- Open Access
The mechanisms by which polyamines accelerate tumor spread
Journal of Experimental & Clinical Cancer Research volume 30, Article number: 95 (2011)
Increased polyamine concentrations in the blood and urine of cancer patients reflect the enhanced levels of polyamine synthesis in cancer tissues arising from increased activity of enzymes responsible for polyamine synthesis. In addition to their de novo polyamine synthesis, cells can take up polyamines from extracellular sources, such as cancer tissues, food, and intestinal microbiota. Because polyamines are indispensable for cell growth, increased polyamine availability enhances cell growth. However, the malignant potential of cancer is determined by its capability to invade to surrounding tissues and metastasize to distant organs. The mechanisms by which increased polyamine levels enhance the malignant potential of cancer cells and decrease anti-tumor immunity are reviewed. Cancer cells with a greater capability to synthesize polyamines are associated with increased production of proteinases, such as serine proteinase, matrix metalloproteinases, cathepsins, and plasminogen activator, which can degrade surrounding tissues. Although cancer tissues produce vascular growth factors, their deregulated growth induces hypoxia, which in turn enhances polyamine uptake by cancer cells to further augment cell migration and suppress CD44 expression. Increased polyamine uptake by immune cells also results in reduced cytokine production needed for anti-tumor activities and decreases expression of adhesion molecules involved in anti-tumor immunity, such as CD11a and CD56. Immune cells in an environment with increased polyamine levels lose anti-tumor immune functions, such as lymphokine activated killer activities. Recent investigations revealed that increased polyamine availability enhances the capability of cancer cells to invade and metastasize to new tissues while diminishing immune cells' anti-tumor immune functions.
Polyamines, which include spermidine and spermine, are polycations with three or four amine groups. Almost all cells can produce polyamines, but their production is especially high in rapidly growing cells. Polyamine concentrations are often increased in the blood and urine of cancer patients, and these increased levels have been shown to correlate with poor prognosis . The increased blood and urinary polyamine levels are attributable to increased polyamine synthesis by cancer cells, since these increases can be abolished by complete eradication of tumors by surgery or radio-chemotherapy [2–5]. The capacity of cancer tissue to produce abundant polyamines likely contributes to cancer cells' enhanced growth rates because polyamines are indispensable for cellular growth, which may at least partially explain why cancer patients with increased polyamine levels have a poorer prognosis [4–9]. However, an important factor that determines the malignant potential of cancer cells is the capability of cells to invade to surrounding tissues and to metastasize to distant organs. Therefore, it is important to understand the role of polyamines in cancer invasion and metastasis. In this review, recent experimental results from our and other groups are discussed.
2. What are polyamines?
The natural polyamines, spermidine, and spermine, are found in almost every living cell at high micromolar to low millimolar quantities . Polyamines are synthesized from arginine and s-adenosylmethionine with arginase converting arginine to ornithine, and ornithine decarboxylase (ODC) catalyzing ornithine decarboxylation to form putrescine, a polyamine precursor containing two amine groups (Figure 1). Polyamines are involved in diverse functions involved in cell growth and differentiation, such as DNA synthesis and stability, regulation of transcription, ion channel regulation, and protein phosphorylation [11–14].
Intracellular spermine and spermidine are degraded by spermidine/spermine N1-acetyltransferase (SSAT) and N1-acetylpolyamine oxidase (APAO). SSAT, a highly inducible enzyme, catalyzes the transfer of an acetyl group from acetyl-coenzyme A to the aminopropyl moiety of spermine and spermidine. APAO was previously described as polyamine oxidase but it preferentially catalyzes the oxidation of the N1-acetylspermine and N1-acetylspermidine produced by SSAT activity. This oxidation results in the production of H2O2, 3-acetoaminopropanal, and putrescine or spermidine (Spd), depending on the initial substrate [15–17]. Mammalian spermine oxidase (SMO) is an inducible enzyme that specifically oxidizes spermine, with the production of H2O2, 3-aminopropanal (3AP) and spermidine [16, 17].
In addition to de novo synthesis and degradation, cellular polyamine concentrations are also regulated by transmembrane transport where cells take up polyamines from their surroundings or export them to the extracellular space (Figure 1).
3. Polyamines and cancer
Polyamine biosynthesis is up-regulated in actively growing cells, including cancer cells [10, 18, 19], therefore polyamine concentration as well as gene expression and activity of enzymes involved in polyamine biosynthesis, especially ODC, are higher in cancer tissues than in normal surrounding tissues [8, 20–25].
Numerous reports have shown that both blood and urine polyamine concentrations are often increased in cancer patients [4, 5, 7, 8, 10]. A close correlation between blood polyamine levels and the amount of urinary polyamines has also been found in cancer patients . Moreover, these levels decrease after tumor eradication and increase after relapse [2–5, 23], indicating that polyamines synthesized by cancer tissues are transferred to the blood circulation and kidney, where they are excreted into the urine .
Polyamines are also produced in other parts of the body and can be transported to various organs and tissues such as the intestinal lumen where polyamines are absorbed quickly to increase portal vein polyamine concentrations . The majority of spermine and spermidine in the intestinal lumen is absorbed in their original forms because there is no apparent enzymatic activity present to catalyze their degradation . Polyamines absorbed by the intestinal lumen are distributed to almost all organs and tissues in the body  as demonstrated by the increased blood polyamine levels in animals and humans produced in response to continuous enhanced polyamine intake for six and two months, respectively [30, 31]. However, short-term increased polyamine intake failed to produce such increases [30–32], possibly because of the homeostasis that inhibits acute changes in intracellular polyamine concentration. On the other hand, reductions in blood polyamine concentration were not achieved only by restricting oral polyamine intake. As such, at least two sources of intestinal polyamines are postulated: foods and intestinal microbiota. Decrease in blood polyamine levels can be successfully achieved by eliminating intestinal microbiota in addition to restricting food polyamines . Taken together, these results indicate that polyamines are not only produced by cancer tissues but are also supplied from the intestinal lumen and together appear to influence polyamine levels in the body of cancer patients.
