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Polyamines and colon cancer

Wallace, Heather M.; Caslake, Robert

European Journal of Gastroenterology & Hepatology: September 2001 - Volume 13 - Issue 9 - p 1033-1039
Review in Depth

Colorectal cancer is a major health problem in the western world and is associated with significant morbidity and mortality. Diet makes a significant contribution to the disease, with high fat, low fibre diets correlating positively with a high incidence of colorectal cancer. Intracellular polyamine concentrations and ornithine decarboxylase activity are both increased in colorectal cancer tissue and in premalignant polyps. Measurement of the polyamine content of serum and urine of individuals has been proposed as a diagnostic marker of malignancy but a number of false positives make this idea untenable. There may, however, still be a role for the measurement of urinary polyamine content as a means of monitoring the efficacy of therapy. Inhibition of polyamine metabolism by polyamine analogues or by non-steroidal anti-inflammatory drugs may be useful in the chemotherapy and/or chemoprevention of colorectal cancer. Preliminary results suggest that a low polyamine diet might be helpful as part of a health care plan for cancer patients.

Departments of Medicine and Therapeutics, and Biomedical Sciences, University of Aberdeen, UK

Correspondence to Dr H. M. Wallace, Depts of Medicine and Therapeutics, and Biomedical Sciences, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UK Tel: +44 (0)1224 552481; fax: +44 (0)1224 699884; e-mail: h.m.wallace@abdn.ac.uk

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Colorectal cancer

Colorectal cancer is one of the most common forms of malignancy in the industrialized world, contributing significantly to cancer mortality and morbidity. It is the second most common cancer in men and the third most common in women [1]. Around 130 000 and 180 000 new cases are diagnosed every year in the US and Europe, respectively [1], which produces a significant drain on health service resources. First-line therapy is radical surgery with adjuvant chemotherapy commonly being treatment with antimetabolites such as 5-fluorouracil. The overall 5 year survival rate for this disease is around 40%[2] although with improved surgical techniques, more effective adjuvant therapy and earlier diagnosis mortality has been decreasing gradually over the last decade [3,4]. Colorectal cancer is, however, still the second most common cause of cancer mortality in the western world [3].

Colorectal cancer is a multifactorial disease with about 75% of cases being sporadic and only 25% being linked to other conditions such as hereditary non-polyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), inflammatory bowel disease and family history [5,6]. The events occurring during the development of colorectal carcinoma form, the now familiar, adenoma–adenocarcinoma sequence proposed by Vogelstein and Kinsler [5]. This sequence outlines the progressive changes that transform a normal epithelial cell into a metastatic carcinoma cell (Fig. 1).

Fig. 1

Fig. 1

The most significant influence on the development of colorectal cancer is, however, the environment, with the diet, in particular, contributing to disease initiation and progression. It is known that diets rich in fat, especially saturated fat, such as found in red meat are associated with the development of colorectal tumours [7]. Similarly, a positive family history of colorectal cancer, smoking, and a high consumption of alcohol are associated with a significantly increased risk of colorectal cancer [8].

On the other hand, inverse relationships exist between colorectal cancer and the consumption of fruit vegetables and, in particular cruciferous vegetables, physical activity, reproductive behaviour and the use of hormone replacement therapy and non-steroidal anti-inflammatory drugs (NSAIDs) (for a review see Reference 8). Convincing evidence of a reduced risk of colorectal cancer has been found for each of the above.

There are many biochemical alterations found in cancer cells but one of the most consistent is a change in the intracellular polyamine content [9], with cancer cells having a higher intracellular polyamine content than the equivalent normal tissue [10–12].

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The polyamines

The polyamines are naturally occurring aliphatic polycations found in almost all living cells [13]. The major polyamines are spermidine and spermine, and their diamine precursor, putrescine. They are positively charged at neutral pH and the charge is distributed along the length of the molecule. This facilitates their interaction with anionic molecules such as DNA and RNA [14]. Polyamines have been shown to be essential for optimal rates of cell growth and differentiation, with high concentrations being found in rapidly growing cells and tissues [9]. They are synthesized from two amino acids, l-ornithine and l-methionine, in an essentially irreversible manner by two decarboxylase enzymes and by two synthases (Fig. 2). The decarboxylases are readily induced by a number of growth promoting stimuli including serum and growth factors [15,16] and have a short half-life of the order of minutes to 1 h. The activity of these two enzymes is highly regulated and one of them, ornithine decarboxylase (ODC), has a number of novel regulatory features including regulation by a unique protein, termed antizyme, which targets ODC for degradation by the 26S proteosome without the need for ubiquitin [17].

