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Anti-cancer therapy: diversion of polyamines in the gut

Pryme, Ian F.a; Bardocz, Susanb

European Journal of Gastroenterology & Hepatology: September 2001 - Volume 13 - Issue 9 - p 1041-1046
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The growth of a murine non-Hodgkin lymphoma (NHL) tumour, either as an intraperitoneal ascites tumour or as a solid subcutaneous tumour, has been shown to be greatly reduced by including phytohaemagglutinin (PHA), a lectin present in raw kidney bean (Phaseolus vulgaris) in the diet. The reduced rate of growth occurred in a dose-dependent manner. Based on the experimental observations it has been suggested that a competition occurs between the gut tissue undergoing hyperplasia and the developing tumour for nutrients (including polyamines) from a common body pool. This may be an important factor with regard to the observed initial low level of tumour growth following the feeding of a PHA-containing diet. Results showing that the level of hyperplasia of the small intestine in response to feeding the PHA diets was higher in non-injected mice compared to those which had been injected with tumour cells substantiated the concept of competition between gut and tumour for nutrients etc. required for growth. The observations suggest that lectins, which exhibit growth-promoting effects on the gut, may have interesting applications in the formulation of new approaches with respect to cancer treatment.

aDepartment of Biochemistry and Molecular Biology, University of Bergen, Norway; and bThe Rowett Research Institute, Aberdeen, UK

Correspondence to Dr I. Pryme, Department of Biochemistry and Molecular Biology, University of Bergen, Årstadveien 19, NO-5009 Bergen, Norway Tel: +47 55 586438; fax: +47 55 586400; e-mail: ian.pryme@ibmb.uib.no

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Introduction

A large number of studies have provided clear evidence that polyamines are involved in mechanisms which control cellular growth (for example, the concentration of polyamines changes during the various stages of the cell cycle) and, importantly, in the development and sustainment of tumours [1–7]. Cells obtain polyamines either from an existing body pool or as a result of de novo synthesis. A very high percentage of polyamines is transported in the blood by the erythrocytes.

It was demonstrated almost 20 years ago that the blood cells of cancer patients carried the highest proportion of polyamines [8]. An increase in the polyamine content (particularly spermine and spermidine) of the cellular component, observed in 77% of cancer patients, was far more frequent than an increase in the plasma (38%). Gerbaut [9] did not find significant amounts of putrescine in the red cells of non-cancer patients but showed a two- to three-fold increase in the erythrocytes of tumour-bearing animals. The content of spermidine and spermine in peripheral erythrocytes increased linearly during a 10 day period of exponential growth of inoculated Ehrlich ascites carcinoma cells [10]. A suppression of tumour growth led to reduced polyamine levels. A similar pattern was observed in human lymphoma patients and other patients with advanced cancer where spermine and spermidine levels in red cells mirrored the progression of the disease [11,12]. In adult patients with glioblastomas an elevated content of spermidine was seen in erythrocytes 1–6 months prior to the disease being clinically detectable [13]. It is apparent that increased uptake and transport of polyamines occurs not only in cancer but as a response to ‘normal’ tissue regeneration.

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Polyamines in tumours

One of the earliest events in the course of cell proliferation is the induction of the enzyme ornithine decarboxylase (ODC) which is the first enzyme in the biosynthetic pathway of polyamines. All known tumour promoters induce ODC, and O-tetradecanoyl-phorbol-13-acetate (TPA) or croton oil, for example, when applied to mouse skin, was shown to cause a 230-fold increase in activity within 4–5 h [14]. The increase was not permanent, however, returning to the control level within the space of 12 h. Increased levels of ODC have been shown to be due to a transient increase in ODC mRNA [15]. An increase in ODC occurs not only in human malignancy alone, but is also characteristic of general tissue proliferation and hyperplasia [16,17]. Westin et al.[18], in studies on patients with advanced cancer of the head and neck, observed that poorly differentiated squamous cell carcinomas were several-fold higher in ODC than more well-differentiated cancers. Patients exhibiting high ODC activity were indicative of short-term survival (1 year).

