The polyamine-biosynthetic pathway represents an inviting target for the development of agents inhibiting carcinogenesis and tumor growth. Polyamines play an essential role in the proliferation and development of mammalian cells. Deranged polyamine metabolism may be an important factor in carcinogenesis. Depletion of polyamines inhibits growth of neoplastic cells in vitro and in animal models. Several different classes of other anticancer agents may under some conditions exert enhanced effects when polyamine levels are depleted. Some suitable inhibitors of polyamine production are currently available and other promising compounds are presently being tested. It should soon prove possible to block polyamine biosynthesis at every step in the pathway. The use of these inhibitors alone and combined either with each other or with other antitumor agents will enable a full examination of the potential of this approach.

https://cancerres.aacrjournals.org/content/canres/48/4/759.full.pdf

Polyamine Metabolism and Its Importance in Neoplastic Growth and as a Target for Chemotherapy

Polyamines are ubiquitous organic cations of low molecular weight. The content of these amines is closely regulated by the cell according to the state of growth. The reactions responsible for the biosynthesis and interconversion of the polyamines and their precursor putrescine are described and the means by which polyamine content can be varied in response to exogenous stimuli are discussed. The role of polyamines in the cell cycle, cell division, tissue growth, and differentiation is considered. Recent studies using highly specific inhibitors of polyamine biosynthesis such as alpha-difluoromethylornithine to prevent accumulation of polyamines have indicated that the synthesis of polyamines is intimately associated with these processes. Such inhibitors have great potential for investigation of the cellular role of polyamines.

https://www.physiology.org/doi/pdf/10.1152/ajpcell.1982.243.5.C212

Polyamine metabolism and function.

/pdf/recent-advances-in-the-biochemistry-of-polyamines-in-382j7cp9ea.pdf

Recent advances in the biochemistry of polyamines in eukaryotes.

Tetrahedron report number 221

https://www.cell.com/cell/pdf/0092-8674(89)90026-3.pdf

Neural and developmental actions of lithium: A unifying hypothesis

Effect of androgens on turnover of ornithine decarboxylase in mouse kidney. Studies using labeling of the enzyme by reaction with [14C] alpha-difluoromethylornithine.

Ornithine decarboxylase has been purified to homogeneity from kidneys of androgen-treated mice. Such kidneys have an enzyme content 2 orders of magnitude greater than that of other mammalian tissues such as induced rat liver, and only a 10350-fold purification was needed for purification. The enzyme preparation gave a single band on isoelectric focusing and on polyacrylamide gel electrophoresis under native and denaturing conditions. These bands corresponded to the enzyme activity and to the migration of ornithine decarboxylase labeled by reaction with alpha-(difluoromethyl) [5-14C]ornithine, a specific inhibitor. The enzyme has a Mr of about 100 000 and is a dimer of subunit Mr 53 000. The Km for L-ornithine was 75 micron and for pyridoxal phosphate, 0.3 micron. The preparation had a specific activity of 50 mumol of CO2 produced min-1 mg-1 and bound a stoichiometric amount of the irreversible inhibitor, alpha-(difluoromethyl)ornithine (one molecule per subunit). The purified enzyme was unstable even in the presence of 2.5 mM dithiothreitol and 40 micron pyridoxal phosphate unless 0.02% Brij 35 was added. In the presence of this detergent, the enzyme could be stored with little loss of activity.

Hannu Pösö

Papers

Effect of androgens on turnover of ornithine decarboxylase in mouse kidney. Studies using labeling of the enzyme by reaction with [14C] alpha-difluoromethylornithine.

Purification of ornithine decarboxylase from kidneys of androgen-treated mice.

Effect of α-difluoromethylornithine on polyamine and DNA synthesis in regenerating rat liver: Reversal of inhibition of DNA synthesis by putrescine

Binding of radioactive α-difluoromethylorithine to rat liver ornithine decarboxylase

S-adenosylmethionine decarboxylase (rat liver).