Fig. 2

Fig. 2

Spermine and spermidine can be recycled by the ‘retroconversion’ pathway (Fig. 2) which is a two enzyme system converting spermine to spermidine and spermidine to putrescine by firstly an acetylation step, catalysed by spermidine/spermine N 1-acetyltransferase (SSAT), followed by an oxidation reaction catalysed by polyamine oxidase (PAO). In addition to this enzymatic metabolism, transport systems exist which, on the one hand, transport polyamines from the extracellular environment into the cell and, on the other, export polyamines from the cell [18]. This combination of biosynthesis, catabolism, uptake and export (Fig. 2) essentially controls the intracellular polyamine content, and disruption to any of these reactions results in alteration to the growth of cells.

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Function of the polyamines

A number of functions have been attributed to the polyamines over the years. Polyamines, as a result of their positive charge, are believed to stabilize DNA but they can cause distortions and alter DNA conformation producing both A and Z forms from the normal B form [19]. These changes in the conformation of DNA can result in a change in gene transcription [20]. Polyamines also stabilize mRNA, rRNA and tRNA, by binding to specific sites on these molecules [21,22]. Polyamines can interact with membranes, which generally leads to an decrease in the fluidity of the membrane. This has important consequences for the movement of proteins and lipids within the membrane [23]. More recently, Ha et al. have suggested that polyamines, especially spermine, may be natural anti-oxidants protecting cells from oxidative damage [24].

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Polyamines and cancer

Diagnostic or prognostic markers?

In the early 1970s, the late Diane Russell first observed that patients with malignant disease excreted higher amounts of polyamines in their urine than normal individuals [25]. On the basis of these results it was proposed that urinary polyamine measurements might be a useful, non-invasive diagnostic marker of cancer. This led to a great deal of research activity in this area but the outcome was disappointing. Patients with other conditions such as Duchenne muscular dystrophy [26], psoriasis [27] and cirrhosis [28] were also found to have an elevated urinary output of polyamines, thus ruling out these polyamine measurements as a diagnostic marker of malignancy.

More-promising correlations were found between urinary polyamine measurements and the response of patients to therapy [29]. After treatment (surgery, radio- or chemotherapy), which usually resulted in an initial elevation in urinary polyamine output, urinary polyamine content was observed to decrease in patients in remission to approximately normal levels (Fig. 3). While the patient remained in remission the urinary polyamine content remained low [29]. However, upon disease recurrence, urinary output of polyamine increased, indicative of relapse. Despite the promise of these observations little use has been made of them clinically, perhaps because it was never shown conclusively that the increase in urinary polyamine output occurred before clinical signs of relapse.

Fig. 3

Fig. 3

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Polyamines and colorectal cancer

As with other tumours, polyamine content of colorectal cancers is increased when compared to the equivalent normal tissue. In our hands, colorectal cancer tissue had approximately 4 times the polyamine content of the colonic mucosa from patients with non-malignant disease [12]. Unfortunately, in colorectal cancer, as opposed to breast cancer, where the polyamine content showed strong positive correlations with prognostic factors and tumour recurrence [11], polyamine content did not correlate significantly with Dukes’ stage, tumour site or size although, in this study, the number of patients was small [12]. Serum polyamine levels were also increased in patients with colorectal carcinoma [30]. In a similar manner to urinary polyamine concentrations, serum polyamine levels were decreased in patients who had undergone curative surgery and remained low up to 15 months’ follow-up in those patients with no evidence of disease [30].

