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Effective Anticancer Drug and Food Choices Based on Polyamine Levels in Cancer Tissues
Satoru Watanabe1,*, Sumika Nagase2,3, Shoichi Sato2 and Seitaro Ohkuma1
Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan; Department of Medical Technology, Kawasaki College of Allied Health Professions, 316 Matsushima, Kurashiki City, Okayama 701-0194, Japan; 3Department of Biomedical Informatics, Division of Health Sciences, Osaka, University Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka, 565-0871, Japan
2 1

Abstract: This review addresses mainly the polyamine levels in various tissues and regional brain of (intact) rats treated with various types of anticancer drugs and those in diverse foods. Results indicate that the most effective combination therapy for cancer patients based on polyamine level is a polyamine-free diet coupled with drugs that reduce the amine in cancer-bearing host tissues.

Key Words: Polyamine, anti-cancer drug, food, cancer, rat, human, therapy. INTRODUCTION Polyamines, putrescine, spermidine and spermine, are a family of low molecular weight organic cations that usually increase in active growth cells. They are not only essential to cell survival, proliferation, DNA synthesis and neoplastic cell growth [1-3] but are also useful in monitoring the therapeutic effects of anti-cancer drugs [4-11]. Chemicals that disturb homeostasis and polyamine metabolism, such as inhibitors of ornithine decarboxylase (ODC), S-adenosylmethionine spermidine/spermine synthase, spermidine/spermine acetyl transferase, ODC anti-enzyme, polyamine analogues and transport inhibitors, decrease polyamine concentrations in cells and inhibit the growth of these cells. That is to say, cell growth is strictly dependent on polyamine concentrations. A strong positive correlation between polyamine levels, tumor growth and the effectiveness of anti-cancer drugs has encouraged the study of polyamines in cancer chemotherapy strategies [12-22]. Thus, this correlation may assist the choice of drugs based on polyamines that stimulate tumor cell growth as anticancer drugs undoubtedly increase or reduce polyamines in specific tissues and/or organs [23]. Chemotherapeutic effects of anticancer drugs might vary depending on depletion of polyamines in the tumor and host tissues. Over the past 20 years, large-scale studies have concentrated on showing how to deplete polyamines by using synthetic antagonists [24] and inhibiting related enzymes in the cancer and tumorbearing host tissues. It continues to be studied even now. Before a drug is used clinically, possible stimulation of tumor cells in tissues or organs by polyamine should be determined. This study can helps evade specific medicine choice beforehand. This Study can Help to Select the Right Specific Medicine Beforehand We indicated the individual polyamines concentration polyamines results in six regions of the brain as well as in fourteen tissues of intact rats given these drugs for five consecutive days. For current cancer treatment, a physician must choose ordinary anti-cancer drugs based on pathological diagnosis and according to the manufacturers guidelines. This method of choosing drugs does not consider the relationship between drug and polyamine concentrations are not known or investigated. Clinically treating cancer patients with anti-cancer drugs by these guidelines can produce severe undesirable side effects and allow re-growth of drugtolerant surviving cells after treatment termination. Judging from polyamines biological actions caused by their drugs, the re-growth may be due to polyamine stimulation and immunosuppression. Analyzing anti-cancer drugs effects on the polyamine concentrations of individual regions in the brain, organs or tissues with various cell-cycle kinetics could be an important tool in improving the clinical management of tumor treatment. Analysis would support the development of new treatment strategies targeting tumor-bearing regions or host tissues. The chemotherapeutic effects of the anticancer drugs might be based, in part, on the depletion of polyamines in the tumor and host tissues. On the other hand, considering the relationship between polyamine increase and drugs chemotherapeutic effects is necessary, as in the case of polyamine depletion. Nevertheless, this matter has scarcely been considered until now. Judging from polyamine levels, either drug or diet should make patients worse or weaken the therapeutic effects of the drugs. Therefore, physicians must pay attention and consider the polyamine increase as well as depletion factors for the best therapeutic outcome. Studying polyamine increases which stimulate tumor cell growth is also very useful in choosing treatments since some anticancer drugs undoubtedly increase polyamines in specific tissues and/or organs. This strongly suggests that drug induced polyamine in host tissues controls the chemotherapeutic effect. That is to say,
2009 Bentham Science Publishers Ltd.