3. Polyamines in the body
In vitro experiments showed that cultured cells take up polyamines from their surroundings [34, 35]. In blood circulation, the majority of polyamines are contained in blood cells, especially in red and white blood cells, and therefore increases in blood polyamine concentration indicate concurrent increases in polyamine levels in blood cells . Similarly, intracellular polyamine concentrations in cells of otherwise normal tissues and organs in cancer patients can be increased . One examination showed that spermidine and spermine levels are increased in the normal colon mucosa of cancer patients compared to the normal colon mucosa from patients without cancer , although another study was unable to detect these differences . Given that polyamine concentrations are increased in the blood cells of cancer patients and numerous blood cells with increased polyamine concentrations exist in normal tissues, the polyamine concentration in normal tissues of cancer patients with increased blood polyamine levels might also be increased. In addition, orally administered radiolabeled polyamines have been shown to be immediately distributed to almost all organs and tissues [29, 39, 40].
Polyamine concentrations in the blood vary considerably among healthy individuals such that concentrations are not necessarily higher in cancer patients than in otherwise normal subjects [41, 42] and this wide variation precludes the use of polyamine levels as a tumor marker as well as making detection of differences in polyamine concentrations in normal tissues of cancer patients and normal subjects difficult. The kinesis of polyamines may allow distant tissues and organs to influence polyamine levels of all cells in an organism.
4. Polyamines and cancer spread
Patients with increased polyamine levels either in the blood or urine are reported to have more advanced disease and worse prognosis compared to those with low levels, regardless of the type of malignancy [4–9]. Because polyamines are essential for cell growth, the increased capability of polyamine synthesis could reflect enhanced tumor proliferation. Therefore, inhibition of polyamine synthesis and availability by cancer cells could retard cancer cell growth. The efficacy of polyamine depletion is prominent in animal experiments. Inhibition of polyamine synthesis by DL-α-difluoromethylornithine (DFMO), an inhibitor of ODC that catalyzes the first rate-limiting step in polyamine biosynthesis, with or without methylglyoxal-bis-guanylhydrazone (MGBG), an inhibitor of S-Adenosylmethionine (SAM) that is required for polyamine synthesis, successfully suppressed tumor growth and prolonged survival of tumor-bearing animals [43–46]. Although the efficacy of polyamine restriction is not as apparent in humans as in animals [47, 48], inhibition of polyamine synthesis by DFMO successfully suppressed the progression of neoplastic disease [49–52].
However, a major factor that directly influences the prognosis of patients with malignant disease is the capability of cancer cells to invade surrounding tissues and organs and evade immune cell defenses to metastasize to distant organs. In animal experiments, inhibition of polyamine synthesis by DFMO and/or MGBG not only reduced tumor growth but also decreased the amount of metastasis, resulting in prolonged survival of tumor bearing animals [43, 44, 46, 53–55]. Therefore, the effect of polyamines on the metastatic potential of cancer cells, the host's anti-tumor immunity, and the corresponding mechanisms involved should be taken into consideration.
5. Mechanism of metastasis and involvement of polyamines (Figure 2)
There are several steps that occur during metastasis: separation of cancer cells from the tumor cluster (5-a); transmigration of cells from the original cluster to the circulation (5-b); and rooting and colonization in new organs and tissues (5-c) [56, 57]. In addition, metastasis is completed only when cancer cells can successfully escape from the anti-tumor immune function of the host during this process (5-d). In this section, the mechanism of cancer metastasis and the involvement of polyamines are discussed.
5-a. Separation of cancer cells from the tumor cluster, and the role of polyamines
Cancer metastasis begins when cancer cells separate from the tumor cluster. This separation is initiated by decreased cell adhesion, which is normally maintained by the presence of adhesion molecules involved in intercellular binding and binding between cells and the extracellular matrix. Hypoxia, a common condition in cancer tissues, exerts a strong pressure on cells to separate from the tumor cluster and migrate into circulation [58, 59]. Despite their de novo angiogenesis, solid tumors have scattered regions where oxygen delivery is compromised due to diffusion limitations, structural abnormalities of tumor microvessels, and disturbed microcirculation . The cellular response to hypoxia involves the stabilization and resultant increase in levels of hypoxia inducible factor-1 (HIF-1), a transcription factor that enhances gene expression to promote angiogenesis, anaerobic metabolism, cell survival, and invasion . Among these, suppression of adhesion molecules induced by hypoxia-induced HIF-1 stabilization is a strong selective pressure that enhances outgrowth of cells with high-grade malignancy. CD44 and E-cadherin are adhesion molecules whose expression decreases in response to hypoxia [62, 63].
In cells exposed to chronic hypoxia, polyamine synthesis is decreased, while the ability to take up polyamines from the surroundings is increased [64, 65]. Cells in a hypoxic environment have a resultant decrease in de novo polyamine synthesis and a concurrent increased capacity to take up polyamines from surrounding tissues, e.g. from cancer cells under normoxic conditions that are capable of producing abundant polyamines. We reported that cancer cells under hypoxia lose regulation of polyamine homeostasis and have increased polyamine uptake from surrounding tissues (Figure 2B, 1) . The expression of the adhesion molecule CD44 is suppressed in response to hypoxia. Reduced CD44 expression is reported to promote cancer metastasis and invasion, allowing detachment of cancer cells from the primary tumor cluster and seems to contribute to the increased migration capacity of hypoxic HT-29 cells [67, 68]. In conjunction with hypoxia, increases in extracellular spermine specifically augmented hypoxia-induced decreases in CD44 expression, and these decreases correlated well with increased migration of cancer cells (HT-29) in a dose-dependent manner . In addition, several experiments indicated a possible role for polyamines in the invasive potential of cancer cells [53, 55, 69].
5-b. Role of polyamines in cancer cell transmigration to the circulation
Cancer invasion is the process in which cancer cells migrate through surrounding tissues and enter into a blood vessel, which enables cancer cells to be transported throughout the body and establish secondary tumors. Blood vessel entry requires that cancer cells not only have increased motility but also secrete enzymes that degrade the surrounding cells' extracellular matrix (ECM), which is composed of the interstitial matrix and basement membrane, and provides structural support to cells. Cancer cells produce various proteinases, such as serine proteinase, matrix metalloproteinases (MMPs), cathepsins, and plasminogen activator that degrade the ECM [70–72]. In addition, cancer cells have the ability to create new blood vessels in the tumor, i.e. angiogenesis, so that cancer cells can obtain supplies of blood and oxygen .
