Targeting polyamine metabolism: a viable therapeutic/preventative solution for cancer?

Abstract

The polyamine pathway has been identified as a target for the design of new antiproliferative drugs, due to the strong positive relationship between intracellular polyamine content and cell, particularly cancer cell growth. A number of single enzyme inhibitors have been synthesised against the two key biosynthetic enzymes, ornithine decarboxylase and S-adenosylmethionine decarboxylase, but their success in the clinic has been limited due to incomplete polyamine depletion and induction of compensatory mechanisms that counteract the effects of enzyme inhibition. Overall, clinical trials of these agents as chemotherapeutic drugs have proved disappointing, with either little clinical efficacy or unacceptable toxicity. The polyamine analogues provide an alternative strategy that shows promise, particularly against diseases other than cancer. Combination of the polyamine inhibitors with classic cytotoxic agents may be an alternative strategy that is showing some promise, at least in vitro. An avenue that is, however, presently more promising is the use of polyamine inhibitors or analogues as chemopreventative agents against a range of human cancers. It seems likely that the future use of these drugs will be in disease prevention rather than treatment. With regard to the newer agents with restricted conformation that are now undergoing clinical trials, it is too early to say whether they will be chemotherapeutic and/or chemopreventative. This article focuses on the clinical use and responses to inhibitors of polyamine metabolism.