Abstract
Polyamines are aliphatic cations present in all cells. In normal cells, polyamine levels are intricately controlled by biosynthetic and catabolic enzymes. The biosynthetic enzymes are ornithine decarboxylase, S‐adenosylmethionine decarboxylase, spermidine synthase, and spermine synthase. The catabolic enzymes include spermidine/spermine acetyltransferase, flavin containing polyamine oxidase, copper containing diamine oxidase, and possibly other amine oxidases. Multiple abnormalities in the control of polyamine metabolism and uptake might be responsible for increased levels of polyamines in cancer cells as compared to that of normal cells. This review is designed to look at the current research in polyamine biosynthesis, catabolism, and transport pathways, enumerate the functions of polyamines, and assess the potential for using polyamine metabolism or function as targets for cancer therapy.
Keywords: polyamines, cancer, ornithine decarboxylase
References
- 1. Russell D. H., Ornithine decarboxylase as a biological and pharmacological tool, Pharmacology, 20: 117–129, 1980. [DOI] [PubMed] [Google Scholar]
- 2. Pegg A. E., McCann P. P., Polyamine metabolism and function, Am. J. Physiol., 243: C212–221, 1982. [DOI] [PubMed] [Google Scholar]
- 3. Tabor C. W., Tabor H., Polyamines, Annu. Rev. Biochem., 53: 749–790, 1984. [DOI] [PubMed] [Google Scholar]
- 4. Thomas T., Thomas T. J., Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications, Cell. Mol. Life Sci., 58: 244–258, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Casero R. A., Pegg A. E., The turning point in polyamine metabolism, FASEB J., 7: 653–661, 1993. [PubMed] [Google Scholar]
- 6. Morgan D. M. L., Polyamines, An overview. Mol. Biotechnol., 11: 229–250, 1999. [DOI] [PubMed] [Google Scholar]
- 7. Seiler N., Delcros J. G., Moulinox J. P., Polyamine transport in mammalian cells. An update, Int. J. Biochem. Cell Biol., 28: 843–861, 1996. [DOI] [PubMed] [Google Scholar]
- 8. Zhu C., Lang D. W., Coffino P., Antizyme 2 is a negative regulator of ornithine decarboxylase and polyamine transport, J. Biol. Chem., 274: 26425–26430, 1999. [DOI] [PubMed] [Google Scholar]
- 9. Behe M., Felsenfeld G., Effects of methylation on a synthetic polynucleotide: the B to Z transition in polydG‐m5dC).poly(dG‐m5dC), Proc. Natl. Acad. Sci. U. S. A., 78: 1619–1623, 1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Thomas T. J., Messner R. P., Structural specificity of polyamines in left‐handed Z‐DNA formation, Immunological and spectroscopic studies, J. Mol. Biol., 201: 463–467, 1988. [DOI] [PubMed] [Google Scholar]
- 11. Peng H. F., Jackson V., In vitro studies on the maintenance of transcription‐induced stress by histones and polyamines, J. Biol. Chem., 275: 657–668, 2000. [DOI] [PubMed] [Google Scholar]
- 12. Weiss M. A., Floppy SOX: mutual induced fit in hmg (high‐mobility group) box‐ DNA recognition, Mol. Endocrinol., 15: 353–362, 2001. [DOI] [PubMed] [Google Scholar]
- 13. Schroth G. P., Chou P. F. J., Ho P. S., Mapping Z‐DNA in the human genome. Computer‐aided mapping reveals nonrandom distribution of potential Z‐DNA‐ forming sequences in human genes, J. Biol. Chem., 267: 11846–11855, 1992. [PubMed] [Google Scholar]
- 14. Rothenburg S., Koch‐Nolte F., Rich A., Haag F., A polymorphic dinucleotide repeat in the rat nucleolin gene forms Z‐DNA and inhibits promoter activity, Proc. Natl. Acad. Sci. U. S. A., 98: 8985–8990, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Thomas T., Gallo M. A., Klinge C. M., Thomas T. J., Polyamine‐induced conformational perturbations in DNA alter the binding of estrogen receptor to poly(dG‐m5dC).poly(dG‐m5dC) and a plasmid containing estrogen response element, J. Steroid Biochem. Mol. Biol., 54: 89–99, 1995. [DOI] [PubMed] [Google Scholar]