A relationship between increase in ODC content of brain tumours and malignancy has been established [19,20] and in patients with astrocytomas both the ODC content and putrescine level increased with malignancy. Volkow et al.[21] injected 14C labelled putrescine into rats with transplanted gliosarcoma tumours and after only a short time were able to detect the brain tumour by autoradiography. The radioactive label could be subsequently followed in the tumour during its metabolic conversion into spermidine and spermine and other metabolites. A much lower level of accumulation of the putrescine was observed in neighbouring normal brain tissue, and its rate of metabolism was considerably lower. In hyperplastic prostate tissue the putrescine content was found to be 40–50% decreased although the spermine content was increased markedly and spermidine slightly elevated [22]. The same workers reported that in patients with renal carcinomas there were only slight increases in putrescine and spermidine, while there was a decrease in spermine content of the tissue. In a separate study on patients with renal carcinomas Matsuda et al.[23] found slight increases in spermidine concentration but other polyamines were unaffected. Although increased levels of all polyamines were found in adenocarcinomas of the human thyroid, there was no difference in the ratio of spermidine to spermine. In addition, the ODC content was elevated.

Thomas and Thomas [24] have suggested that polyamines may play a role in the evolution of mammary cancer since oestradiol mediated control of the division of breast cancer cells by cyclins was inhibited following polyamine restriction. In patients with either Hodgkin’s disease or non-Hodgkin’s lymphoma both putrescine and spermidine were found to increase in the urine, the actual levels reflecting the progression and severity of the disease. Reduced urinary polyamine levels were observed upon successful treatment of the lymphoma.

When a selective inhibitor of ODC activity, α-difluoromethylornithine (DFMO), became available [25] great hopes in cancer treatment arose because the inhibitor was shown to be very effective in curtailing growth of transformed cells in culture. Unfortunately, however, clinical trials did not live up to expectations since DFMO was found to have only limited effects on tumour growth [26,27] and failed to inhibit the compensatory growth of organs [28]. Another drawback of DFMO was demonstrated by Hirvonen et al. [29] who showed that both human and mouse tumour cell lines developed resistance to the inhibitor. It also became apparent that under conditions of reduced ability to synthesize polyamines de novo due to DFMO administration, organs and tumours can compensate by increasing their capacity to take up polyamines from the blood. This process is a carrier mediated, energy dependent mechanism and many cell types appear to have a single transporter for putrescine, spermine and spermidine [30].

The limited success of DFMO has been attributed to three factors: (1) the tumour is able to obtain sufficient polyamines to sustain growth from the body pool, since the diet, a major source of polyamines [31] would provide a continuous exogenous supply; (2) intestinal bacteria may represent a potential limited source of polyamines; and (3) polyamines may be effectively re-utilized following their release from dead cells, especially those of the gut. A cancer treatment strategy based solely on inhibition of polyamine synthesis by DFMO is thus doomed to fail for the following reasons: (1) since polyamines are present in essentially all foodstuffs, and at present diets with limited polyamine content are not available, dietary control of polyamine intake is not possible; (2) sterilization of the gut (e.g. by the use of antibiotics) is in practice impossible to achieve, thus a potential contribution of polyamines from bacterial sources will be unavoidable; and finally, (3) one cannot interfere with the re-use of polyamines which already exist in the body.

Taking these facts into consideration Bardocz, Pryme and Pusztai and colleagues have recently developed a new approach in attempts to modulate the levels of polyamines in the body. The overall aim is to reduce the availability of polyamines for tumour cells. In order to accomplish this these workers have utilized the properties of the plant lectin phytohaemagglutinin (PHA), which, when included in the diet, causes a marked accumulation of polyamines in the gut tissues. This response occurs during the induction of hyperplastic growth of the small bowel. It was reasoned that this reversible growth stimulus may effectively function as a competitor for extraneous polyamines for the growing tumour by reducing the body pool, and in doing so reduce the rate of tumour growth.