*Address correspondence to this author at the Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 7010192, Japan; Tel: (+81)(86)462-1111; Fax: (+81)(86)462-1199; E-mail: sunsw@med.kawasaki-m.ac.jp

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the concentration of polyamines and stimulation of tumor cells should be determined before drugs are used clinically. It is easy to suppose that polyamines reducing drugs would be a good choice for treatment of tumor-bearing tissues and organs as well as regional brain tissues, but drugs that increase polyamines in rats must not be used because they stimulate the growth of the tumor cells. For clinical management and treatment of cancer patients, in addition to polyamine increase factors in the tissues and body of the cancer patient, it is quite important to know that body polyamine contents are also mainly dependent on the dietary intake. Polyamines are generally contained in most kind of foods and absorbed easily from the gastrointestinal tract. Dietary polyamine assists the cell regeneration and growth [25] while affecting the cell growth of colorectal cancer [26] and other tumors [27]. The direct relationship between dietary polyamine content and cancer growth has been reported in the prostate cancer cases as a nutritional therapy [28-30]. For this aim, Fred Hutchinson Cancer Center food frequency questionnaire (FFQ) provides polyamine database development for assessing dietary intake as a means of estimating polyamine intake and contributing to cancer polyamine investigation relationship [31]. PRESENT DATA OF TISSUE POLYAMINE LEVEL MODIFIED BY ANTI-CANCER DRUGS Introduction The determination of drug modified polyamine concentration improves the chemotherapeutic efficacies by enabling anticancer drugs choices on the basis of each host tissues polyamine levels. Even though the anti-cancer drugs that modify polyamines in specific tissues are very useful for their chemotherapeutic effects, there has been no research on polyamines in intact rat tissues except for our researches. Therefore, comparatively detailed analysis of the relationship between anticancer drugs, polyamine concentration and tissues seems to be useful in tissue specific treatment based on polyamine concentration in the host tissues. This polyamine determination is also useful for combination therapy with the drugs that reduce polyamine in corresponding tissues. The combined treatment of tumorous animals with an ornithine decarboxylase and polyamine oxidase inhibitors very often indicates an antitumoral effect superior to that of either drug alone. The combination treatment of some anticancer drugs with ornithine decarboxylase and polyamine oxidase inhibitors completely prevents Lewis lung carcinoma growth, and considerably prolongs the average life span of L1210 leukemia mice [27]. Results and Discussion The effects of anti-cancer drugs, (5-FU, Ara-C, adriamycin, cisplatin, methotrexate, cyclophosphamide and etoposide, and Vincristine, 6-Mercaptopurine, etoposide, Ranimustine and Nimustine), on the putrescine, spermidine and spermine concentrations in the prostate, seminal vesicles, testis, thymus, spleen, kidney, heart, liver, small intestine, large intestine, stomach, tongue, skeletal muscle (femoral), lung, cerebellum, hippocampus, corpus striatum, cortex, combined thalamus, hypothalamus, and diencephalon has been examined respectively in intact rats that had been given the drugs