Increased polyamine synthesis appears to be accompanied by cancer invasiveness as ODC overexpression enhances the invasive characteristics of cancer cells . In contrast, inhibition of polyamine synthesis by the ODC inhibitor DFMO attenuates the invasive characteristics of cancer cells [53, 55, 75], and supplementation with polyamine reverses the DFMO-induced decrease in invasive qualities . The close correlation between increased polyamine synthesis and increased MMP synthesis has also been shown using DFMO, which caused decreases in cancer cell expression and concentrations of MMPs, such as matrilysin, meprin, and MMP-7 [76, 77].
As mentioned above, increased polyamine synthesis is also accompanied by angiogenesis that is stimulated by cellular production of several factors, including vascular endothelial growth factor, which allow tumor tissues to grow and survive by obtaining sufficient blood supplies . DFMO has been shown to exert its anti-tumor activity by inhibiting the proliferation of endothelial cells .
5-c. Possible role of polyamines on cell rooting and colonization at secondary tumor sites
Cancer cells that invade blood vessels and escape from immune system detection in circulation anchor to endothelial vasculature to establish new sites of growth. Upon vessel entry, cancer cells have access to abundant oxygen supplies that could enable cancer cells to restore their original activities such as increased gene expression that translates to enhanced enzymatic activities for polyamine synthesis, proteinase, and angiogenesis factors. Considering the results of our study, the expression of CD44 of normoxic cancer cells is higher than that of hypoxic cells , suggesting that the circulating cancer cells possibly recover their original adhesion characteristics. Once cancer cells anchor to the vessel wall of tissues and organs at secondary growth sites, they invade and rapidly grow because of their increased capacity to synthesize polyamines indispensable for cell growth and proteins that degrade the tissue matrix and create new vessels.
5-d. Polyamines help cancer cells escape immune system detection
Immune suppression, often observed in cancer patients, accelerates cancer spread. Various defects in cellular functions indicative of immune suppression have been reported, including attenuated adhesion properties of peripheral blood mononuclear cells (PBMCs) [80–82], impaired production of tumoricidal cytokines and chemokines [83–85], and decreased cytotoxic activity of killer cells, especially lymphokine activated killer (LAK) cells [86–89]. Several investigators have suggested that circulating factors that inhibit host immune activities are present in cancer patients [89–91]. The suppression of immune function in cancer patients can be restored following tumor eradication, further suggesting the presence of increased immunosuppressive substance(s) in cancer patients [83, 84, 89, 91].
The increases in blood polyamine concentrations in cancer patients reflect increased polyamine concentrations in blood cells, mainly in red and white blood cells (Figure 2B, 2). The in vitro effects of polyamines on immune functions were first reported over 30 years ago . However, later analysis revealed that the reported immunosuppressive effects are induced not by the direct effect of polyamines but by substances produced by the interaction between polyamines and serum amine oxidase, present exclusively in ruminants, making these results difficult to extend to humans, which lack this enzyme. Nonetheless, animal experiments have shown that polyamine deprivation prevents the development of tumor-induced immunosuppression .
The adhesion characteristics of immune cells are important for eliciting anti-tumor cytotoxic activity, because adhesion is crucial for immune cell recognition of tumor cells . Due to decreased adhesion, immune cells fail to recognize cancer cells or exert tumoricidal activities. Such decreases in immune cell adhesion are observed not only in cancer patients but also in patients having non-cancerous lesions . These findings suggest the possibility that common factor(s), not specifically produced in cancer patients, can induce immunosuppressive conditions. Polyamines are one such factor, because blood polyamine levels, namely levels in blood cells including immune cells, are often increased in patients with various diseases [36, 95–97].
Immune cells also take up polyamines form their surroundings [98, 99], and the increase in blood polyamine concentrations often observed in cancer patients as well as in patients with other diseases reflects the increased polyamine levels in leukocytes [36, 100]. We have shown that increased concentrations of spermine or spermidine in cultured human PBMCs suppress adhesion without sacrificing cell viability and activity.
The time- and dose-dependent decrease in adhesion produced by polyamines was accompanied by decreases in the expression of lymphocyte function-associated antigen-1 (LFA-1), which consists of an integrin alpha L (CD11a) and beta 2 (CD18) chain . Polyamines in particular decrease the number of cells expressing bright CD11a. Such suppression was exclusively observed for LFA-1 with most other adhesion molecules tested unaffected by polyamines. The suppression of LFA-1 expression by polyamines was further confirmed in human healthy volunteers with polyamines suppressing LFA-1 expression on PBMCs, regardless of the volunteer's age . In addition to LFA-1 suppression by polyamines, the number of CD56 bright cells was decreased by polyamines in vitro, although the effect was not confirmed in vivo. LFA-1 and CD56 contribute to the induction of tumoricidal cell activities, especially lymphokine activated killer (LAK) activity [101, 102]. LAK cells, which have tumoricidal activities against established (existing) tumors, are induced by co-culture with IL-2 [103, 104]. In animal experiments, polyamine deprivation reversed the tumor inoculation-induced suppression of IL-2 production without decreasing the number of T lymphocytes . In addition, polyamines (spermine and spermidine) inhibit the production of tumoricidal cytokines, such as tumor necrosis factor (TNF), and chemokines in vitro, while they do not inhibit production of transforming growth factor beta, which has immunosuppressive properties [105–107]. Conversely, in animal experiments, polyamine deprivation has been shown to enhance chemokine production, reverse tumor inoculation-induced inhibition of killer cell activity, and prevent tumor-induced immune suppression [108, 109].
TNF is able to induce apoptotic cell death and to attack and destroy cancer cells , while LFA-1 and CD56, especially bright CD11a and bright CD56 cells, are required for the induction of LAK cell cytotoxic activity [111, 112]. Polyamines suppress LAK cytotoxicity without decreasing cell viability and activity in vitro, and the changes in blood spermine levels are negatively associated with changes in LAK cytotoxicity in cancer patients .
6. Sources of polyamines other than cancer cells
Food is an important source of polyamines. Polyamines in the intestinal lumen are absorbed quickly and distributed to all organs and tissues [29, 39, 40]. Moreover, continuous intake of polyamine-rich food gradually increases blood polyamine levels [30, 31]. Therefore, the restricted intake of food polyamine and inhibition of polyamine synthesis by microbiota in the intestine with or without inhibitor-induced inhibition of polyamine synthesis is reported to have favorable effects on cancer therapy [33, 113–115].