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Dietary PHA and growth of non-Hodgkin lymphoma tumours

It was shown in experiments where mice were injected either intraperitoneally (i.p.) or subcutaneously (s.c.) with non-Hodgkin lymphoma (NHL) cells that mice fed on a kidney bean diet (which contains the lectin PHA) developed tumours at a slower rate than animals fed on a control, lactalbumin based (LA) diet [32]. The kidney bean diet contained 7 mg of PHA/g diet, and calculated on a daily food intake of approximately 6 g/day, the diet thus provided about 42 mg PHA/mouse/day. In a subsequent experiment where purified PHA replaced the raw kidney bean protein in the LA diet, essentially identical results were obtained [33]. Ingestion of PHA resulted in hyperplastic growth of the bowel, especially of the jejunum and small intestine [33,34]. Analysis of the mucosa of the jejunum showed a marked increase in the content of protein, RNA and polyamines [33,34]. It would seem that the increased polyamine requirement of the gut is dependent on exogenous sources because no marked elevation in ODC activity has been observed in the gut tissue [35]. Bardocz et al. [35] and Pusztai et al. [36] have provided evidence that the lectin causes an increased transport of polyamines from the blood into the gut mucosa. Parallel to the stimulation of gut growth PHA initiates an extensive absorption of amino acids and other nutrients from the intestinal lumen [31,37].

In mice injected i.p. the number of cells in ascites tumours which developed in mice fed on the PHA and LA diets, respectively, were quantified. The results showed that cell proliferation in relation to time after inoculation of NHL cells was quite different under the separate dietary conditions. When rates of cell production were analysed during the course of three time periods of growth of the ascites tumours it was evident that the rate of cell proliferation in the mice fed PHA was much slower during the middle phase of the growth period (days 5–8) when compared with that in the LA fed animals [38]. Taking into consideration the PHA directed hyperplastic growth and simultaneous observed sequestration of polyamines in the jejunum the authors suggested that the slow rate of propagation of NHL cells growing in PHA fed mice could be partially attributed to a decreased availability of polyamines. During a later phase of growth (days 9–12) the degree of hyperplastic growth had levelled off and the growth rate of NHL tumour cells in PHA fed mice increased. These observations may have reflected a normalization of the body polyamine pool during the later phase of growth (days 9–12) which resulted in an accelerated rate of cell division of the proliferating NHL tumour cells [39,40]. The results supported the concept of an initial competition between the developing tumour and PHA stimulated gut hyperplasia for polyamines from a body pool.

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Polyamines in cells and organs

Bardocz et al. [33,34] have shown that the PHA-induced hyperplasia of the gut is associated with an accumulation of polyamines in the intestinal mucosa. This occurs prior to the actual onset of growth. Changes in the weight and polyamine content of a series of tissues indicated that an inter-organ competition between a tumour and body organs could be used to manipulate the metabolism of mice bearing NHL tumours [33].

In the presence of the growing tumour spermidine levels were elevated in both the small and large intestine but not in organs such as the liver and spleen [41]. When mice were fed PHA, however, the picture was somewhat different. Spermidine levels were reduced both in the liver and kidney in mice with developing NHL tumours while PHA caused a large increase in the spleen in both non-injected and injected animals in comparison to an LA fed group. In PHA fed mice both the small and large intestine showed significantly higher levels of spermidine in the presence of a proliferating tumour despite the fact that the degree of hyperplasia was somewhat lower under these conditions [34]. These results clearly indicated that the developing tumour caused an effect on the relative distribution of polyamines among various organs. Furthermore, they suggest that some organs may respond to a signal from a growing tumour to increase their production of polyamines, perhaps for export to transport systems in the blood in order to maintain the level of the body pool, and in doing so satisfy the demands made by the developing tumour for an increased extraneous supply. This would in turn imply that de novo synthesis of polyamines by tumour cells themselves alone is inadequate to support tumour growth, illustrating the importance of extraneous sources, including the diet.

