Polyamines are essential for the growth and function of normal cells. They interact with various macromolecules, both electrostatically and covalently and, as a consequence, have a variety of cellular effects. The complexity of polyamine metabolism and the multitude of compensatory mechanisms that are invoked to maintain polyamine homoeostasis argue that these amines are critical to cell survival. The regulation of polyamine content within cells occurs at several levels, including transcription and translation. In addition, novel features such as the +1 frameshift required for antizyme production and the rapid turnover of several of the enzymes involved in the pathway make the regulation of polyamine metabolism a fascinating subject. The link between polyamine content and human disease is unequivocal, and significant success has been obtained in the treatment of a number of parasitic infections. Targeting the polyamine pathway as a means of treating cancer has met with limited success, although the development of drugs such as DFMO (α-difluoromethylornithine), a rationally designed anticancer agent, has revolutionized our understanding of polyamine function in cell growth and provided ‘proof of concept’ that influencing polyamine metabolism and content within tumour cells will prevent tumour growth. The more recent development of the polyamine analogues has been pivotal in advancing our understanding of the necessity to deplete all three polyamines to induce apoptosis in tumour cells. The current thinking is that the polyamine inhibitors/analogues may also be useful agents in the chemoprevention of cancer and, in this area, we may yet see a revival of DFMO. The future will be in adopting a functional genomics approach to identifying polyamine-regulated genes linked to either carcinogenesis or apoptosis.
Abbreviations used: AZ, antizyme; AZI, AZ inhibitor; cdk, cyclin-dependent kinase; CHENSpm, N1-ethyl-N4-[(cycloheptyl)methyl]-4,8-diazaundecane; dcSAM, decarboxylated S-adenosylmethionine; DFMO, α-difluoromethylornithine; MDL 72527, N1,N4-bis(buta-2,3-dienyl)butane-1,4-diamine; MGBG, methyglyoxal bis(guanylhydrazone); Nrf-2, nuclear factor-E2-related factor 2; ODC, ornithine decarboxylase; PAO, polyamine oxidase; PRE, polyamine response element; SAMDC, S-adenosylmethionine decarboxylase; SMO, spermine oxidase; SSAT, spermidine/spermine N1-acetyltransferase; UTR, untranslated region.