- 16. Panagiotidis C. A., Artandi S., Calame K., Silverstein S. J., Polyamines alter sequence‐specific DNA‐protein interactions, Nucleic Acids Res., 23: 1800–1809, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Shah N., Thomas T. J, Lewis J. S., Klinge C. M., Shirahata A., Gelinas C., Thomas T., Regulation of estrogenic and nuclear factor kB functions by polyamines and their role in polyamine analog‐induced apoptosis of breast cancer cells, Oncogene, 20: 1715–1729, 2001. [DOI] [PubMed] [Google Scholar]
- 18. Desiderio M. A., Dansi P., Tacchini L., Bernelli‐Zazzera A., Influence of polyamines on DNA binding of heat shock and activator protein 1 transcription factors induced by heat shock, FEBS Lett., 455: 149–153, 1999. [DOI] [PubMed] [Google Scholar]
- 19. Johnson T. D., Polyamines and cerebral ischemia, Prog. Drug. Res., 50: 193–258, 1998. [DOI] [PubMed] [Google Scholar]
- 20. Yamakura T., Shimoji K., Subunit‐ and site‐specific pharmacology of the NMDA receptor channel, Prog. Neurobiol., 59: 279–98, 1999. [DOI] [PubMed] [Google Scholar]
- 21. Littleton J. M., Lovinger D., Liljequist S., Ticku R., Matsumoto I., Barron S., Role of polyamines and NMDA receptors in ethanol dependence and withdrawal, Alcohol Clin. Exp. Res., 25: 132S–136S, 2001. [DOI] [PubMed] [Google Scholar]
- 22. Thomas T., Kiang D. T., Structural alterations and stabilization of rabbit uterine estrogen receptors by natural polyamines, Cancer Res., 47: 1799–804, 1987. [PubMed] [Google Scholar]
- 23. Thomas T., Shah N., Klinge C. M., Faaland C. A., Adihkarakunnathu S., Gallo M. A., Thomas T. J., Polyamine biosynthesis inhibitors alter protein‐ protein interactions involving estrogen receptor in MCF‐7 breast cancer cells, J. Mol. Endocrinol., 22: 131–139, 1999. [DOI] [PubMed] [Google Scholar]
- 24. Maeda Y., Rachez C., Hawel L. 3rd, Byus C. V., Freedman L. P., Sladek F. M., Polyamines modulate the interaction between nuclear receptors and vitamin D receptor‐interacting protein, Mol. Endocrinol., 16: 1502–10, 2002. [DOI] [PubMed] [Google Scholar]
- 25. Seiler N., Functions of polyamine acetylation, Can. J. Physiol. Pharmacol., 65: 2024–35, 1987. [DOI] [PubMed] [Google Scholar]
- 26. Mudumba S., Menezes A., Fries D., Blankenship J., Differentiation of PC12 cells induced by N8‐acetylspermidine and by N8‐acetylspermidine deacetylase inhibition, Biochem. Pharmacol., 63: 2011–2018, 2002. [DOI] [PubMed] [Google Scholar]
- 27. Gundogus‐Ozcanli N., Sayilir C., Criss W. E., Effects of polyamines, polyamine synthesis inhibitors, and polyamine analogs on casein kinase II using Myc oncoprotein as substrate, Biochem. Pharmacol., 58: 251–254, 1999. [DOI] [PubMed] [Google Scholar]
- 28. Bauer P. M., Buga G. M., Ignarro L. J., Role of p42/p44 mitogen‐activated‐ protein kinase and p21WAF1/CIP1 in the regulation of vascular smooth muscle cell proliferation by nitric oxide, Proc. Natl. Acad. Sci. U.S.A., 98: 12802–7, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Gartel A. L., Tyner A. L., The role of the cyclin‐dependent kinase inhibitor p21 in apoptosis, Mol. Cancer Ther., 1: 639–649, 2002. [PubMed] [Google Scholar]
- 30. Flamigni F., Facchini A., Capanni C., Stefanelli C., Tantini B., Caldarera C. M., p44/42 mitogen‐activated protein kinase is involved in the expression of ornithine decarboxylase in leukaemia L1210 cells, Biochem J., 341: 363–369, 1999. [PMC free article] [PubMed] [Google Scholar]
- 31. Manni A., Wechter R., Gilmour S., Verderame M. F., Mauger D., Demers L. M., Ornithine decarboxylase over‐expression stimulates mitogen‐activated protein kinase and anchorage‐independent growth of human breast epithelial cells. Int. J. Cancer., 70: 175–182, 1997. [DOI] [PubMed] [Google Scholar]
- 32. O'Brien T. G., Simsiman R. C., Boutwell R. K., Induction of the polyamine‐ biosynthetic enzymes in mouse epidermis by tumor‐promoting agents, Cancer Res., 35: 1662–1670, 1975. [PubMed] [Google Scholar]
- 33. Auvinen M., Laine A., Paasinen‐Sohns A., Kangas A., Kangas L., Saksela O., Andersson L. C., Holtta E., Human ornithine decarboxylase‐overproducing NIH3T3 cells induce rapidly growing, highly vascularized tumors in nude mice. Cancer Res., 57: 3016–3025, 1997. [PubMed] [Google Scholar]
