Ornithine decarboxylase as a target for chemoprevention

Anthony Pegg, Lisa Shantz, Catherine Coleman

Research output: Contribution to journalArticle

160 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)132-138
Number of pages7
JournalJournal of Cellular Biochemistry
Volume59
Issue number22 S
DOIs
StatePublished - Jan 1 1995

Fingerprint

Eflornithine
Ornithine Decarboxylase
Chemoprevention
Polyamines
NIH 3T3 Cells
Carcinogens
Transfection
Tumors
Plasmids
Lead compounds
Pharmacokinetics
Carboxy-Lyases
Putrescine
Spermidine
Spermine
Growth
Oncogenes
Neoplasms
Animals
Complementary DNA

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

@article{f4b865e791294a25abb69d6b6cbb6377,
title = "Ornithine decarboxylase as a target for chemoprevention",
abstract = "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.",
author = "Anthony Pegg and Lisa Shantz and Catherine Coleman",
year = "1995",
month = "1",
day = "1",
doi = "10.1002/jcb.240590817",
language = "English (US)",
volume = "59",
pages = "132--138",
journal = "Journal of Cellular Biochemistry",
issn = "0730-2312",
publisher = "Wiley-Liss Inc.",
number = "22 S",

}

Ornithine decarboxylase as a target for chemoprevention. / Pegg, Anthony; Shantz, Lisa; Coleman, Catherine.

In: Journal of Cellular Biochemistry, Vol. 59, No. 22 S, 01.01.1995, p. 132-138.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ornithine decarboxylase as a target for chemoprevention

AU - Pegg, Anthony

AU - Shantz, Lisa

AU - Coleman, Catherine

PY - 1995/1/1

Y1 - 1995/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84986505824&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84986505824&partnerID=8YFLogxK

U2 - 10.1002/jcb.240590817

DO - 10.1002/jcb.240590817

M3 - Article

C2 - 8538190

AN - SCOPUS:0029455991

VL - 59

SP - 132

EP - 138

JO - Journal of Cellular Biochemistry

JF - Journal of Cellular Biochemistry

SN - 0730-2312

IS - 22 S

ER -