Trauma, such as surgery, is itself considered to increase the risk of cancer spread through various mechanisms [116–118]. Blood concentration and urinary excretion of polyamines are known to increase after surgery, although the origin of this increase is not well established [97, 119]. Our previous study showed that increases in blood polyamine levels are inversely associated with anti-tumor LAK cytotoxicities in patients who have undergone surgery . In addition to mechanisms previously postulated for post-traumatic cancer spread, post-operative increases in polyamines may be another factor that accelerates tumor growth.
As polyamines are essential for cell growth, one of the mechanisms by which polyamines accelerate tumor growth is through the increased availability of this indispensable growth factor. In addition, polyamines seem to accelerate tumor invasion and metastasis not only by suppressing immune system activity against established (already existing) tumors but also by enhancing the ability of invasive and metastatic capability of cancer cells. When considering the mechanism by which polyamines elicit their biological activities on immune and cancer cell functions, inhibition of polyamine uptake by cells seems to be an important target for polyamine-based cancer therapy particularly because inhibition of polyamine synthesis alone failed to produce a favorable effect on cancer treatments in several clinical trials. In addition to inhibiting polyamine synthesis and supply, inhibition of polyamine uptake via the polyamine transporter may have beneficial effects [120, 121].
hypoxia inducible factor-1
lymphokine activated killer
lymphocyte function-associated antigen-1
peripheral blood mononuclear cells
tumor necrosis factor.
Durie BG, Salmon SE, Russell DH: Polyamines as markers of response and disease activity in cancer chemotherapy. Cancer Res. 1977, 37: 214-221.
Loser C, Folsch UR, Paprotny C, Creutzfeldt W: Polyamines in colorectal cancer. Evaluation of polyamine concentrations in the colon tissue, serum, and urine of 50 patients with colorectal cancer. Cancer. 1990, 65: 958-966. 10.1002/1097-0142(19900215)65:4<958::AID-CNCR2820650423>3.0.CO;2-Z.
Chatel M, Darcel F, Quemener V, Hercouet H, Moulinoux JP: Red blood cell polyamines as biochemical markers of supratentorial malignant gliomas. Anticancer Res. 1987, 7: 33-38.
Kubota S, Okada M, Yoshimoto M, Murata N, Yamasaki Z, Wada T, Imahori K, Ohsawa N, Takaku F: Urinary polyamines as a tumor marker. Cancer Detect Prev. 1985, 8: 189-192.
Uehara N, Shirakawa S, Uchino H, Saeki Y: Elevated contents of spermidine and spermine in the erythrocytes of cancer patients. Cancer. 1980, 45: 108-111. 10.1002/1097-0142(19800101)45:1<108::AID-CNCR2820450120>3.0.CO;2-W.
Cipolla B, Guille F, Moulinoux JP, Bansard JY, Roth S, Staerman F, Corbel L, Quemener V, Lobel B: Erythrocyte polyamines and prognosis in stage D2 prostatic carcinoma patients. J Urol. 1994, 151: 629-633.
Weiss TS, Bernhardt G, Buschauer A, Thasler WE, Dolgner D, Zirngibl H, Jauch KW: Polyamine levels of human colorectal adenocarcinomas are correlated with tumor stage and grade. Int J Colorectal Dis. 2002, 17: 381-387. 10.1007/s00384-002-0394-7.
Linsalata M, Caruso MG, Leo S, Guerra V, D'Attoma B, Di Leo A: Prognostic value of tissue polyamine levels in human colorectal carcinoma. Anticancer Res. 2002, 22: 2465-2469.
Bergeron C, Bansard JY, Le Moine P, Bouet F, Goasguen JE, Moulinoux JP, Le Gall E, Catros-Quemener V: Erythrocyte spermine levels: a prognostic parameter in childhood common acute lymphoblastic leukemia. Leukemia. 1997, 11: 31-36. 10.1038/sj.leu.2400531.
Russell DH: Clinical relevance of polyamines. Crit Rev Clin Lab Sci. 1983, 18: 261-311.
Hochman J, Katz A, Bachrach U: Polyamines and protein kinase II. Effect of polyamines on cyclic AMP--dependent protein kinase from rat liver. Life Sci. 1978, 22: 1481-1484. 10.1016/0024-3205(78)90002-4.
Tabib A, Bachrach U: Activation of the proto-oncogene c-myc and c-fos by c-ras: involvement of polyamines. Biochem Biophys Res Commun. 1994, 202: 720-727. 10.1006/bbrc.1994.1990.
Panagiotidis CA, Artandi S, Calame K, Silverstein SJ: Polyamines alter sequence-specific DNA-protein interactions. Nucleic Acids Res. 1995, 23: 1800-1809. 10.1093/nar/23.10.1800.
Childs AC, Mehta DJ, Gerner EW: Polyamine-dependent gene expression. Cell Mol Life Sci. 2003, 60: 1394-1406. 10.1007/s00018-003-2332-4.
Seiler N: Polyamine oxidase, properties and functions. Prog Brain Res. 1995, 106: 333-344.
Casero RA, Pegg AE: Polyamine catabolism and disease. Biochem J. 2009, 421: 323-338. 10.1042/BJ20090598.
Pegg AE: Mammalian polyamine metabolism and function. IUBMB Life. 2009, 61: 880-894. 10.1002/iub.230.
Gerner EW, Meyskens FL: Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer. 2004, 4: 781-792. 10.1038/nrc1454.
Erdman SH, Ignatenko NA, Powell MB, Blohm-Mangone KA, Holubec H, Guillen-Rodriguez JM, Gerner EW: APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the Min mouse. Carcinogenesis. 1999, 20: 1709-1713. 10.1093/carcin/20.9.1709.
Becciolini A, Porciani S, Lanini A, Balzi M, Cionini L, Bandettini L: Polyamine levels in healthy and tumor tissues of patients with colon adenocarcinoma. Dis Colon Rectum. 1991, 34: 167-173. 10.1007/BF02049993.
Canizares F, Salinas J, de las Heras M, Diaz J, Tovar I, Martinez P, Penafiel R: Prognostic value of ornithine decarboxylase and polyamines in human breast cancer: correlation with clinicopathologic parameters. Clin Cancer Res. 1999, 5: 2035-2041.