- 34. Moshier J. A., Dosescu J., Skunca M., Luk G. D., Transformation of NIH/3T3 cells by ornithine decarboxylase overexpression. Cancer Res., 53: 2618–2622, 1993. [PubMed] [Google Scholar]
- 35. Metcalf B. W., Bey P., Danzin C., Jung M. J., Casara P., Vevert J. P., Catalytic irreversible inhibition of mammalian ornithine decarboxylase by substrate and product analogues. J. Amer. Chem. Soc., 100: 2551–2553, 1978. [Google Scholar]
- 36. Marton L. J., Pegg A. E., Polyamines as targets for therapeutic intervention, Annu. Rev. Pharmacol. Toxicol., 35: 55–91, 1995. [DOI] [PubMed] [Google Scholar]
- 37. Thomas T., Kiang D. T., Additive growth‐inhibitory effects of difluoromethylornithine and antiestrogens on MCF‐7 cell line, Biochem. Biophys. Res. Commun., 148: 1338–1345, 1987. [DOI] [PubMed] [Google Scholar]
- 38. Pegg A. E., Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy, Cancer Res., 48: 759–774, 1988. [PubMed] [Google Scholar]
- 39. Love R. R., Jacoby R., Newton M. A., Tutsch K. D., Simon K., Pomplun M., Verma A. K., A randomized, placebo‐controlled trial of low‐dose an α‐ difluoromethylornithine in individuals at risk for colorectal cancer, Cancer Epidemiol. Biomarkers Prev., 7: 989–992, 1998. [PubMed] [Google Scholar]
- 40. Alhonen L., Halmekyto M., Kosma V. M., Wahlfors J., Kauppinen R., Janne J., Life‐long over‐expression of ornithine decarboxylase (ODC) gene in transgenic mice does not lead to generally enhanced tumorigenesis or neuronal degeneration, Int. J. Cancer, 63: 402–404, 1995. [DOI] [PubMed] [Google Scholar]
- 41. Smith, M. K. , Trempus, C. S. , Gilmour, S. K. , Cooperation between follicular ornithine decarboxylase and v‐Ha‐ras induces spontaneous papillomas and malignant conversion in transgenic skin, Carcinogenesis, 19: 1409–1415, 1998. [DOI] [PubMed] [Google Scholar]
- 42. Hibshoosh H., Johnson M., Weinstein I. B., Effects of overexpression of ornithine decarboxylase (ODC) on growth control and oncogene‐induced cell transformation. Oncogene, 6: 739–743, 1991. [PubMed] [Google Scholar]
- 43. O'Brien T. G., Megosh L. C., Gilliard G., Soler A. P., Ornithine decarboxylase overexpression is a sufficient condition for tumor promotion in mouse skin, Cancer Res., 57: 2630–7, 1997. [PubMed] [Google Scholar]
- 44. Guo Y., Zhao J., Sawicki J., Peralta S. A., O'Brien T. G., Conversion of C57B1/6 mice from a tumor promotion‐resistant to a ‐sensitive phenotype by enhanced ornithine decarboxylase expression, Mol. Carcinog., 26: 32–36, 1999. [PubMed] [Google Scholar]
- 45. Fodde R., Smits R., Disease model: familial adenomatous polyposis, Trends Mol. Med., 7: 369–373, 2001. [DOI] [PubMed] [Google Scholar]
- 46. Fultz K. E., Gerner E. W., APC‐dependent regulation of ornithine decarboxylase in human colon tumor cells, Mol. Carcinog., 34: 10–18, 2002. [DOI] [PubMed] [Google Scholar]
- 47. Rebel H., van Steeg H., Beems R. B., Schouten R., de Gruijl F. R., Terleth C., Suppression of UV carcinogenesis by difluoromethylornithine in nucleotide excision repair‐deficient Xpa knockout mice, Cancer Res., 62: 1338–1342, 2002. [PubMed] [Google Scholar]
- 48. Benhamou S., Sarasin A., ERCC2/XPD gene polymorphisms and cancer risk, Mutagenesis, 17: 463–469, 2002. [DOI] [PubMed] [Google Scholar]
- 49. Williams‐Ashman H. G., Schenone A., Methyl glyoxal bis(guanylhydrazone) as a potent inhibitor of mammalian and yeast S‐adenosylmethionine decarboxylases, Biochem. Biophys. Res. Commun., 46: 288–295, 1972. [DOI] [PubMed] [Google Scholar]
- 50. Brady L. J., Brady P. S., Gandour R. D., Effect of methylglyoxal bis(guanylhydrazone) on hepatic, heart and skeletal muscle mitochondrial carnitine palmitoyltransferase and beta‐oxidation of fatty acids, Biochem. Pharmacol., 36: 447–452, 1987. [DOI] [PubMed] [Google Scholar]