Figure 1A shows that after 12 days on a PHA containing diet tumour growth, as measured by tumour protein content, is reduced by about 30%. When putrescine or a mixture of polyamines is added to the PHA diet then tumour growth appeared to be stimulated. The small intestine, however, gained weight when the protein content of the tissue in LA fed mice is compared with that in those fed PHA (Fig. 1B). This was due to the hyperplasia induced by the lectin. The addition of either putrescine or a mixture of polyamines caused a further increase in tissue mass as judged by protein content. The content of putrescine, spermidine and spermine in the small intestine and tumour tissue was measured and related to protein content (Fig. 2). Figure 2A shows that PHA promoted a large increase in putrescine content in the small intestine and this was not affected by addition of exogenous putrescine or a mixture of polyamines to the PHA containing diet. The putrescine content of the tumour, however, was not affected by PHA or addition of polyamines to the diet. Neither spermidine (Fig. 2B) nor spermine levels (Fig. 2C) were affected in the small intestine or tumour tissue by PHA or addition of polyamines. Interestingly, the magnitude of putrescine content in the small intestine and tumour was similar in LA fed animals, and this was not affected to any large degree by altered diet. On the other hand the levels of spermidine and spermine in the tumour, irrespective of diet, were approximately half of the corresponding values in the small intestine.

Fig. 1

Fig. 1

Fig. 2

Fig. 2

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Polyamines in dietary switch experiments

In dietary switch experiments Pryme et al. [39,42–44] showed that the volume of NHL ascites tumours in mice pre-fed on PHA (7 mg/g diet), injected and then maintained on the same diet showed a significant decrease in tumour volume and cell content compared with mice only fed LA. The levels of putrescine, spermidine and spermine in NHL tumour cells obtained from the control group, and mice fed only PHA indicated a build-up of polyamines in the cells in the latter group. This occurred before the tumour entered its most proliferative phase of growth. Tumour cells in the ascitic fluid of mice fed PHA for either 3 or 8 days contained intermediary levels of all three polyamines. These results show that when the animals are fed PHA, and gut hyperplasia is induced, then tumour growth is slow during the initial stages of epithelial proliferation. There is thus a correlation in time with the polyamine requirement of the gut and limited tumour growth [45]. It appears, therefore, that the cells of the gut are more efficient in procuring polyamines from the body pool than the tumour cells, further illustrating the point that the tumour is unable to produce sufficient polyamines by the de novo route to support growth. Recent experiments have demonstrated that the growth of an NHL tumour in mice fed a polyamine-poor diet was stimulated by addition of polyamines to the diet [46]. These observations lend support to the concept that dietary polyamines are important in the support of tumour growth.

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Conclusion

In summary, it would appear that the two different growth signals, the induction of growth of a tumour and the PHA-induced hyperplasia of the gut, compete with one another for important exogenous nutrients such as polyamines. The data demonstrate that tumour proliferation is initially slowed by the gut hyperplasia, though growth, however, is not completely arrested. Since it has been established that extraneous polyamines from the diet are required to sustain tumour growth, and the hyperplastic growth of the gut which occurs in response to ingesting the lectin is a polyamine dependent process, then it is evident that this latter growth signal can be used to effectively compete with tumour growth. Results obtained so far have clearly shown that inclusion of the plant lectin PHA in the diet causes an initial low rate of proliferation of NHL tumours in mice, growing either as solid, subcutaneous tumours or as ascites tumours in the peritoneal cavity. The results concerning changes in the weight and polyamine content of tissues indicate that inter-organ competition between the tumour and vital organs can be used to manipulate the metabolism of tumour-bearing mice. The promising results obtained hitherto with PHA indicate that lectins which exhibit such growth-promoting properties may be of extreme value concerning the development of new directions in anti-cancer strategy.

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Acknowledgements

This work forms part of the COST 917 Programme of the European Commission. The Norwegian Cancer Society is thanked for financial support. SB received support from SOAFD.

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Annotated references

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Keywords:

hyperplasia; lectin; non-Hodgkin lymphoma; phytohaemagglutinin; polyamines; tumour growth

© 2001 Lippincott Williams & Wilkins, Inc.