In addition to changes in polyamine content, ODC activity has also been found to be increased significantly in adenocarcinoma tissue compared to microscopically normal tissue from the same patients [31]. Similar findings were observed in human colonic surgical specimens with both ODC activity and polyamine content of the malignant tissue being increased [32]. Intratumour content of spermidine and spermine was increased in line with the increase in ODC activity. The ratio of spermidine to spermine was also increased markedly in poorly differentiated adenocarcinomas when compared to their well-differentiated counterparts, perhaps suggesting that an increase in this ratio is indicative of a poor prognosis.

Polyamine oxidase (PAO), the enzyme responsible for the catabolism of N 1-acetylspermine and N 1-acetylspermidine, has been reported to be decreased in colorectal cancer [33]. Similar observations have been made recently in breast carcinoma [34]. Reports of altered spermidine/spermine N 1-acetyltransferase activity have also been recorded.

Some of the most convincing evidence for the involvement of polyamines in colorectal cancer has come from studies using the specific inhibitor of ODC, α-difluoromethylornithine (DFMO). DFMO is a suicide inhibitor that binds irreversibly to ODC at its main catalytic site and so permanently inactivates the enzyme [35]. It has been shown to block the growth of a number of types of tumour cells in vitro, although clinical trials have failed to repeat this finding [36]. The failure of DFMO monotherapy in man has been shown to be due to a compensatory increase induced in polyamine uptake by polyamine depletion [37]. This can, however, be overcome by removal of the major exogenous polyamine sources: by decontamination of the gut with antibiotics and provision of a low polyamine diet. This regimen has been used to improve the efficacy of DFMO and has met with some success [38]. In a separate study, rats treated with the carcinogen 1,2-dimethylhydrazine and fed a low polyamine diet showed a significant reduction in abnormal colonic crypts [39]. These data, together with the fact that dietary fat can induce ODC activity [31], suggest that dietary manipulation of polyamine metabolism may be useful in the management of colon cancer patients.

An alternative approach to inhibition of single enzymes in the polyamine biosynthetic pathway is to use analogues of the polyamines. This approach was first pioneered by Porter et al. [40]. It makes use of the fact that polyamine analogues can be accumulated within cells using the polyamine uptake pathway. Once inside the cell, the analogues inhibit biosynthesis by feedback repression of the synthetic pathway. An added bonus of the analogues is that many of them, particularly the symmetrically substituted analogues, also ‘superinduce’ the catabolic pathway at the level of SSAT (for a review see Reference 13). Thus the analogues have three lines of attack on polyamine content: competition for uptake, inhibition of biosynthesis, and stimulation of breakdown making them potentially more efficient in depletion of intracellular polyamine content.

Several analogues of the polyamines are now available including the symmetrically substituted bis(ethyl)polyamines [41], the unsymmetrically substituted compounds such as N 1-ethyl-N 11-[(cyclopropyl)methyl]-4,8-diazaundecane (CHENspm) and N 1-ethyl-N 11-[(cycloheptyl)methyl]-4,8-diazaundecane (CPENspm) [42] and compounds derived from the S-adenosylmethionine decarboxylase inhibitor, methylglyoxal bis(guanylhydrazone) (MGBG), such as CGP48664 [43]. Although these have not yet been tested clinically in colorectal cancer these compounds are having some success in the treatment of other tumours. One interesting possibility suggesting that the analogues might be effective in cancer cells, is the low level of PAO activity observed in both colorectal and breast cancer tissue. This may prevent these drugs being degraded and hence increase their half-life and therefore efficacy in vivo.

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Non-malignant disease

Familial adenomatous polyposis (FAP) is a dominantly inherited disease affecting approximately 1 in 7000 individuals [6] and patients with this disease are at increased risk of developing colorectal cancer. Patients develop hundreds to thousands of colonic adenomatous polyps in their 20s and 30s. The polyps are benign, but as a result of the large numbers the chance of one developing into a carcinoma is greatly increased. Analysis of dysplastic mucosa in FAP patients showed that ODC activity was increased when compared to normal mucosa in the same patients [44]. Increased ODC activity and polyamine concentrations have also been observed in the colons of presymptomatic FAP patients in comparison to those of normal control patients [45]. A preliminary study in Aberdeen examining the polyamine content of colonic polyps found a graded response that correlated with histological grade (Wallace and Nuttall, unpublished observations). Non-malignant polyps had a polyamine content within the normal range, while neoplastic polyps had greatly increased polyamine content similar, in fact, to that found in tumours (Table 1). Thus, increases in polyamine content seem to be a feature of increased cell growth and not malignancy per se.