- 51. Herr H., Warrel R. P., Burchenal J. H., Phase I trial of alpha‐difluoromethyl ornithine (DFMO) and methylglyoxal bis (guanylhydrazone) (MGBG) in patients with advanced prostatic cancer, Urology, 28: 508–511, 1986. [DOI] [PubMed] [Google Scholar]
- 52. Siu L. L., Rowinsky E. K., Hammond L. A., Weiss G. R., Hidalgo M., Clark G. M., Moczygemba J., Choi L., Linnartz R., Barbet N. C., Sklenar I. T., Capdeville R., Gan G., Porter C. W., von Hoff D. D., Eckhardt S. G., A phase I and pharmacokinetic study of SAM486A, a novel polyamine biosynthesis inhibitor, administered on a daily‐times‐five every‐three‐week schedule in patients with advanced solid malignancies, Clin. Cancer Res., 8: 2157–2166, 2002. [PubMed] [Google Scholar]
- 53. Paridaens R., Uges D. R., Barbet N., Choi L., Seeghers M., van der Graaf W. T., Groen H. J., Dumez H., Buuren I. V., Muskiet F., Capdeville R., Oosterom A. T., de Vries E. G., A phase I study of a new polyamine biosynthesis inhibitor, SAM486A, in cancer patients with solid tumours, Br. J. Cancer, 83: 594–601, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54. Paasinen‐Sohns A., Kielosto M., Kaariainen E., Eloranta T., Laine A., Janne O. A., Birrer M. J., Holtta E., c‐Jun activation‐dependent tumorigenic transformation induced paradoxically by overexpression or block of S‐ adenosylmethionine decarboxylase, J. Cell Biol., 151: 801–810, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55. Sharma T. A., Reynolds I. J., Characterization of the effects of polyamines on [125I]MK‐801 binding to recombinant N‐methyl‐D‐aspartate receptors, J. Pharmacol. Exp. Ther., 289: 1041–1047, 1999. [PubMed] [Google Scholar]
- 56. Pegg A. E., Poulin R., Coward J. K., Use of aminopropyltransferase inhibitors and of non‐metabolizable analogs to study polyamine regulation and function, Int. J. Biochem. Cell Biol., 27: 425–442, 1995. [DOI] [PubMed] [Google Scholar]
- 57. Baillon J. G., Kolb M., Mamont P. S., Inhibition of mammalian spermine synthase by N‐alkylated‐1,3‐diaminopropane derivatives in vitro and in cultured rat hepatoma cells, Eur. J. Biochem., 179: 17–21, 1989. [DOI] [PubMed] [Google Scholar]
- 58. Shirahata A., Morohohi T., Fukai M., Akatsu S., Samejima K., Putrescine or spermidine binding site of aminopropyltransferases and competitive inhibitors. Biochem. Pharmacol, 41: 205–12, 1991. [DOI] [PubMed] [Google Scholar]
- 59. Tang K. C., Mariuza R., Coward J. K., Synthesis and evaluation of some stable multisubstrate adducts as specific inhibitors of spermidine synthase, J. Med. Chem., 24: 1277–1284, 1981. [DOI] [PubMed] [Google Scholar]
- 60. Woster P. M., Black A. Y., Duff K. J., Coward J. K., Pegg A. E., Synthesis and biological evaluation of S‐adenosyl‐1,12‐diamino‐3‐thio‐9‐azadodecane, a multisubstrate adduct inhibitor of spermine synthase, J. Med. Chem. 32: 1300–1307, 1989. [DOI] [PubMed] [Google Scholar]
- 61. Holm I., Persson L., Pegg A. E., Heby O., Effects of S‐adenosyl‐1,8‐diamino‐3‐ thio‐octane and S‐methyl‐5′‐ methylthioadenosine on polyamine synthesis in Ehrlich ascites‐tumour cells, Biochem. J., 261: 205–210, 1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62. Shirahata A., Takahashi N., Beppu T., Hosoda H., Samejima K., Effects of inhibitors of spermidine synthase and spermine synthase on polyamine synthesis in rat tissues, Biochem Pharmacol., 45: 1897–1903, 1993. [DOI] [PubMed] [Google Scholar]
- 63. Pegg A. E., Wechter R., Poulin R., Woster P. M., Coward J. K., Effect of S‐ adenosyl‐1,12‐diamino‐3‐ thio‐9‐azadodecane, a multisubstrate adduct inhibitor of spermine synthase, on polyamine metabolism in mammalian cells, Biochemistry, 28: 8446–8453, 1989. [DOI] [PubMed] [Google Scholar]
- 64. Huber M., Poulin R., Antiproliferative effect of spermine depletion by N‐cyclohexyl‐1,3‐diaminopropane in human breast cancer cells, Cancer Res., 55: 934–943, 1995. [PubMed] [Google Scholar]
- 65. Thomas T. J., Bloomfield V. A., Canellakis Z. N., Differential effects on the B‐ to‐Z transition of poly(dG‐me5dC).poly(dG‐me5dC) produced by N1‐ and N8‐ acetylspermidine, Biopolymers, 24: 725–729, 1985. [DOI] [PubMed] [Google Scholar]
