ISSN:
0730-2312
Keywords:
α-Difluoromethylornithine
;
enzyme-activated irreversible inhibitors
;
oncogens
;
polyamines
;
putrescine
;
tumor promoters
;
Life and Medical Sciences
;
Cell & Developmental Biology
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
Notes:
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 α-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 transaltion of mRNAs with extensive secondary structures in the 5′UTR. In both cases, unregulated overexpresion 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 preneoplasic conditions and tumor samples show high levels of ODC, these results suggest that ODC may act as an oncogene in an appropiate background. This provides a rationale for the possible use of a ODC inhibitors as chemopreventive agents. Further support comes from studies showing that reducing ODC activity with DFMO abolishes the transformed phenotype of the NIH 3T3 cells overexpressing ODC; many studies found that treatment with DFMO reduces tumor incidence in experimental animal exposed to carcinogens. Although these results provide strong support for initial testing of DFMO as a chemopreventive agents, other means of reducing ODC activity should not be overlooked, including the use of other enzyme-acivated irreversible inhibitors with higher potency and/or better pharmacokinetics than DFMO, use of dominant negative mutations or ribzymes to reduce actic ODC levels, and use of regulator of ODC expression.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/jcb.240590817
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