Table 1

Table 1

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Chemoprevention

Chemoprevention is the long-term use of synthetic chemical agents by healthy individuals to prevent or delay the onset of disease. It is a controversial topic and is difficult to quantify the benefits due to the very long-term nature of chemopreventative studies. Since colorectal cancer has a significant environmental component it is an ideal disease in which to evaluate the potential benefits of chemopreventative agents. The diet naturally contains a number of substances that act either as tumour blocking or tumour suppressing agents. These include the anti-oxidant vitamins A and E as well as indoles, flavones, retinoids, flavanoids and other micronutrients [46]. As these compounds are all components of our diet, it is difficult to choose one and prove, definitively, that it has a significant role in chemoprevention.

An alternative is to use drugs and the most successful of these, to date, are the NSAIDs such as aspirin and naproxen. NSAIDs inhibit the enzyme, cyclo-oxygenase (COX), which is involved in the metabolism of arachidonic acid to the prostanoids [47]. Many case–control and cohort studies now support the fact that regular NSAID treatment reduces the incidence of colorectal cancer by up to 50%[48]. Similar findings have been observed in animal models and in studies in vitro using human colorectal cancer cell lines [49,50]. While initially it was assumed that the mechanism of chemoprevention was linked to the inhibition of COX and the synthesis of the prostaglandins it is becoming increasingly evident that COX inhibition does not explain the chemopreventative effects of the NSAIDs. Some of the most convincing evidence for this comes from in vitro studies using colorectal cancer cell lines that are devoid of COX activity but which still respond to NSAIDs [51]. In vivo, a metabolite of sulindac that does not possess COX inhibitory activity is still able to prevent tumour occurrence and to cause tumour regression [52]. Therefore an alternative mechanism of action is required.

One possibility is that NSAIDs act through inhibition of the polyamine pathway activation of which normally leads to cell growth. Aspirin, for example, is toxic to human colorectal cancer cells (Fig. 4). This toxicity is accompanied by a loss of intracellular polyamine content and by inhibition of ODC activity (Table 2). (It is interesting that aspirin per se has no effect on ODC activity indicating that NSAIDs are interacting with ODC at the cellular level.) Preliminary observations suggest that exogenous polyamine addition can, at least, partially reverse the cytotoxic effects of NSAIDs (Wallace and Hughes, unpublished observations). Thus it may be that the polyamine pathway forms part of a signalling cascade responding to NSAID treatment.

Fig. 4

Fig. 4

Table 2

Table 2

In support of this suggestion, DFMO has been shown to have potential as a chemopreventative agent in colorectal cancer with limited but reversible toxicity. Animal studies were encouraging [53] and clinical trials are ongoing.

In summary, therefore, polyamines are clearly involved in the development of colorectal as well as other cancers. However, a number of false positives make measurements of polyamines in body fluids untenable as diagnostic markers. It is clear that increased ODC activity and polyamine content are associated both with the premalignant conditions such as FAP as well as with adenocarcinoma (see Fig. 1). Potentially, measurement of polyamine content in excised polyps has more promise as a biomarker of disease as polyamine content (and ODC activity) tend to increase with polyp size. However, further development of this concept is required. The most promising new avenue for further research seems to be the possibility that ODC and the polyamines have a role in the chemoprevention of colorectal cancer. Since NSAIDs and DFMO both produce similar effects on colorectal cancer cell growth and polyamine biosynthesis it may be that it is ODC that is the key factor in chemoprevention.

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Acknowledgements

We would like to thank Aberdeen Royal Hospitals NHS Trust for their support of this work.

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Annotated references

 Of special interest

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    Keywords:

    cancer chemotherapy; ornithine decarboxylase; putrescine; spermidine; spermine

    © 2001 Lippincott Williams & Wilkins, Inc.