for five consecutive days as is shown in Tables 1-3. Statistically significant changes in polyamine concentrations were seen in the prostate, seminal vesicles, testis, thymus, spleen, kidney and heart of the intact rats treated with 5-furuorouracil (5-FU), arabiofuranosyl cytosine (Ara-C), adriamycin, cisplatin, methotrexate, cyclophosphamide and etoposide. Statistically significant changes in polyamine concentrations were seen in the liver, small intestine, large intestine, stomach, tongue, skeletal muscle (femoral) and lung the intact rats treated with 5-furuorouracil (5-FU), arabiofuranosyl cytosine (Ara-C), adriamycin, cisplatin, methotrexate, cyclophosphamide and etoposide. The observations of the significantly increased polyamines in the 5-FU and Ara-C-treated small intestine, 5-FUtreated-seminal vesicles, spermidine and spermine in 5FUtreated prostate and testis, Ara-C-treated stomach, adriamycin-treated seminal vesicles and large intestine and cisplatintreated seminal vesicles of the rats, discourage similar future treatments, as is shown in Tables 1 and 2. Polyamine levels did not indicated significant decrease in tissues or organs of 5-FU- and Ara-C-treated rats. These results show that these treatments must be avoided and, if used, the physician should pay scrupulous attention to the patients condition. On the other hand, the decreases of all polyamines in the adriamycin-treated heart and skeletal muscle, methotrexatetreated thymus and spleen, prostate, seminal vesicles, thymus, spleen, kidney and heart, and cyclophosphamide-treated small intestine, and etoposide-treated thymus prove the value of these treatments for these tissues. The decreases of putrescine and spermidine, in the adriamycin-treated prostate, testis and thymus and in etoposide-treated skeletal muscle and lung may be significant for treatment of these tissues. Furthermore, the significant decreases of polyamines, spermidine and spermine in the adriamycin-treated spleen and cisplatin-treated heart indicate these drugs to be successful treatments. These results may assist in combination therapy and choosing of anti-caner drugs based on polyamine levels. For example, the most effective combination of anti-cancer drugs for the thymus and spleen was methotrexate and Cyclophosphamide because all polyamines in these organs were decreased (Table 1). Of course, etoposide and cisplatin may be suitable for treating the heart and lung because this combination decreased all polyamines. Physicians may pay attention the use of drugs that did not influence polyamine levels. In the regional brain, etoposide was suitable for treating the cortex cancer because all polyamines decreased at a higher dosage (Table 3). Statistically significant changes in polyamine concentrations were seen in the cerebellum, hippocampus, corpus striatum, cortex, combined thalamus and hypothalamus and diencephalon regions of the brains of intact rats treated with vincristine, 6-mercaptopurine, etoposide, ranimustine and nimustine. The decreases of spermidine and spermine in etoposide-, ranimustine- and nimustine-treated hippocampus, cortex and corpus striatum indicate these treatments to be proper choices as is shown in Table 3. These tables might provide useful information for the brain tumor therapeutic treatment. That is to say, physicians can choose the drug based on polyamine concentration whether it must

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Table 1.

Statistical Significant Change of Polyamines in Various Tissues of Rats Treated with Various Anti-Cancer Drugs

5-FU

Polyamine put

Prostate

Semial Vesicles ++

Testis

Thymus

Spleen

Kidney

Heart

(33.0 mg/Kg) Ara-C

spd spm put

++ ++

++ ++

+ + ++ + ++

(63.0 mg/Kg) Adriamycin

spd spm put + ++

(2.0 mg/Kg) Cisplatin

spd spm put

+ +

(5.0 mg/Kg) Methotrexate

spd spm put

+ +

(2.5 mg/Kg) Cyclo-phosphamide (5.0 mg/Kg ) Cyclo -phosphamide (5.0 mg/Kg ) Etoposide

spd spm

put spd spm put

(4.0 mg/Kg) Etoposide

spd spm put +

(8.0 mg/Kg)

spd spm ++ ++

Abbreviations: put, putrescine; spd, spermidine; spm, spermine. ++ and + , and and blank show statistically significant increase, decrease or no change, respectively. Statistical differences were examined by Student's t-test. ++ and : p<0.01, + and : p<0.05.