- 66. Alhonen L., Parkkinen J. J., Keinanen T., Sinervirta R., Herzig, K. H. , Janne, J. , Activation of polyamine catabolism in transgenic rats induces acute pancreatitis, Proc. Natl. Acad. Sci. U S A, 97: 8290–5829, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67. Fogel‐Petrovic M., Vujcic S., Brown P. J., Haddox M. K., Porter C. W., Effects of polyamines, polyamine analogs, and inhibitors of protein synthesis on spermidine‐ spermine N1‐acetyltransferase gene expression, Biochemistry, 35: 14436–14444, 1996. [DOI] [PubMed] [Google Scholar]
- 68. Chopra S., Wallace H. M., Induction of spermidine/spermine N1‐ acetyltransferase in human cancer cells in response to increased production of reactive oxygen species, Biochem. Pharmacol., 55: 1119–11123, 1998. [DOI] [PubMed] [Google Scholar]
- 69. Zahedi K., Wang Z., Barone S., Prada A. E., Kelly C. N., Casero R. A., Yokota N., Porter C. W., Rabb H., Soleimani M., Expression of SSAT, a novel biomarker of tubular cell damage, increase in kidney ischemia‐reperfusion injury, Am. J. Physiol. (Renal. Physiol.), 284: F1046–1055, 2003. [DOI] [PubMed] [Google Scholar]
- 70. Desiderio M. A., Weibel M., Mamont P. S., Spermidine nuclear acetylation in rat hepatocytes and in logarithmically growing rat hepatoma cells: comparison with histone acetylation, Exp. Cell Res., 202: 501–506, 1992. [DOI] [PubMed] [Google Scholar]
- 71. Hobbs C. A., Paul B. A., Gilmour S. K., Deregulation of polyamine biosynthesis alters intrinsic histone acetyltransferase and deacetylase activities in murine skin and tumors, Cancer Res., 62: 67–74, 2002. [PubMed] [Google Scholar]
- 72. Pietila M., Alhonen L., Halmekyto M., Kanter P., Janne J., Porter C. W., Activation of polyamine catabolism profoundly alters tissue polyamine pools and affects hair growth and female fertility in transgenic mice overexpressing spermidine/spermine N1‐ acetyltransferase, J. Biol. Chem., 272: 18746–18751, 1997. [DOI] [PubMed] [Google Scholar]
- 73. Min S. H., Simmen R. C., Alhonen L., Halmekyto M., Porter C. W., Janne J., Simmen F. A., Altered levels of growth‐related and novel gene transcripts in reproductive and other tissues of female mice overexpressing spermidine/spermine N1‐acetyltransferase (SSAT), J. Biol. Chem., 277: 3647–3657, 2002. [DOI] [PubMed] [Google Scholar]
- 74. Coleman C. S., Pegg A. E., Megosh L. C., Guo Y., Sawicki J. A., O'Brien T. G., Targeted expression of spermidine/spermine N1‐acetyltransferase increases susceptibility to chemically induced skin carcinogenesis, Carcinogenesis, 23: 359–364, 2002. [DOI] [PubMed] [Google Scholar]
- 75. Alhonen L., Pietila M., Halmekyto M., Kramer D. L., Janne, J. , Porter, C. W. , Transgenic mice with activated polyamine catabolism due to overexpression of spermidine/spermine N1‐acetyltransferase show enhanced sensitivity to the polyamine analog, N1, N11‐diethylnorspermine, Mol. Pharmacol., 55: 693–698, 1999. [PubMed] [Google Scholar]
- 76. Niiranen K., Pietila M., Pirttila T. J., Jarvinen A., Halmekyto M., Korhonen V. P., Keinanen T. A., Alhonen L., Janne J., Targeted disruption of spermidine/spermine N1‐acetyltransferase gene in mouse embryonic stem cells. Effects on polyamine homeostasis and sensitivity to polyamine analogues, J. Biol. Chem., 277: 25323–25328, 2002. [DOI] [PubMed] [Google Scholar]
- 77. Vujcic S., Liang P., Diegelman P., Kramer D. L., Porter C. W., Genomic identification and biochemical characterization of the mammalian polyamine oxidase involved in polyamine back‐conversion, Biochem. J., 370: 19–28, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78. Seiler N., Polyamine oxidase, properties and functions, Prog. Brain Res., 106: 333–344, 1995. [DOI] [PubMed] [Google Scholar]
- 79. Massey V., The chemical and biological versatility of riboflavin, Biochem. Soc. Trans., 28: 283–296, 2000. [PubMed] [Google Scholar]