Radford DM, Nakai H, Eddy RL, Haley LL, Byers MG, Henry WM, Lawrence DD, Porter CW, Shows TB: Two chromosomal locations for human ornithine decarboxylase gene sequences and elevated expression in colorectal neoplasia. Cancer Res. 1990, 50: 6146-6153.
Kingsnorth AN, Lumsden AB, Wallace HM: Polyamines in colorectal cancer. Br J Surg. 1984, 71: 791-794. 10.1002/bjs.1800711019.
LaMuraglia GM, Lacaine F, Malt RA: High ornithine decarboxylase activity and polyamine levels in human colorectal neoplasia. Ann Surg. 1986, 204: 89-93. 10.1097/00000658-198607000-00013.
Takenoshita S, Matsuzaki S, Nakano G, Kimura H, Hoshi H, Shoda H, Nakamura T: Selective elevation of the N1-acetylspermidine level in human colorectal adenocarcinomas. Cancer Res. 1984, 44: 845-847.
Moulinoux JP, Quemener V, Khan NA, Delcros JG, Havouis R: Spermidine uptake by erythrocytes from normal and Lewis lung carcinoma (3LL) grafted mice: I. In vitro study. Anticancer Res. 1989, 9: 1057-1062.
Uda K, Tsujikawa T, Fujiyama Y, Bamba T: Rapid absorption of luminal polyamines in a rat small intestine ex vivo model. J Gastroenterol Hepatol. 2003, 18: 554-559. 10.1046/j.1440-1746.2003.03020.x.
Bardocz S, Brown DS, Grant G, Pusztai A: Luminal and basolateral polyamine uptake by rat small intestine stimulated to grow by Phaseolus vulgaris lectin phytohaemagglutinin in vivo. Biochim Biophys Acta. 1990, 1034: 46-52.
Bardocz S, Grant G, Brown DS, Ralph A, Pusztai A: Polyamines in food--implications for growth and health. J Nutr Biochem. 1993, 4: 66-71. 10.1016/0955-2863(93)90001-D.
Soda K, Kano Y, Sakuragi M, Takao K, Lefor A, Konishi F: Long-term oral polyamine intake increases blood polyamine concentrations. J Nutr Sci Vitaminol (Tokyo). 2009, 55: 361-366. 10.3177/jnsv.55.361.
Soda K, Dobashi Y, Kano Y, Tsujinaka S, Konishi F: Polyamine-rich food decreases age-associated pathology and mortality in aged mice. Exp Gerontol. 2009, 44: 727-732. 10.1016/j.exger.2009.08.013.
Brodal BP, Eliassen KA, Ronning H, Osmundsen H: Effects of dietary polyamines and clofibrate on metabolism of polyamines in the rat. J Nutr Biochem. 1999, 10: 700-708. 10.1016/S0955-2863(99)00058-3.
Sarhan S, Knodgen B, Seiler N: The gastrointestinal tract as polyamine source for tumor growth. Anticancer Res. 1989, 9: 215-223.
D'Agostino L, Pignata S, Daniele B, D'Adamo G, Ferraro C, Silvestro G, Tagliaferri P, Contegiacomo A, Gentile R, Tritto G, et al: Polyamine uptake by human colon carcinoma cell line CaCo-2. Digestion. 1990, 46 (Suppl 2): 352-359.
Feige JJ, Chambaz EM: Polyamine uptake by bovine adrenocortical cells. Biochim Biophys Acta. 1985, 846: 93-100. 10.1016/0167-4889(85)90114-4.
Cooper KD, Shukla JB, Rennert OM: Polyamine compartmentalization in various human disease states. Clin Chim Acta. 1978, 82: 1-7.
Upp JR, Saydjari R, Townsend CM, Singh P, Barranco SC, Thompson JC: Polyamine levels and gastrin receptors in colon cancers. Ann Surg. 1988, 207: 662-669. 10.1097/00000658-198806000-00004.
Hixson LJ, Garewal HS, McGee DL, Sloan D, Fennerty MB, Sampliner RE, Gerner EW: Ornithine decarboxylase and polyamines in colorectal neoplasia and mucosa. Cancer Epidemiol Biomarkers Prev. 1993, 2: 369-374.
Osborne DL, Seidel ER: Gastrointestinal luminal polyamines: cellular accumulation and enterohepatic circulation. Am J Physiol. 1990, 258: G576-584.
Kobayashi M, Xu YJ, Samejima K, Goda H, Niitsu M, Takahashi M, Hashimoto Y: Fate of orally administered 15N-labeled polyamines in rats bearing solid tumors. Biol Pharm Bull. 2003, 26: 285-288. 10.1248/bpb.26.285.
Soda K, Kano Y, Nakamura T, Kasono K, Kawakami M, Konishi F: Spermine, a natural polyamine, suppresses LFA-1 expression on human lymphocyte. J Immunol. 2005, 175: 237-245.
Kano Y, Soda K, Nakamura T, Saitoh M, Kawakami M, Konishi F: Increased blood spermine levels decrease the cytotoxic activity of lymphokine-activated killer cells: a novel mechanism of cancer evasion. Cancer Immunol Immunother. 2007, 56: 771-781. 10.1007/s00262-006-0229-4.
Klein S, Miret JJ, Algranati ID, de Lustig ES: Effect of alpha-difluoromethylornithine in lung metastases before and after surgery of primary adenocarcinoma tumors in mice. Biol Cell. 1985, 53: 33-36.
Herr HW, Kleinert EL, Conti PS, Burchenal JH, Whitmore WF: Effects of alpha-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) on the growth of experimental renal adenocarcinoma in mice. Cancer Res. 1984, 44: 4382-4385.
Luk GD, Abeloff MD, Griffin CA, Baylin SB: Successful treatment with DL-alpha-difluoromethylornithine in established human small cell variant lung carcinoma implants in athymic mice. Cancer Res. 1983, 43: 4239-4243.
Kingsnorth AN, McCann PP, Diekema KA, Ross JS, Malt RA: Effects of alpha-difluoromethylornithine on the growth of experimental Wilms' tumor and renal adenocarcinoma. Cancer Res. 1983, 43: 4031-4034.