be a combination or single therapy. Polyamine levels in the drug-treated tongue and cerebellum were not affected at all. Conclusion For cancer treatments, physician should not use the drugs that induce increase of all polyamines in tumor-bearing tissues or organ, however physician should choose the drugs that reduce all polyamines with alone or combination of drug in their tissues judging from Tables 1-3. POLYAMINE ORIGIN FROM FOODS Having a working knowledge of food polyamine concentrations reduce the risk of the cancer growth by enabling the evasion of the intake of polyamine. That is to say, the study

of all possible polyamine sources is important for the clinical management and treatment of cancer patients. Exogenous polyamines will be eliminated by administrating a polyamine-free diet and flushing the gastrointestinal tract. Oral intake of ordinary foods containing polyamines and polyamine directly effects cancer treatments since cancer growth can be reduced by evading dietary polyamine intake. For this reason, we compiled a list of polyamine-containing foods. Food polyamines are easily absorbed by the intestines. The intake of these foods might increase polyamines that may stimulate cancer cells. Physicians generally suggest eating polyamine-rich nutritious food and taking amino acid supplements such as lysine [32] and ornithine [33] to maintain physical strength. Polyamine activates cell activity in the body and nutritious foods recover physical strength before

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Table 2.

Statistical Significant Change of Polyamines in Various Tissues of Rats Treated with Various Anti-Cancer Drugs

Polyamine 5-FU put spd (33.0 mg/Kg) Ara-C spm put spd (63.0 mg/Kg) Adriamycin spm put spd (2.0 mg/Kg) Cisplatin spm put spd (5.0 mg/Kg) Methotrexate spm put spd (2.5 mg/Kg) Cyclo -phosphaminde (5.0 mg/Kg) Etoposide spm put spd spm put spd (4.0 mg/Kg Etoposide spm put spd (8.0 mg/Kg) spm

Liver

Small Intestine ++ ++

Large Intestine

Stomach

Tongue

Skeletal Muscle

Lung

++

++

++ ++ ++ + + ++ + +

++

++ ++

++

Abbreviations and explanations are the same as in Table 1.

and after surgery. Ornithine that is a precursor of polyamine directly increases polyamine in the body. However, physicians have scarcely considered these increasing factors of polyamine when treating cancer patients. Taking polyamine nutritious foods, at their doctors suggestion, patients can not avoid the oral intake polyamines. As a cause for misunderstanding, it is well known and has become common practice to prescribe polyamine-rich foods and ornithine pellets to non-cancer patients. Physicians should notice the different dietary need of non-cancer and cancer patients. This is a big and unbelievable oversight that most physicians, when it comes to the cancer treatment do not pay any attention to polyamine levels at all. Another serious problems is the shortage of polyamine knowledge or its relationship to cancer and the little clinical focus on polyamine content in food.

This concept must be promptly publicized and put into practice as soon as possible. Effects of a Low Polyamine Diet on the Cancer Patient The positive effects of a low polyamine diet on the cancer patient were clinically demonstrated in the prostate tumor [28-30] cases. Effects of a long term polyamine reduced diet on the prostate carcinoma patients have been studied. A polyamine reduced diet was given as nutritional therapy to prostate carcinoma patients. Reducing polyamine dietary intake and intestinal decontamination is a well-observed and tolerated regimen and seems to be effective for pain control in prostate carcinoma models. Furthermore, the evaluation of a new anticancer treatment, using a combination of polyamine antimetabolites, an anticancer agent and a low-polyamine feeding state has led to the conclusion that in mice,

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Table 3.

Statistical Significant Change of Polyamine in Regional Brain of Rats Treated with Various Anti-Cancer Drugs

Polyamine

Cerebellum

Hippo -Campus

Corpus Striatum

Cortex

Thalamus + hypothalams

DienCephalon

Vincristine

put spd

(0.1 mg/Kg) 6-Mercaptopurine

spm put spd

(0.4 mg/Kg) Etoposide

spm put spd +

(4.0 mg/Kg) Etoposide

spm put spd +

++ + ++

(8.0 mg/Kg) Ranimustine

spm put spd

(10.0 mg/Kg) Nimustine

spm put spd ++ ++

(10.0 mg/Kg)

spm

Abbreviations and explanations are the same as in Table 1.