- 80. Hu R. H., Pegg A. E., Rapid induction of apoptosis by deregulated uptake of polyamine analogues, Biochem. J., 328: 307–316, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81. Ha H. C., Woster P. M., Yager J. D., Casero R. A. Jr., The role of polyamine catabolism in polyamine analogue‐induced programmed cell death, Proc. Natl. Acad. Sci. USA, 94: 11557–11562, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82. Wang Y., Devereux W., Woster P. M., Stewart T. M., Hacker, A. , Casero R. A. Jr., Cloning and characterization of a human polyamine oxidase that is inducible by polyamine analogue exposure, Cancer Res., 61: 5370–5373, 2001. [PubMed] [Google Scholar]
- 83. Dai H., Kramer D. L., Yang C., Murti K. G., Porter C. W., Cleveland J. L., The polyamine oxidase inhibitor MDL‐72,527 selectively induces apoptosis of transformed hematopoietic cells through lysosomotropic effects, Cancer Res., 59: 4944–4954, 1999. [PubMed] [Google Scholar]
- 84. Binda C., Mattevi A., Edmondson D. E., Structure‐function relationships in flavoenzyme‐dependent amine oxidations: a comparison of polyamine oxidase and monoamine oxidase, J. Biol. Chem., 277: 23973–23976, 2002. [DOI] [PubMed] [Google Scholar]
- 85. Morgan D. M. L., Polyamine oxidases and oxidized polyamines In: The Physiology of Polyamines, Bachrach U. & Heimer Y. M., (Eds) CRC Press, Boca Raton , 1989. [Google Scholar]
- 86. Flescher E., Bowlin T. L., Ballester A., Houk R., Talal N., Increased polyamines may downregulate interleukin 2 production in rheumatoid arthritis, J. Clin. Invest., 83: 1356–1362, 1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87. Illei G., Morgan D. M., Serum polyamine‐oxidase activity in spontaneous abortion, Brit. J. Obst. Gyn., 89: 199–201, 1982. [DOI] [PubMed] [Google Scholar]
- 88. Murray‐Stewart T., Wang Y., Devereux W., Casero R. A. Jr., Cloning and characterization of multiple human polyamine oxidase splice variants that code for isoenzymes with different biochemical characteristics, Biochem. J., 368: 673–677, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89. Hessels J., Kingma A. W., Ferwerda H., Keij J., van den Berg G. A., Muskiet F. A., Microbial flora in the gastrointestinal tract abolishes cytostatic effects of alpha‐difluoromethylornithine in vivo, Int. J. Cancer, 43: 1155–1164, 1989. [DOI] [PubMed] [Google Scholar]
- 90. Leveque J., Burtin F., Catros‐Quemener V., Havouis R., Moulinoux J. P., The gastrointestinal polyamine source depletion enhances DFMO induced polyamine depletion in MCF‐7 human breast cancer cells in vivo , Anticancer Res., 18: 2663–2668, 1998. [PubMed] [Google Scholar]
- 91. Smith L. L., Young Scientists Award lecture 1981: The identification of an accumulation system for diamines and polyamines into the lung and its relevance to paraquat toxicity, Arch. Toxicol. Suppl. 5: 1–14, 1982. [DOI] [PubMed] [Google Scholar]
- 92. Rannels D. E., Pegg A. E., Clark R. S., Addison J. L., Interaction of paraquat and amine uptake by rat lungs perfused in situ, Am. J. Physiol. 249: E506–513, 1985. [DOI] [PubMed] [Google Scholar]
- 93. Minchin R. F., Martin R. L., Summers L. A., Ilett K. F., Inhibition of putrescine uptake by polypyridinium quaternary salts in B16 melanoma cells treated with difluoromethylornithine, Biochem. J., 262: 391–395, 1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94. Huber M., Pelletier J. G., Torossian K., Dionne P., Gamache I., Charest‐Gaudreault R., Audette M., Poulin R., 2,2′‐Dithiobis(N‐ethyl‐spermine‐5‐ carboxamide) is a high affinity, membrane‐impermeant antagonist of the mammalian polyamine transport system, J. Biol. Chem., 271: 27556–27563, 1996. [DOI] [PubMed] [Google Scholar]
- 95. Covassin L., Desjardins M., Charest‐Gaudreault R., Audette M., Bonneau M. J., Poulin R., Synthesis of spermidine and norspermidine dimers as high affinity polyamine transport inhibitors, Bioorg. Med. Chem. Lett., 9: 1709–1714, 1999. [DOI] [PubMed] [Google Scholar]
