Polyamine Pools and Cancer Prevention

Abstract

Polyamine contents increase during epithelial carcinogenesis in both rodents and humans. The activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis in mammals, is increased in epithelial cancers, and ODC has become a target for cancer chemoprevention. Difluoromethylornithine (DFMO) is a specific inhibitor of ODC and is under evaluation in clinical trials for prevention of epithelial cancers, including those of the colon, prostate, and skin. Tissue, serum, and other bodily fluid endpoints have been used to monitor effects of DFMO in human clinical chemoprevention trials. Cell and tissue polyamine contents are regulated by mechanisms influencing synthesis, catabolism, uptake, and efflux. These regulatory mechanisms include both transcriptional and posttranscriptional processes. Tissue measurements of ODC enzyme activity have often failed to be reliable measures of either carcinogenesis or response to DFMO. Levels of target tissue polyamines are less subject to measurement variability than are measures of ODC enzyme activity, and are closely associated with administered DFMO dose in randomized clinical chemoprevention trials in humans. Target tissue polyamine contents are validated biomarkers for the biochemical efficacy of DFMO in clinical cancer chemoprevention trials. There is a need for new predictive biomarkers of agents that affect polyamine metabolism that could be measured in sources other than target tissues.