the combined therapy with alphadifluoromethylornithine (DFMO) plus mitomycin C and a low polyamine diet is a safe and effective regimen for the treatment of gastric cancer [34]. These studies clearly show the effectiveness of a low polyamine diet on cancer treatment. Polyamines and Fermentation in the Gut Gastrointestinal polyamines are of alimentary origin, and are also formed by aerobic and anaerobic microorganisms in the gut. They can be reduced by feeding a polyamine deficient diet together with gastrointestinal tract antibiotics. Selected species representing the numerically dominant population groups of the human gut flora were examined for their ability to synthesize intracellular polyamines and demonstrated the ability of bacteroides, fusobacteria and anaerobic cocci to synthesize high amounts of putrescine and spermidine [35]. Calculations based on these results suggest that the intestinal microflora are a major source of polyamines in the contents of the large intestine. Nondigestible but fermentable dietary fructans, such as oligofructose that exerts many effects on gut physiology through its fermentation end products such as short-chain fatty acids have been taken to lose weight [36]. The modulation of hepatic lipid metabolism indicated that a diet enriched with oligofructose almost doubled the concentration of putrescine in the cecal contents. The concentration of all three polyamines in the cecal tissue

was significantly greater than in controls. The greater level of polyamines in cecal tissue may be related to the cell proliferation resulting from a diet enriched with oligofructose fermentation in the gut. The concentration of spermidine in portal plasma was lower in rats fed diet enriched oligofructose, whereas the treatment did not affect the polyamine concentrations in the liver. Dietary guar gum and pectin also stimulate intestinal microbial polyamine synthesis in rats [35]. Fermented Foods Among fermented foods, soy sauces were rich in putrescine and histamine, while Japanese sake contained plenty of agmatine [37]. These polyamines are produced from amino acids during the fermentation with amino acid decarboxylases formed by microorganisms. The fermentation of food increases product polyamines, whether taking place in the gut or outside of the body. Effects of Fatty Acids and Oils on Polyamines The effects of amino acids and oils on polyamine concentration essentially seems to be quite similar to the case of foods fermentation because the fermentation end products are amino and fatty acids. The modulating effect of fatty acid on liver and colon mucosal ODC showed that the effect of dietary corn oil on colon carcinogenesis depends on the

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amount and its type [38]. Furthermore, the highest concentrations of intestinal polyamines were observed in rats fed a soy protein diet. The amino acid mix also elicited rapid and substantial increases in ODC and S-adenosylmethionine decarboxylase (SAMDC) activities in liver, kidney and intestine. Effects of the dietary regulation of two key enzymes in polyamine biosynthesis, (ODC) and SAMDC activities in the rat tissues have been investigated [39]. The amino acid mix as well as the complete diet, elicited substantial increases in ODC and SAMDC activities in liver and intestine. In the brain and muscles only SAMDC activities were increased. Experiments that were conducted to determine the effect of dietary lysine on hepatic and renal polyamine synthesis in chick by using high arginine-requiring and low argininerequiring strains, showed decreased renal concentrations of arginine. Lysine and ornithine concentrations, however, increased in both strains increasing dietary lysine [40]. It was concluded that excess dietary lysine increased renal concentrations of ornithine due to induction of arginase. This accumulation of polyamine precursor resulted in increased concentrations of putrescine despite feedback inhibition of ODC. Polyamines in Some Foods Soybeans, tea leaf, and mushrooms were conspicuously rich in spermidine, while oranges contained a large amount of putrescine. The most tea leaf may be classified in fermentation product [37] as mentioned in above Fermented Foods. Tissue polyamine concentrations in the European sea bass (Dicentrarchus labrax L.) change with age and season of the year [41]. In addition, effects of alcohol and popular luxury goods on the polyamine contents in body are discussed a little. Furthermore, low polyamine content foods and inhibitory materials of polyamine synthesis in foods also are discussed a little. Polyamines in Milk It is well known that growing infants take all their nourishment from their mother's milk. Human milk contains a considerable amount of polyamine, the profile of which is shown in this article. It would appear that milk polyamines are derived from the high polyamine contents in the mammary gland and that they may be important in infant nutrition [42]. Furthermore, in artificial powdered formulas, the polyamine concentration was approximately 10 times lower than in human milk, with no difference in putrescine and spermine contents between first-age and second-age formulas [43]. By contrast, semi-elemental diets prepared by hydrolytic procedures using crude extracts of pancreatic enzymes were shown to be major sources of polyamines with a profile similar to that of human milk. Compared with first-age formulas, mean concentrations in spermine and spermidine were 39 and six times higher, respectively, in these semielemental diets, whereas putrescine levels remained almost equivalent in all types of milk tested. These data indicate that human milk and some semi-elemental diets provide substantial amounts of spermine and spermidine to neonates and infants that could potentially modulate intestinal maturation. Under the present conditions, an infant with cancer can not

