ORNITHINE DECARBOXYLASE AS A TARGET FOR CHEMOPREVENTION

l-Ornithine decarboxylase (ODC) is essential for polyamine synthesis a nd growth in mammalian cells; it provides putrescine that is usually c onverted into the higher polyamines, spermidine and spermine. Many hig hly specific and potent inhibitors of ODC are based on the lead compou nd alpha-difluoromethylornithine (DFMO), which is an enzyme-activated irreversible inhibitor. DFMO is accepted as a substrate by ODC and is decarboxylated, leading to the formation of a highly reactive species that forms a covalent adduct with either cysteine-360 (90%) or lysine- 69 (10%). Both modifications inactivate the enzyme. ODC activity is no rmally very highly regulated at both transcriptional and post-transcri ptional levels according to the growth state of the cell and the intra cellular polyamine content. Experimental over-production of ODC can be caused by either transfection with plasmids containing the ODC cDNA w ith part of the 5'-untranslated region (5'UTR) deleted under the contr ol of a very strong viral promoter, or transfection of plasmids that c ause the overproduction of eIF-4E, reported to be a limiting factor in the translation of mRNAs with extensive secondary structures in the 5 'UTR. In both cases, unregulated overexpression of ODC transforms NIH 3T3 cells to a neoplastic state. Along with studies showing that many tumor promoters increase ODC activity and that a number of preneoplast ic conditions and tumor samples show high levels of ODC, these results suggest that ODC may act as an oncogene in an appropriate background. This provides a rationale for the possible use of ODC inhibitors as c hemopreventive agents. Further support comes from studies showing that reducing ODC activity with DFMO abolishes the transformed phenotype o f the NTH 3T3 cells overexpressing ODC; many studies found that treatm ent with DFMO reduces tumor incidence in experimental animals exposed to carcinogens. Although these results provide strong support for init ial testing of DFMO as a chemopreventive agent, other means of reducin g ODC activity should not be overlooked, including the use of other en zyme-activated irreversible inhibitors with higher potency and/or bett er pharmacokinetics than DFMO, use of dominant negative mutations or r ibzymes to reduce active ODC levels, and use of regulators of ODC expr ession. (C) 1995 Wiley-Liss, Inc.