Recent advances in the understanding of mammalian polyamine catabolism the regulation and potential role of polyamine catabolism in drug response and disease processes

As more data emerge, the significance of polyamine catabolism in polyamine homeostasis, drug response, and disease etiology is expanding. Importantly, the regulation and function of the polyamine catabolic pathway has emerged as a rational target for drug intervention in both chemotherapeutic and chemopreventive strategies. Mammalian intracellular polyamine catabolism had long been thought to be a two-step process primarily regulated by a rate-limiting acetyltransferase, spermidine/spermine N1-acetyltransferase (SSAT), followed by the activity of a constitutively expressed acetylpolyamine oxidase (PAO). However, as recent reports have clearly demonstrated, mammalian polyamine catabolism also includes the activity of a previously unrecognized spermine oxidase (SMO/PAOh1). The production of reactive oxygen species (ROS) and other toxic products by these various polyamine catabolic enzymes can result in both useful and potentially dangerous consequences. This chapter will examine some of the most recent findings related to polyamine catabolism and will address the cloning and characterization of mammalian polyamine oxidases, including the newly discovered SMO/PAOh1. Additionally, further characterization of the highly regulated SSAT, as facilitated by many recent advances with transgenic models, will be discussed with respect to the potential role that it and the oxidases play in determining response to various drugs and stimuli. Although the polyamine catabolic pathway is well described and being studied in multiple organisms, this work will focus primarily on results directly related to mammalian systems, with special emphasis given to the relationship between polyamine catabolism and human disease. Specifically, data indicating that the induction of polyamine catabolism by specific antitumor polyamine analogs plays a direct role in determining drug response will be discussed. Also to be examined is the recent recognition that the oxidation of polyamines contributes to disease processes, and the potential targeting of polyamine catabolism as a strategy for chemoprevention.