avoid consuming polyamines from milk and baby food. Development of polyamine free milk and baby food is an urgent necessary. Foods Inhibiting Polyamine Synthesis Essential [44], olive and fish oils reduce polyamine in the tissues and body [38]. Flavanols and procyanidins of cocoa and chocolate inhibit growth and polyamine biosynthesis of human colonic cancer cells [45]. Including these in a cancer patients diet may be suitable due to their inhibiting ODC and SAMDC. Polyamine Concentration in Refrigerated Foods The content of polyamine in spinach seems to change during refrigeration. Spermidine that was studied in 18 market samples of spinach in Spain was detected in relatively high amounts in all samples in the ranges of 15.6-53.0 mg/kg. Changes in amine content during storage at 6 degrees C were studied. The content of most of the amines remained constant during storage, spermidine showed a clear decreasing trend. This means that cancer patients must pay attention both to storage period and temperature before eating spinach [46]. These results tell us that cancer patients must make careful vegetable choices and be shown how to store them. FACTORS OTHER THAN FOOD AND DRUG THAT INFLUENCE POLYAMINE LEVELS Physical Exercise Apart from dietary intake, the role of physical exercise and testosterone on the polyamine levels is also of interest. Measurements of polyamine-synthesizing enzymes, ODC and SAMDC and polyamine content in skeletal muscle of male rats exposed to endurance or resistance exercise have been taken. Physical exercise induces polyamine accumulation in the skeletal muscle. This is closely related to the occurrence of secondary testosterone production [47]. Accordingly, patients with prostate cancer, in whom the cell growth is dependent on testosterone level, might be better off refraining from physical exercise. Fasting and Polyamines Fasting and breaking fast dramatically alters small intestinal mucosal growth that is greatly dependent on polyamine biosynthesis and transport [48,49]. The examination of diamine putrescine uptake by brush-border membrane vesicles from the small intestine of rats fasted for 3 days or fed a standard diet after a period of fasting showed 1.85-fold higher putresucine levels than in ad libitum-fed controls. Fasted rats refed for 24 h showed a 31% decrease in Vmax levels, however that value remained 1.27-fold higher than in the control rats. Both polyamine mucosal biosynthesis and intestinal content are altered by fasting. The increased absorption rate may have a modest role in preventing polyamine tissue loss during fasting. Therefore, cancer patients should have low polyamine meals rather than fast. CONCLUSION The most effective combination therapy for cancer patients based on polyamine level is a polyamine-free diet coupled with drugs that reduce cancer-bearing host tissues. To

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[30] [31]

[4] [5] [6] [7] [8]

[32] [33] [34]

[35] [36]

[9] [10]

[37] [38]

[11] [12]

[13] [14] [15] [16]

[39]

[40] [41]

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[49]

Received: November 20, 2008

Revised: March 20, 2009