Prados MD, Wara WM, Sneed PK, McDermott M, Chang SM, Rabbitt J, Page M, Malec M, Davis RL, Gutin PH, et al: Phase III trial of accelerated hyperfractionation with or without difluromethylornithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2001, 49: 71-77. 10.1016/S0360-3016(00)01458-9.
Messing E, Kim KM, Sharkey F, Schultz M, Parnes H, Kim D, Saltzstein D, Wilding G: Randomized prospective phase III trial of difluoromethylornithine vs placebo in preventing recurrence of completely resected low risk superficial bladder cancer. J Urol. 2006, 176: 500-504. 10.1016/j.juro.2006.03.061.
Meyskens FL, McLaren CE, Pelot D, Fujikawa-Brooks S, Carpenter PM, Hawk E, Kelloff G, Lawson MJ, Kidao J, McCracken J, et al: Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res (Phila). 2008, 1: 32-38. 10.1158/1940-6207.CAPR-08-0042.
Quemener V, Moulinoux JP, Havouis R, Seiler N: Polyamine deprivation enhances antitumoral efficacy of chemotherapy. Anticancer Res. 1992, 12: 1447-1453.
Thompson PA, Wertheim BC, Zell JA, Chen WP, McLaren CE, LaFleur BJ, Meyskens FL, Gerner EW: Levels of rectal mucosal polyamines and prostaglandin E2 predict ability of DFMO and sulindac to prevent colorectal adenoma. Gastroenterology. 2010, 139: 797-805. 10.1053/j.gastro.2010.06.005. 805 e791
Levin VA, Hess KR, Choucair A, Flynn PJ, Jaeckle KA, Kyritsis AP, Yung WK, Prados MD, Bruner JM, Ictech S, et al: Phase III randomized study of postradiotherapy chemotherapy with combination alpha-difluoromethylornithine-PCV versus PCV for anaplastic gliomas. Clin Cancer Res. 2003, 9: 981-990.
Jun JY, Griffith JW, Bruggeman R, Washington S, Demers LM, Verderame MF, Manni A: Effects of polyamine depletion by alpha-difluoromethylornithine on in vitro and in vivo biological properties of 4T1 murine mammary cancer cells. Breast Cancer Res Treat. 2008, 107: 33-40.
Kubota S, Ohsawa N, Takaku F: Effects of DL-alpha-difluoromethylornithine on the growth and metastasis of B16 melanoma in vivo. Int J Cancer. 1987, 39: 244-247. 10.1002/ijc.2910390220.
Manni A, Washington S, Hu X, Griffith JW, Bruggeman R, Demers LM, Mauger D, Verderame MF: Effects of polyamine synthesis inhibitors on primary tumor features and metastatic capacity of human breast cancer cells. Clin Exp Metastasis. 2005, 22: 255-263. 10.1007/s10585-005-8480-1.
MacDonald NJ, Steeg PS: Molecular basis of tumour metastasis. Cancer Surv. 1993, 16: 175-199.
Liotta LA, Rao CN, Barsky SH: Tumor invasion and the extracellular matrix. Lab Invest. 1983, 49: 636-649.
Klymkowsky MW, Savagner P: Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe. Am J Pathol. 2009, 174: 1588-1593. 10.2353/ajpath.2009.080545.
Pouyssegur J, Dayan F, Mazure NM: Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006, 441: 437-443. 10.1038/nature04871.
Hockel M, Vaupel P: Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001, 93: 266-276. 10.1093/jnci/93.4.266.
Harris AL: Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer. 2002, 2: 38-47. 10.1038/nrc704.
Beavon IR: Regulation of E-cadherin: does hypoxia initiate the metastatic cascade?. Mol Pathol. 1999, 52: 179-188. 10.1136/mp.52.4.179.
Hasan NM, Adams GE, Joiner MC, Marshall JF, Hart IR: Hypoxia facilitates tumour cell detachment by reducing expression of surface adhesion molecules and adhesion to extracellular matrices without loss of cell viability. Br J Cancer. 1998, 77: 1799-1805. 10.1038/bjc.1998.299.
Tantini B, Fiumana E, Cetrullo S, Pignatti C, Bonavita F, Shantz LM, Giordano E, Muscari C, Flamigni F, Guarnieri C, et al: Involvement of polyamines in apoptosis of cardiac myoblasts in a model of simulated ischemia. J Mol Cell Cardiol. 2006, 40: 775-782. 10.1016/j.yjmcc.2006.03.002.
Aziz SM, Olson JW, Gillespie MN: Multiple polyamine transport pathways in cultured pulmonary artery smooth muscle cells: regulation by hypoxia. Am J Respir Cell Mol Biol. 1994, 10: 160-166.
Tsujinaka S, Soda K, Kano Y, Konishi F: Spermine accelerates hypoxia-initiated cancer cell migration. Int J Oncol. 2011, 38: 305-312.
De Marzo AM, Bradshaw C, Sauvageot J, Epstein JI, Miller GJ: CD44 and CD44v6 downregulation in clinical prostatic carcinoma: relation to Gleason grade and cytoarchitecture. Prostate. 1998, 34: 162-168. 10.1002/(SICI)1097-0045(19980215)34:3<162::AID-PROS2>3.0.CO;2-K.
Kallakury BV, Yang F, Figge J, Smith KE, Kausik SJ, Tacy NJ, Fisher HA, Kaufman R, Figge H, Ross JS: Decreased levels of CD44 protein and mRNA in prostate carcinoma. Correlation with tumor grade and ploidy. Cancer. 1996, 78: 1461-1469. 10.1002/(SICI)1097-0142(19961001)78:7<1461::AID-CNCR13>3.0.CO;2-Y.
Sunkara PS, Rosenberger AL: Antimetastatic activity of DL-alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis, in mice. Cancer Res. 1987, 47: 933-935.
Basset P, Okada A, Chenard MP, Kannan R, Stoll I, Anglard P, Bellocq JP, Rio MC: Matrix metalloproteinases as stromal effectors of human carcinoma progression: therapeutic implications. Matrix Biol. 1997, 15: 535-541. 10.1016/S0945-053X(97)90028-7.
Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM: Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol. 2000, 18: 1135-1149.
Kessenbrock K, Plaks V, Werb Z: Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010, 141: 52-67. 10.1016/j.cell.2010.03.015.
Dvorak HF, Weaver VM, Tlsty TD, Bergers G: Tumor microenvironment and progression. J Surg Oncol. 2011, 103: 468-474. 10.1002/jso.21709.