- 96. Aziz S. M., Gillespie M. N., Crooks P. A., Tofiq S. F., Tsuboi C. P., Olson J. W., Gosland M. P., The potential of a novel polyamine transport inhibitor in cancer chemotherapy, J. Pharmacol. Exp. Ther., 278: 185–92, 1996. [PubMed] [Google Scholar]
- 97. Burns M. R., Carlson C. L., Vanderwerf S. M., Ziemer J. R., Weeks R. S., Cai F., Webb H. K., Graminski G. F., Amino acid/spermine conjugates: polyamine amides as potent spermidine uptake inhibitors, J. Med. Chem., 44: 3632–3644, 2001. [DOI] [PubMed] [Google Scholar]
- 98. Li Y., MacKerell A. D. Jr., Egorin M. J., Ballesteros M. F., Rosen D. M., Wu Y. Y., Blamble D. A., Callery P. S., Comparative molecular field analysis‐based predictive model of structure‐function relationships of polyamine transport inhibitors in L1210 cells. Cancer Res., 57: 234, 1997. [PubMed] [Google Scholar]
- 99. Seiler N., Delcros J. G., Moulinoux J. P., Polyamine transport in mammalian cells. An update, Int. J. Biochem. Cell Biol., 28: 843–861, 1996. [DOI] [PubMed] [Google Scholar]
- 100. Kaouass M., Audette M., Ramotar D., Verma S., De Montigny D., Gamache I., Torossian K., Poulin R., The STK2 gene, which encodes a putative Ser/Thr protein kinase, is required for high‐affinity spermidine transport in Saccharomyces cerevisiae, Mol. Cell Biol., 17: 2994–3004, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 101. Nozaki T., Nishimura K., Michael A. J., Maruyama T., Kakinuma Y., Igarashi K., A second gene encoding a putative serine/threonine protein kinase which enhances spermine uptake in Saccharomyces cerevisiae, Biochem. Biophys. Res. Commun. 228: 452–458, 1996. [DOI] [PubMed] [Google Scholar]
- 102. Sakata K., Kashiwagi K., Igarashi K., Properties of a polyamine transporter regulated by antizyme, Biochem. J., 347: 297–303, 2000. [PMC free article] [PubMed] [Google Scholar]
- 103. Satriano J., Isome M., Casero R. A. Jr., Thomson S. C., Blantz R. C., Polyamine transport system mediates agmatine transport in mammalian cells, Am. J. Physiol. Cell Physiol., 281: C329–334, 2001. [DOI] [PubMed] [Google Scholar]
- 104. Igarashi K., Kashiwagi K., Polyamine transport in bacteria and yeast, Biochem. J., 344: 633–642, 1999. [PMC free article] [PubMed] [Google Scholar]
- 105. Bercovich Z., Rosenberg‐Hasson Y., Ciechanover A., Kahana C., Degradation of ornithine decarboxylase in reticulocyte lysate is ATP‐dependent but ubiquitin‐ independent, J. Biol. Chem. 264: 15949–5952, 1989. [PubMed] [Google Scholar]
- 106. Coffino P., Antizyme, a mediator of ubiquitin‐independent proteasomal degradation, Biochimie, 83: 319–323, 2001. [DOI] [PubMed] [Google Scholar]
- 107. Tsuji T., Todd R., Meyer C., McBride J., Liao P. H., Huang M. F., Chou M. Y., Donoff R. B., Wong D. T., Reduction of ornithine decarboxylase antizyme (ODCAz) level in the 7,12‐dimethylbenz(a)anthracene‐induced hamster buccal pouch carcinogenesis model, Oncogene, 16: 3379–3385, 1998. [DOI] [PubMed] [Google Scholar]
- 108. Koike C., Chao D. T., Zetter B. R., Sensitivity to polyamine‐induced growth arrest correlates with antizyme induction in prostate carcinoma cells, Cancer Res., 59: 6109–6112, 1999. [PubMed] [Google Scholar]
- 109. Yang D., Hayashi H., Takii T., Mizutani Y., Inukai Y., Onozaki K., Interleukin‐1‐induced growth inhibition of human melanoma cells. Interleukin‐1‐induced antizyme expression is responsible for ornithine decarboxylase activity down‐regulation, J. Biol. Chem., 272: 3376–3383, 1997. [DOI] [PubMed] [Google Scholar]
- 110. Mitchell J. L., Leyser A., Holtorff M. S., Bates J. S., Frydman B., Valasinas A. L., Reddy V. K., Marton L. J., Antizyme induction by polyamine analogues as a factor of cell growth inhibition, Biochem. J., 366: 663–671, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 111. Ivanov I. P., Gesteland R. F., Atkins J. F., A second mammalian antizyme: conservation of programmed ribosomal frameshifting, Genomics, 52: 119–129, 1998. [DOI] [PubMed] [Google Scholar]
