A Comparison of Structure−Activity Relationships between Spermidine and Spermine Analogue Antineoplastics

Abstract

A systematic investigation of the impact of spermidine analogues both in vitro and in vivo is described. The study characterizes the effects of these analogues on L1210 cell growth, polyamine pools, ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase, spermidine/spermine N1-acetyltransferase, the maintenance of cellular charge, i.e., cationic equivalence associated with the polyamines and their analogues, and compares their ability to compete with spermidine for transport. The findings clearly demonstrate that the activity of the linear polyamine analogues is highly dependent on the length of the triamines and the size of the N(alpha),N(omega)-substituents. It appears that there is an optimum chain length for various activities and that the larger the N(alpha),N(omega)-alkyls, the less active the compound. Metabolic transformation including N-dealkylation of these compounds is also evaluated. While there is no monotonic relationship between chain length and the ability of the analogue to be metabolized, the dipropyl triamines are clearly more actively catabolized than the corresponding methyl and ethyl systems. A comparison of the triamines with the corresponding tetraamines is made throughout the text regarding both in vitro activity against L1210 cells and in vivo toxicity measurements, suggesting that several triamine analogues may offer therapeutic advantages over the corresponding tetraamines.

In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells

“…Although inhibitors of virtually all of the biosynthetic enzymes in polyamine metabolism have been synthesized, none has demonstrated clinical efficacy as a single agent in clinical trails for cancer (see [20]). In an attempt to overcome the limitations encountered with specific inhibitors of enzyme function, we and others have exploited the self-regulatory properties of polyamine metabolism for therapeutic advantage through the use of structural analogues of the natural polyamines [4,5,8,18,39,43,44,49]. The initial studies with polyamine analogues, particularly with BENSpm, were promising, but clinical trials with a number of analogues in lung, breast, and other tumors did not reveal efficacy as single agents.…”

Polyamine analogues inhibit the ubiquitination of spermidine/spermine N1-acetyltransferase and prevent its targeting to the proteasome for degradation

“…Such analogues probably act by mimicking the ability of the natural polyamines, but are more potent due to a stronger interaction with the regulatory sites, and due to the fact that they are not themselves substrates for SSAT, so that their effect is not limited by SSATmediated degradation. BE-3-3-3 and BE-3-4-3 are effective antitumour agents in cell culture and animal models [13,14] and are currently undergoing clinical trials for this purpose. The induction of SSAT is clearly implicated in their anti-neoplastic activity, since cell lines resistant to these analogues do not induce SSAT, and restoration of SSAT in such cell lines restores sensitivity [15].…”

Metabolic and Antiproliferative Consequences of Activated Polyamine Catabolism in LNCaP Prostate Carcinoma Cells

“…It has been demonstrated, for example, that polyamine analogues such as N 1 ,N 11 -diethylnorspermine (DENSPM) down-regulate polyamine biosynthesis at the level of ODC and SAMDC and, at the same time, potently (i.e. Ͼ200-fold) up-regulate polyamine catabolism at the level of spermidine/spermine N 1 -acetyltransferase (SSAT) (1,(21)(22)(23)(24)(25)(26)(27). Several lines of evidence support the idea that analogue induction of SSAT and hence, activation of polyamine catabolism, is a critical determinant of DENSPM drug action.…”