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Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases

Key Points

  • 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.

Abstract

The polyamines spermidine and spermine and their diamine precursor putrescine are naturally occurring, polycationic alkylamines that are essential for eukaryotic cell growth. The requirement for and the metabolism of polyamines are frequently dysregulated in cancer and other hyperproliferative diseases, thus making polyamine function and metabolism attractive targets for therapeutic intervention. Recent advances in our understanding of polyamine function, metabolic regulation, and differences between normal cells and tumour cells with respect to polyamine biology, have reinforced the interest in this target-rich pathway for drug development.

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Figure 1: Targets in the polyamine metabolic pathway.
Figure 2: Structures of specific inhibitors of polyamine metabolism.
Figure 3: Potential targets of polyamine analogues.
Figure 4: Examples of symmetrically substituted poly-amine analogues.
Figure 5: Examples of non-symmetrically substituted polyamine analogues.
Figure 6: Conformationally restricted polyamine analogues currently in clinical trials.
Figure 7: Representative oligoamines.
Figure 8: Macrocyclic polyamine analogues.

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Acknowledgements

The authors wish to thank J. Cleveland for his contributions in preparing Box 1. Work in the Casero laboratory is supported by grants from the National Institutes of Health and the Patrick C. Walsh Prostate Cancer Research Fund for which R.A.C. is the Schwartz Scholar.

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L.J.M. is employed by and has a personal financial interest in Cellgate.

R.A.C. serves as a consultant to Cellgate, and his laboratory has received research funds from Cellgate.

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Glossary

ODC antizyme

A mammalian protein that inhibits ornithine decarboxylase (ODC) and downregulates polyamine transport, the translation of which is controlled by intracellular polyamine concentrations.

5′-deoxy-5′-(methylthio)adenosine

(MTA). A product of the aminopropyl transferase reaction. The frequent loss of this salvage enzyme in tumours presents itself as an excellent target for a reverse prodrug strategy, such that only tumour cells that are unable to inactivate the cytotoxic agent are targeted.

Objective responses

These are defined by the voluntary international standard known as the Response Evaluation Criteria in Solid Tumors (RECIST). They are: complete response (CR), a complete disappearance of all target lesions; partial response (PR) a 30% or greater decrease in the sum of longest diameter of target lesion; stable disease (SD) <20% increase in the sum of the longest diameter of the target lesion.

Protonatable

Protonatable refers here to an amine or imine nitrogen molecule that is able to accept a proton, thus existing as a positively charged molecule at a physiological pH.

Bovine serum amine oxidase

(BSAO). BSAO is an extracellular, copper-containing oxidase found in the serum of many animals that oxidizes polyamines, producing H2O2 and aldehydes by a mechanism distinct from either N1-acetylpolyamine oxidase or spermine oxidase.

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Casero, R., Marton, L. Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat Rev Drug Discov 6, 373–390 (2007). https://doi.org/10.1038/nrd2243

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