Ornithine decarboxylase as a target for chemoprevention.
l-Ornithine decarboxylase (ODC) is essential for polyamine synthesis and growth in mammalian cells; it provides putrescine that is usually converted into the higher polyamines, spermidine and spermine. Many highly specific and potent inhibitors of ODC are based on the lead compound 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 normally very highly regulated at both transcriptional and post-transcriptional levels according to the growth state of the cell and the intracellular polyamine content. Experimental over-production of ODC can be caused by either transfection with plasmids containing the ODC cDNA with part of the 5'-untranslated region (5'UTR) deleted under the control of a very strong viral promoter, or transfection of plasmids that cause 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 preneoplastic 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 chemopreventive agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Pegg
A E
AE
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey 17033, USA.
Shantz
L M
LM
Coleman
C S
CS
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009955:Ornithine Decarboxylase / Q000737:chemistry / Q000502:physiology; D065108:Ornithine Decarboxylase Inhibitors; D013329:Structure-Activity Relationship
D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D009955:Ornithine Decarboxylase