- 112. Ivanov I. P., Rohrwasser A., Terreros D. A., Gesteland R. F., Atkins J. F., Discovery of a spermatogenesis stage‐specific ornithine decarboxylase antizyme: antizyme 3, Proc. Natl. Acad. Sci. U.S.A., 97: 4808–4813, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113. Sakata K., Kashiwagi K., Igarashi K., Properties of a polyamine transporter regulated by antizyme, Biochem. J., 347: 297–303, 2000. [PMC free article] [PubMed] [Google Scholar]
- 114. Porter C. W., Bergeron R. J., Regulation of polyamine biosynthetic activity by spermidine and spermine analogs—a novel antiproliferative strategy, Adv. Exp. Med. Biol., 250: 677–690, 1988. [DOI] [PubMed] [Google Scholar]
- 115. Thomas T., Balabhadrapathruni S., Gallo M. A., Thomas T. J., Development of polyamine analogs as cancer therapeutic agents, Oncol. Res., 13: 123–135, 2002. [PubMed] [Google Scholar]
- 116. Porter C. W., McManis J., Casero R. A., Bergeron R. J., Relative abilities of bis(ethyl) derivatives of putrescine, spermidine, and spermine to regulate polyamine biosynthesis and inhibit L1210 leukemia cell growth, Cancer Res., 47: 2821–2825, 1987. [PubMed] [Google Scholar]
- 117. Seiler N., Delcros J. G., Vaultier M., Le Roch N., Havouis R., Douaud F., Moulinoux J. P., Bis(7‐amino‐4‐azaheptyl)dimethlysilane and bis(7‐ethylamino‐4‐azaheptyl)dimethylsilane: inhibition of tumor cell growth in vitro and in vivo , Cancer Res., 56: 5624–5630. [PubMed] [Google Scholar]
- 118. Bacchi C., Weiss L. M., Lane S., Frydman B., Valasinas A., Reddy V., Sun J. S., Marton L. J., Khan I. A., Moretto M., Yarlett N., Wittner M., Novel synthetic polyamines are effective in the treatment of experimental microsporidiosis, an opportunistic AIDS‐associated infection, Antimicrob. Agents Chemother., 46: 55–61, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 119. Webb H., Wu Z., Sirisoma N., Ha H. C., Casero R. A. Jr, Woster P. M., 1‐(N‐alkylamino)‐11‐(N‐ethylamino)‐ 4,8‐diazaundecanes: simple synthetic polyamine analogues that differentially alter tubulin polymerization, J. Med. Chem., 42: 1415–21, 1999. [DOI] [PubMed] [Google Scholar]
- 120. Faaland C. A., Thomas T. J., Balabhadrapathruni S., Langer T., Mian S., Shirahata A., Gallo M. A., Thomas T., Molecular correlates of the action of bis(ethyl)polyamines in breast cancer cell growth inhibition and apoptosis, Biochem. Cell Biol., 78: 415–426, 2000. [PubMed] [Google Scholar]
- 121. Saminathan M., Thomas T., Shirahata A., Pillai C. K., Thomas T. J., Polyamine structural effects on the induction and stabilization of liquid crystalline DNA: potential applications to DNA packaging, gene therapy and polyamine therapeutics. Nucleic Acids Res., 30: 3722–3731, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122. Thomas T., Thomas T. J., Regulation of cyclin B1 by estradiol and polyamines in MCF‐7 breast cancer cells, Cancer Res., 54: 1077–1084, 1994. [PubMed] [Google Scholar]
- 123. Thomas T. J., Shah N., Faaland C. A., Gallo M. A., Yurkow E., Satyaswaroop P. G., Thomas T., Effects of a bis(benzyl)spermine analog on MCF‐7 breast cancer cells in culture and nude mice xenografts, Oncology Reports, 4, 15–21, 1997. [PubMed] [Google Scholar]
- 124. Kramer D. L., Chang B. D., Chen Y., Diegelman P., Alm K., Black A. R., Roninson I. B., Porter C. W., Polyamine depletion in human melanoma cells leads to G1 arrest associated with induction of p21WAF1/CIP1/SDI1, changes in the expression of p21‐regulated genes, and a senescence‐like phenotype, Cancer Res., 61: 7754–7762., 2001. [PubMed] [Google Scholar]
- 125. Veress I., Haghighi S., Pulkka A., Pajunen A., Changes in gene expression in response to polyamine depletion indicate selective stabilization of mRNAs, Biochem. J., 346: 185–191, 2000. [PMC free article] [PubMed] [Google Scholar]
- 126. Chen Y., Kramer D. L., Diegelman P., Vujcic S., Porterm C. W., Apoptotic signaling in polyamine analogue‐treated SK‐MEL‐28 human melanoma cells, Cancer Res., 61: 6437–6444, 2001. [PubMed] [Google Scholar]