Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 2. Structural analogues and derivatives.
Owing to their role in growth-related processes the natural polyamines (PAs), putrescine (Put), spermidine (Spd) and spermine (Spm) were identified about 30 years ago as potential targets for the development of anticancer drugs. It was presumed that inhibition of a key enzyme of PA biosynthesis, followed by the depletion of the intracellular PA pools results in the prevention of cell growth. Initial efforts were nearly exclusively focused on the design and synthesis of selective inhibitors of the PA biosynthetic enzymes. This period is reviewed in the 1st part. Selective inhibition of ODC caused in various cell lines growth inhibition, but was usually not sufficient to inhibit tumour growth, because the PA regulatory system outbalances selective enzyme blockade by enhancing compensatory reactions, and because exogenous PAs are used if de nova synthesis is impaired. When these facts were recognized, new targets were envisaged. Among these the PA uptake system and the deregulation of PA homeostasis became most attractive. They are the major topic of the present 2nd part. Inhibition of PA uptake from the cellular environment is expected to improve the efficacy of drugs, which rely on the depletion of intracellular PA pools. During the past few years several potent inhibitors of the PA uptake system became known. However, more work will be needed to allow their assessment as anticancer drugs in combination with DFMO and other compounds capable of depleting PA pools. The PA transport system also offers the possibility to improve the accumulation by tumors of compounds, which are tethered to PA structures. This can be achieved for the following reasons: (a) Structural requirements of the PA uptake systems are not stringent. (b) Tumour cells accumulate PAs more avidly than most non-transformed cells. (c) The transport rate for PAs is higher in cells with depleted PA pools, than in cells with a normal PA content. (d) In cells, which proliferate rapidly, PA depletion by biosynthesis inhibitors is more effective, than in slowly growing cells. The most actively pursued approach is currently based on the inhibition of tumour growth by cytotoxic structural analogues of the natural PAs. Some of these compounds mimic regulatory properties of the natural PAs. If a PA mimetic accumulates in cells, it induces catabolic processes, suppresses biosynthetic reactions, and depletes the pools of Put. Spd and Spm. N1,N11 -bis(ethyl)norspermine is a prototype of the PA mimetics. During the last decade a very large number of PA derivatives and structural analogues have been prepared, which are capable of inhibiting cell growth at low microM concentrations. Among the new PA-like structures several compounds were identified, which prevent cells from growing, without depleting PA pools to an extent that would be necessary to prevent cell growth. They may be considered as PA antagonists, although their mode of action is not well understood. A therapeutically useful drug has not yet been identified among the PA analogues. In many instances investigations were stopped at a preliminary stage. Recently synthesized compounds have not yet been pursued far enough to justify the initiation of clinical trials. Only very few toxicological results of the new structures have been reported, although the knowledge of the toxicology of Spm analogues is of eminent importance. PAs are ubiquitous cell constituents and are indispensable for normal cell function. However. extracellular PAs, and particularly extracellular Spm is cytotoxic and neurotoxic. These properties are shared by close structural analogues. A major difficulty in the development of PA analogues to therapeutically useful drugs is, therefore, the identification of structures, which do not share neurotoxic properties with Spm. Several tetramines are presently in early phases of clinical trials. It will be a matter of a few more years to allow one to decide, whether PA-related approaches of cancer therapy are a success or a failure.