Kubota S, Kiyosawa H, Nomura Y, Yamada T, Seyama Y: Ornithine decarboxylase overexpression in mouse 10T1/2 fibroblasts: cellular transformation and invasion. J Natl Cancer Inst. 1997, 89: 567-571. 10.1093/jnci/89.8.567.
Ashida Y, Kido J, Kinoshita F, Nishino M, Shinkai K, Akedo H, Inoue H: Putrescine-dependent invasive capacity of rat ascites hepatoma cells. Cancer Res. 1992, 52: 5313-5316.
Wallon UM, Shassetz LR, Cress AE, Bowden GT, Gerner EW: Polyamine-dependent expression of the matrix metalloproteinase matrilysin in a human colon cancer-derived cell line. Mol Carcinog. 1994, 11: 138-144. 10.1002/mc.2940110304.
Matters GL, Manni A, Bond JS: Inhibitors of polyamine biosynthesis decrease the expression of the metalloproteases meprin alpha and MMP-7 in hormone-independent human breast cancer cells. Clin Exp Metastasis. 2005, 22: 331-339. 10.1007/s10585-005-0660-5.
Auvinen M, Laine A, Paasinen-Sohns A, Kangas A, Kangas L, Saksela O, Andersson LC, Holtta E: Human ornithine decarboxylase-overproducing NIH3T3 cells induce rapidly growing, highly vascularized tumors in nude mice. Cancer Res. 1997, 57: 3016-3025.
Takigawa M, Enomoto M, Nishida Y, Pan HO, Kinoshita A, Suzuki F: Tumor angiogenesis and polyamines: alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, inhibits B16 melanoma-induced angiogenesis in ovo and the proliferation of vascular endothelial cells in vitro. Cancer Res. 1990, 50: 4131-4138.
Hersh EM, Gschwind C, Morris DL, Murphy S: Deficient strongly adherent monocytes in the peripheral blood of cancer patients. Cancer Immunol Immunother. 1982, 14: 105-109.
Grosser N, Marti JH, Proctor JW, Thomson DM: Tube leukocyte adherence inhibition assay for the detection of anti-tumor immunity. I. Monocyte is the reactive cell. Int J Cancer. 1976, 18: 39-47. 10.1002/ijc.2910180107.
MacFarlane JK, Thomson DM, Phelan K, Shenouda G, Scanzano R: Predictive value of tube leukocyte adherence inhibition (LAI) assay for breast, colorectal, stomach and pancreatic cancer. Cancer. 1982, 49: 1185-1193. 10.1002/1097-0142(19820315)49:6<1185::AID-CNCR2820490620>3.0.CO;2-E.
Heriot AG, Marriott JB, Cookson S, Kumar D, Dalgleish AG: Reduction in cytokine production in colorectal cancer patients: association with stage and reversal by resection. Br J Cancer. 2000, 82: 1009-1012. 10.1054/bjoc.1999.1034.
Rampone B, Rampone A, Tirabasso S, Panariello S, Rampone N: Immunological variations in women suffering from ovarian cancer. Influence of radical surgical treatment. Minerva Ginecol. 2001, 53: 116-119.
Monson JR, Ramsden C, Guillou PJ: Decreased interleukin-2 production in patients with gastrointestinal cancer. Br J Surg. 1986, 73: 483-486. 10.1002/bjs.1800730620.
Wood NL, Kitces EN, Blaylock WK: Depressed lymphokine activated killer cell activity in mycosis fungoides. A possible marker for aggressive disease. Arch Dermatol. 1990, 126: 907-913. 10.1001/archderm.126.7.907.
Hermann GG, Petersen KR, Steven K, Zeuthen J: Reduced LAK cytotoxicity of peripheral blood mononuclear cells in patients with bladder cancer: decreased LAK cytotoxicity caused by a low incidence of CD56+ and CD57+ mononuclear blood cells. J Clin Immunol. 1990, 10: 311-320. 10.1007/BF00917476.
Funk J, Schmitz G, Failing K, Burkhardt E: Natural killer (NK) and lymphokine-activated killer (LAK) cell functions from healthy dogs and 29 dogs with a variety of spontaneous neoplasms. Cancer Immunol Immunother. 2005, 54: 87-92. 10.1007/s00262-004-0555-3.
Balch CM, Itoh K, Tilden AB: Cellular immune defects in patients with melanoma involving interleukin-2-activated lymphocyte cytotoxicity and a serum suppressor factor. Surgery. 1985, 98: 151-157.
Hersey P, Bindon C, Czerniecki M, Spurling A, Wass J, McCarthy WH: Inhibition of interleukin 2 production by factors released from tumor cells. J Immunol. 1983, 131: 2837-2842.
Taylor DD, Bender DP, Gercel-Taylor C, Stanson J, Whiteside TL: Modulation of TcR/CD3-zeta chain expression by a circulating factor derived from ovarian cancer patients. Br J Cancer. 2001, 84: 1624-1629. 10.1054/bjoc.2001.1847.
Byrd WJ, Jacobs DM, Amoss MS: Synthetic polyamines added to cultures containing bovine sera reversibly inhibit in vitro parameters of immunity. Nature. 1977, 267: 621-623. 10.1038/267621a0.
Chamaillard L, Catros-Quemener V, Delcros JG, Bansard JY, Havouis R, Desury D, Commeurec A, Genetet N, Moulinoux JP: Polyamine deprivation prevents the development of tumour-induced immune suppression. Br J Cancer. 1997, 76: 365-370. 10.1038/bjc.1997.391.
Lotzova E, Savary CA, Totpal K, Schachner J, Lichtiger B, McCredie KB, Freireich EJ: Highly oncolytic adherent lymphocytes: therapeutic relevance for leukemia. Leuk Res. 1991, 15: 245-254. 10.1016/0145-2126(91)90127-F.
Loser C, Folsch UR, Paprotny C, Creutzfeldt W: Polyamine concentrations in pancreatic tissue, serum, and urine of patients with pancreatic cancer. Pancreas. 1990, 5: 119-127. 10.1097/00006676-199003000-00001.
Nishiguchi S, Tamori A, Koh N, Fujimoto S, Takeda T, Shiomi S, Oka H, Yano Y, Otani S, Kuroki T: Erythrocyte-binding polyamine as a tumor growth marker for human hepatocellular carcinoma. Hepatogastroenterology. 2002, 49: 504-507.
