Polyamines and cancer: old molecules, new understanding

Abstract

Polyamines are naturally occurring organic cations found in plants, animals and microbes. They are formed by the enzymatic decarboxylation of the amino acids 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) tumour-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 tumour formation in Apc^Min/+ mice, a murine model of human FAP. Treatment of Apc^Min/+ mice with DFMO suppresses intestinal tumour 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.