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Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases

Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases The polyamines are present in virtually all cells, prokaryotic or eukaryotic. Their biosynthesis and metabolism are highly regulated and unique active cellular transporters exist. They are known to be crucial to cellular viability and function, and cells that have been modulated genetically or pharmacologically, in a non-lethal fashion, require exogenous polyamines for viability and/or growth. Polyamine metabolism and requirements are frequently dysregulated in cancer and other hyperproliferative diseases, thus making this pathway an attractive target for therapeutic intervention. It has been demonstrated that the first biosynthetic enzyme in the pathway, ornithine decarboxylase (ODC), is a transcriptional target for the oncogene MYC, and that inhibition of ODC abrogates the effects of MYC upregulation. It is well known that polyamines interact strongly with nucleic acids and chromatin, and emerging data indicate that the polyamines are involved in methylation and acetylation of histones. Specific inhibition of both the biosynthetic and catabolic enzymatic pathways have been studied with regard to possible therapeutic intervention. Inhibition of ODC has already provided an approved drug for a parasitic disease, although its original intended use for cancer therapy has not yet been realized. The creation of polyamine analogues that might modulate biosynthesis, metabolism, transport and polyamine function has resulted in the advancement of several compounds into clinical study. As these analogues can affect multiple polyamine targets, single mutations, other than those possibly related to transport are not likely to abrogate function. Polyamine analogues are not substrates for p-glycoprotein-related resistance. From a pharmacological point of view, most polyamine analogues are readily synthesized, highly water soluble, and remarkably stable. Several polyamine analogues are currently in Phase I or II clinical trials for cancer. Phase I trials for age-related macular degeneration are also ongoing. The polyamine metabolic pathway remains an intriguing target for chemoprevention. The results of ongoing trials with inhibitors of polyamine biosynthesis may also reveal additional potential for the many new polyamine analogues now available. With our knowledge of the polyamines expanding rapidly, the reality that intervening in this pathway affects intracellular modifications downstream of many of the validated anticancer targets, and potentially at points that are convergent for many of these targets, and intriguing data emerging from clinical trials, this therapeutic area is worthy of attention. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Drug Discovery Springer Journals

Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases

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References (356)

Publisher
Springer Journals
Copyright
Copyright © 2007 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Pharmacology/Toxicology; Biotechnology; Medicinal Chemistry; Molecular Medicine; Cancer Research
ISSN
1474-1776
eISSN
1474-1784
DOI
10.1038/nrd2243
Publisher site
See Article on Publisher Site

Abstract

The polyamines are present in virtually all cells, prokaryotic or eukaryotic. Their biosynthesis and metabolism are highly regulated and unique active cellular transporters exist. They are known to be crucial to cellular viability and function, and cells that have been modulated genetically or pharmacologically, in a non-lethal fashion, require exogenous polyamines for viability and/or growth. Polyamine metabolism and requirements are frequently dysregulated in cancer and other hyperproliferative diseases, thus making this pathway an attractive target for therapeutic intervention. It has been demonstrated that the first biosynthetic enzyme in the pathway, ornithine decarboxylase (ODC), is a transcriptional target for the oncogene MYC, and that inhibition of ODC abrogates the effects of MYC upregulation. It is well known that polyamines interact strongly with nucleic acids and chromatin, and emerging data indicate that the polyamines are involved in methylation and acetylation of histones. Specific inhibition of both the biosynthetic and catabolic enzymatic pathways have been studied with regard to possible therapeutic intervention. Inhibition of ODC has already provided an approved drug for a parasitic disease, although its original intended use for cancer therapy has not yet been realized. The creation of polyamine analogues that might modulate biosynthesis, metabolism, transport and polyamine function has resulted in the advancement of several compounds into clinical study. As these analogues can affect multiple polyamine targets, single mutations, other than those possibly related to transport are not likely to abrogate function. Polyamine analogues are not substrates for p-glycoprotein-related resistance. From a pharmacological point of view, most polyamine analogues are readily synthesized, highly water soluble, and remarkably stable. Several polyamine analogues are currently in Phase I or II clinical trials for cancer. Phase I trials for age-related macular degeneration are also ongoing. The polyamine metabolic pathway remains an intriguing target for chemoprevention. The results of ongoing trials with inhibitors of polyamine biosynthesis may also reveal additional potential for the many new polyamine analogues now available. With our knowledge of the polyamines expanding rapidly, the reality that intervening in this pathway affects intracellular modifications downstream of many of the validated anticancer targets, and potentially at points that are convergent for many of these targets, and intriguing data emerging from clinical trials, this therapeutic area is worthy of attention.

Journal

Nature Reviews Drug Discovery – Springer Journals

Published: May 1, 2007

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