Nishioka K, Romsdahl MM, McMurtrey MJ: Serum polyamine alterations in surgical patients with colorectal carcinoma. J Surg Oncol. 1977, 9: 555-562. 10.1002/jso.2930090605.
Colombatto S, Fasulo L, Fulgosi B, Grillo MA: Transport and metabolism of polyamines in human lymphocytes. Int J Biochem. 1990, 22: 489-492. 10.1016/0020-711X(90)90262-2.
Bardocz S, Grant G, Brown DS, Ewen SW, Nevison I, Pusztai A: Polyamine metabolism and uptake during Phaseolus vulgaris lectin, PHA-induced growth of rat small intestine. Digestion. 1990, 46 (Suppl 2): 360-366.
Cohen LF, Lundgren DW, Farrell PM: Distribution of spermidine and spermine in blood from cystic fibrosis patients and control subjects. Blood. 1976, 48: 469-475.
Ellis TM, Fisher RI: Functional heterogeneity of Leu 19"bright"+ and Leu 19"dim"+ lymphokine-activated killer cells. J Immunol. 1989, 142: 2949-2954.
Weil-Hillman G, Fisch P, Prieve AF, Sosman JA, Hank JA, Sondel PM: Lymphokine-activated killer activity induced by in vivo interleukin 2 therapy: predominant role for lymphocytes with increased expression of CD2 and leu19 antigens but negative expression of CD16 antigens. Cancer Res. 1989, 49: 3680-3688.
Mule JJ, Shu S, Schwarz SL, Rosenberg SA: Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science. 1984, 225: 1487-1489. 10.1126/science.6332379.
Rosenberg SA, Mule JJ, Spiess PJ, Reichert CM, Schwarz SL: Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med. 1985, 161: 1169-1188. 10.1084/jem.161.5.1169.
Soda K, Kano Y, Nakamura T, Kawakami M, Konishi F: Spermine and spermidine induce some of the immune suppression observed in cancer patients. Annals of Cancer Research and Therapy. 2003, 11: 243-253.
Zhang M, Caragine T, Wang H, Cohen PS, Botchkina G, Soda K, Bianchi M, Ulrich P, Cerami A, Sherry B, Tracey KJ: Spermine inhibits proinflammatory cytokine synthesis in human mononuclear cells: a counterregulatory mechanism that restrains the immune response. J Exp Med. 1997, 185: 1759-1768. 10.1084/jem.185.10.1759.
Hasko G, Kuhel DG, Marton A, Nemeth ZH, Deitch EA, Szabo C: Spermine differentially regulates the production of interleukin-12 p40 and interleukin-10 and suppresses the release of the T helper 1 cytokine interferon-gamma. Shock. 2000, 14: 144-149. 10.1097/00024382-200014020-00012.
Bowlin TL, McKown BJ, Sunkara PS: The effect of alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis, on mitogen-induced interleukin 2 production. Immunopharmacology. 1987, 13: 143-147. 10.1016/0162-3109(87)90051-8.
Chamaillard L, Quemener V, Havouis R, Moulinoux JP: Polyamine deprivation stimulates natural killer cell activity in cancerous mice. Anticancer Res. 1993, 13: 1027-1033.
Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B: An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA. 1975, 72: 3666-3670. 10.1073/pnas.72.9.3666.
Wacholtz MC, Patel SS, Lipsky PE: Leukocyte function-associated antigen 1 is an activation molecule for human T cells. J Exp Med. 1989, 170: 431-448. 10.1084/jem.170.2.431.
Ferrini S, Sforzini S, Cambiaggi A, Poggi A, Meazza R, Canevari S, Colnaghi MI, Moretta L: The LFA-1/ICAM cell adhesion pathway is involved in tumor-cell lysis mediated by bispecific monoclonal-antibody-targeted T lymphocytes. Int J Cancer. 1994, 56: 846-852. 10.1002/ijc.2910560616.
Sarhan S, Weibel M, Seiler N: Effect of polyamine deprivation on the survival of intracranial glioblastoma bearing rats. Anticancer Res. 1991, 11: 987-992.
Seiler N, Sarhan S, Grauffel C, Jones R, Knodgen B, Moulinoux JP: Endogenous and exogenous polyamines in support of tumor growth. Cancer Res. 1990, 50: 5077-5083.
Cipolla BG, Havouis R, Moulinoux JP: Polyamine reduced diet (PRD) nutrition therapy in hormone refractory prostate cancer patients. Biomed Pharmacother. 2010, 64: 363-368. 10.1016/j.biopha.2009.09.022.
Page GG, Ben-Eliyahu S, Liebeskind JC: The role of LGL/NK cells in surgery-induced promotion of metastasis and its attenuation by morphine. Brain Behav Immun. 1994, 8: 241-250. 10.1006/brbi.1994.1022.
Pollock RE, Babcock GF, Romsdahl MM, Nishioka K: Surgical stress-mediated suppression of murine natural killer cell cytotoxicity. Cancer Res. 1984, 44: 3888-3891.
Hattori T, Hamai Y, Harada T, Ikeda H, Ikeda T: Enhancing effect of thoracotomy and/or laparotomy on the development of the lung metastases in rats after intravenous inoculation of tumor cells. Jpn J Surg. 1977, 7: 263-268. 10.1007/BF02469360.
Tsukamoto T, Kinoshita H, Hirohashi K, Kubo S, Otani S: Human erythrocyte polyamine levels after partial hepatectomy. Hepatogastroenterology. 1997, 44: 744-750.
Aziz SM, Gillespie MN, Crooks PA, Tofiq SF, Tsuboi CP, Olson JW, Gosland MP: The potential of a novel polyamine transport inhibitor in cancer chemotherapy. J Pharmacol Exp Ther. 1996, 278: 185-192.
Chen Y, Weeks RS, Burns MR, Boorman DW, Klein-Szanto A, O'Brien TG: Combination therapy with 2-difluoromethylornithine and a polyamine transport inhibitor against murine squamous cell carcinoma. Int J Cancer. 2006, 118: 2344-2349. 10.1002/ijc.21621.
The authors declare that they have no competing interests.
KS contributed solely to the writing and submission of this work.