarboxylase (ODC) is the first enzyme in the polyamine synthesis pathway in mammals and is the target for difluoromethylornithine (DFMO), a substrate analogue and specific inhibitor that irreversibly inactivates ODC when it binds to the active site of the enzyme. ODC and several other polyamine metabolic proteins are essential for normal cell and tissue functions, including growth, development, and tissue repair. ODC and polyamine content are increased in many cancers arising from epithelial tissues, such as the skin and colon. Polyamines exert their effects in eukaryotic cells in part by regulating specific gene expression. In murine and human colonic mucosal tissue, ODC is negatively regulated by the adenomatous polyposis coli (APC) tumor-suppressor gene. APC is mutated or deleted in the germline of people with familial adenomatous polyposis (FAP), a genetic syndrome associated with a high risk of colon cancer. APC is also mutated or deleted in somatic colon epithelial cells in most sporadic, or non-genetic, forms of colon cancer. Loss of APC function causes an increase in ODC activity and polyamine biosynthesis, and tumor formation in ApcMin/+ mice, a murine model of human FAP. Treatment of ApcMin/+ mice with DFMO suppresses intestinal tumor formation. Several non-steroidal anti-inflammatory drugs (NSAIDs), the use of which is associated with decreased risk of epithelial cancers, activate the transcription of spermidine/spermine N1-acetyltransferase, the first enzyme in the polyamine catabolic pathway. Experimental studies indicate that combinations of DFMO and NSAIDs are potent inhibitors of colon and intestinal cancer development in murine models. Clinical studies have shown that DFMO is well tolerated and can prevent the development of precancerous lesions in the skin. Several large randomized trials involving the skin, colon, and other organ sites are underway. DFMO is a specific ODC inhibitor that has proven to be effective in the treatment of certain hyperproliferative and infectious diseases, including removal of excess facial hair in women and in the treatment of African sleeping sickness. The development of these selective inhibitors of polyamine metabolism enabled the closer examination of effects of polyamine depletion in cell culture. The inhibitors were also evaluated in combination with cytotoxic anticancer agents and were found to have modest interactive effects in animal models. DFMO was chosen over other ODC inhibitors in these early clinical trials for several reasons, including activity in animal models and pharmacokinetic properties in humans that allowed favourable physiologically significant concentrations of the drug in serum. DFMO is a potent inhibitor of carcinogenesis. Chemical and physicalPolyamines are organic cations derived from amino acids and are found in all organisms. They are formed by the enzymatic decarboxylation of ornithine or arginine. Ornithine decarboxylase (ODC) is the first enzyme in the polyamine synthesis pathway in mammals and is the target for difluoromethylornithine (DFMO), a substrate analogue and specific inhibitor that irreversibly inactivates ODC when it binds to the active site of the enzyme. ODC and several other polyamine metabolic proteins are essential for normal cell and tissue functions, including growth, development, and tissue repair. ODC and polyamine content are increased in many cancers arising from epithelial tissues, such as the skin and colon. Polyamines exert their effects in eukaryotic cells in part by regulating specific gene expression. In murine and human colonic mucosal tissue, ODC is negatively regulated by the adenomatous polyposis coli (APC) tumor-suppressor gene. APC is mutated or deleted in the germline of people with familial adenomatous polyposis (FAP), a genetic syndrome associated with a high risk of colon cancer. APC is also mutated or deleted in somatic colon epithelial cells in most sporadic, or non-genetic, forms of colon cancer. Loss of APC function causes an increase in ODC activity and polyamine biosynthesis, and tumor formation in ApcMin/+ mice, a murine model of human FAP. Treatment of ApcMin/+ mice with DFMO suppresses intestinal tumor formation. Several non-steroidal anti-inflammatory drugs (NSAIDs), the use of which is associated with decreased risk of epithelial cancers, activate the transcription of spermidine/spermine N1-acetyltransferase, the first enzyme in the polyamine catabolic pathway. Experimental studies indicate that combinations of DFMO and NSAIDs are potent inhibitors of colon and intestinal cancer development in murine models. Clinical studies have shown that DFMO is well tolerated and can prevent the development of precancerous lesions in the skin. Several large randomized trials involving the skin, colon, and other organ sites are underway. DFMO is a specific ODC inhibitor that has proven to be effective in the treatment of certain hyperproliferative and infectious diseases, including removal of excess facial hair in women and in the treatment of African sleeping sickness. The development of these selective inhibitors of polyamine metabolism enabled the closer examination of effects of polyamine depletion in cell culture. The inhibitors were also evaluated in combination with cytotoxic anticancer agents and were found to have modest interactive effects in animal models. DFMO was chosen over other ODC inhibitors in these early clinical trials for several reasons, including activity in animal models and pharmacokinetic properties in humans that allowed favourable physiologically significant concentrations of the drug in serum. DFMO is a potent inhibitor of carcinogenesis. Chemical and physical