The polyamine oxidase inactivator MDL 72527.
Polyamine oxidase is a FAD-dependent amine oxidase, which is constitutively expressed in nearly all tissues of the vertebrate organism. In 1985, N1,N4-bis(2,3-butadienyl)-1,4-butanediamine (MDL 72527) was designed as a selective enzyme-activated irreversible inhibitor of polyamine oxidase (EC 1.5.3.11). It inactivates, at micromolar concentration and time-dependently, the enzyme in cells, as well as in all organs of experimental animals, without inhibiting other enzymes of polyamine metabolism. MDL 72527 served during nearly two decades as a unique tool in the elucidation of the physiological roles of polyamine oxidase. The compound has anticancer and contragestational effects, and it improves the anticancer effect of the ornithine decarboxylase inactivator (D,L)-2-(difluoromethyl)ornithine (DFMO). Profound depletion of the polyamine pools of tumour cells and effects on different components of the immune defence system are responsible for the anticancer effects of MDL 72527/DFMO combinations. Recently a direct cytotoxic effect of MDL 72527 at concentrations above those required for polyamine oxidase inactivation was observed. The induction of apoptosis by MDL 72527 was ascribed to its lysosomotropic properties. Therapeutic potentials of the apoptotic effect of MDL 72527 need to be explored. Polyamine oxidase is the last enzyme of the polyamine interconversion pathway that awaits the detailed elucidation of its structure and regulation. MDL 72527 should be useful as a lead in the development of inactivators which are selective for the isoforms of polyamine oxidase. Isozyme-selective inhibitors will give more profound insights into and reveal a diversity of specific functions of polyamine oxidase.
Seiler
Nikolaus
N
Laboratory of Nutritional Oncology, INSERM U-392, Institut de Recherche Contre les Cancers de l'Appareil Digestif (IRCAD), 1, Place de l'Hĵpital B.P. 426 67091 Strasbourg, France.
Duranton
Benoit
B
Raul
Francis
F
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007107:Immune System / Q000187:drug effects / Q000201:enzymology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011700:Putrescine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000097667:Polyamine Oxidase
D004791:Enzyme Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011700:Putrescine; D000097667:Polyamine Oxidase; C044445:MDL 72527