Polyamines and cancer: Old molecules, new understanding

Nature Reviews Cancer

Volumn 4, Issue 10, 2004, Pages 781-792

  Gerner, Eugene W ^a   Meyskens Jr , Frank L ^b  

^a UNIVERSITY OF ARIZONA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMIDINO 1 INDANONE 2' AMIDINOHYDRAZONE; 6 HEPTYNE 2,5 DIAMINE; ACYLTRANSFERASE; ADENOSYLMETHIONINE DECARBOXYLASE; ADENOSYLMETHIONINE DECARBOXYLASE INHIBITOR; AMINO ACID DERIVATIVE; ANTINEOPLASTIC AGENT; ARGININE; CELECOXIB; EFLORNITHINE; ENZYME INHIBITOR; FINASTERIDE; MITOGUAZONE; N1,N11 DIETHYLNORSPERMINE; N1,N14 DIETHYLHOMOSPERMINE; NONSTEROID ANTIINFLAMMATORY AGENT; ORNITHINE DECARBOXYLASE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; POLYAMINE; POLYAMINE DERIVATIVE; POLYAMINE OXIDASE; POLYAMINE SYNTHESIS INHIBITOR; PUTRESCINE; RETINOID; SAM 4861; SPERMIDINE; SPERMINE; SPERMINE N ACETYLTRANSFERASE; SULINDAC; UNCLASSIFIED DRUG; UNINDEXED DRUG;

CANCER GROWTH; CANCER PREVENTION; CANCER RISK; CANCER SURVIVAL; CARCINOGENESIS; CLINICAL TRIAL; DRUG EFFICACY; DRUG TARGETING; DRUG UTILIZATION; ENZYME ACTIVITY; GENE FUNCTION; HIGH RISK POPULATION; HUMAN; LIVER TOXICITY; MOUTH CANCER; NEUROTOXICITY; NONHUMAN; ONCOGENE; POLYAMINE METABOLISM; POLYAMINE SYNTHESIS; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN EXPRESSION; REGULATORY MECHANISM; REVIEW; TECHNIQUE; TISSUE REPAIR; TUMOR SUPPRESSOR GENE; UTERINE CERVIX CANCER;

ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTINEOPLASTIC AGENTS; CHEMOPREVENTION; COLORECTAL NEOPLASMS; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITORS; CYCLOOXYGENASE INHIBITORS; DRUG DESIGN; EFLORNITHINE; ENZYME INHIBITORS; FORECASTING; GENES, TUMOR SUPPRESSOR; HUMANS; ISOENZYMES; MEMBRANE PROTEINS; MODELS, BIOLOGICAL; NEOPLASMS; ONCOGENES; ORNITHINE DECARBOXYLASE; POLYAMINES; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES;

EID: 4944242891     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc1454     Document Type: Review

References (121)

1. Cohen, S. S. A Guide to the Polyamines. (Oxford Univ. Press, New York, 1998).
2. Morris, S. M. Jr. Regulation of enzymes of the urea cycle and arginine metabolism. Annu. Rev. Nutr. 22, 87-105 (2002).
3. Bardocz, S. et al. The importance of dietary polyamines in cell regeneration and growth. Br. J. Nutr. 73, 819-828 (1995).
4. Milovic, V. Polyamines in the gut lumen: bioavailability and biodistribution. Eur. J. Gastroenterol. Hepatol. 13, 1021-1025 (2001).
5. Tabor, H., Hafner, E. W. & Tabor, C. W. Construction of an Escherichia coli strain unable to synthesize putrescine, spermidine, or cadaverine: characterization of two genes controlling lysine decarboxylase. J. Bacteriol. 144, 952-956 (1980).
6. Tabor, C. W., Tabor, H., Tyagi, A. K. & Cohn, M. S. The biochemistry, genetics, and regulation of polyamine biosynthesis in Saccharomyces cerevisiae. Fed. Proc. 41, 3084-3088 (1982).
7. Pendeville, H. et al. The omithine decarboxylase gene is essential for cell survival during early murine development. Mol. Cell. Biol. 21, 6549-6558 (2001). Showed that ODC is an essential gene in mammals and that lack of ODC function resulted in increased apoptosis in developing embryos.
8. Chang, Z. F. & Chen, K. Y. Regulation of ornithine decarboxylase and other cell cycle-dependent genes during senescence of IMR-90 human diploid fibroblasts. J. Biol. Chem. 263, 11431-11435 (1988).
9. Gerner, E. W., Garewal, H. S., Emerson, S. S. & Sampliner, R. E. Gastrointestinal tissue polyamine contents of patients with Barrett's esophagus treated with α-difluoromethylornithine. Cancer Epidemiol. Biomarkers Prev. 3, 325-330 (1994).
10. Russell, D. & Snyder, S. H. Amine synthesis in rapidly growing tissues: ornithine decarboxylase activity in regenerating rat liver, chick embryo, and various tumors. Proc. Natl Acad. Sci. USA 60, 1420-1427 (1968).
11. Andersson, G. & Heby, O. Polyamine and nucleic acid concentrations in Ehrlich ascites carcinoma cells and liver of tumor-bearing mice at various stages of tumor growth. J. Natl Cancer Inst 48, 165-172 (1972).
12. Wallace, H. M. & Caslake, R. Polyamines and colon cancer. Eur. J. Gastroenterol. Hepatol. 13, 1033-1039 (2001).
13. O'Brien, T. G., Simsiman, R. C. & Boutwel, R. K. Induction of the polyamine-biosynthetic enzymes in mouse epidermis by tumor-promoting agents. Cancer Res. 35, 1662-1670 (1975).
14. Ahmad, N., Gilliam, A. C., Katiyar, S. K., O'Brien, T. G. & Mukhtar, H. A definitive role of ornithine decarboxylase in photocarcinogenesis. Am. J. Pathol. 159, 885-892 (2001).
15. Marsh, J. P. & Mossman, B. T. Role of asbestos and active oxygen species in actuation and expression of omithine decarboxylase in hamster tracheal epithelial cells. Cancer Res. 51, 167-173 (1991).
16. Crozat, A., Palvimo, J. J., Julkunen, M. & Janne, O. A. Comparison of androgen regulation of ornithine decarboxylase and S-adenosylmethionine decarboxylase gene expression in rodent kidney and accessory sex organs. Endocrinology 130, 1131-1144 (1992).
17. Mohan, R. R. et al. Overexpression of omithine decarboxylase in prostate cancer and prostatic fluid in humans. Clin. Cancer Res. 5, 143-147 (1999).
18. Meyskens, F. L. Jr. & Gerner, E. W. Development of difluoromethylomithine (DFMO) as a chemoprevention agent. Clin. Cancer Res. 5, 945-951 (1999).
19. Thomas, T., Faaland, C. A., Adhikarakunnathu, S. & Thomas, T. J. Structure-activity relations of S-adenosylmethionine decarboxylase inhibitors on the growth of MCF-7 breast cancer cells. Breast Cancer Res. Treat 39, 293-306 (1996).
20. Casero, R. A. Jr. et al. The role of polyamine catabolism in anti-tumour drug response. Biochem. Soc. Trans. 31, 361-365 (2003).
21. Eskens, F. A. et al. Phase I and pharmacological study of weekly administration of the polyamine synthesis inhibitor SAM 486A (OGP 48 664) in patients with solid tumors. European Organization for Research and Treatment of Cancer Early Clinical Studies Group. Clin. Cancer Res. 6, 1736-1743 (2000).
22. 11-diethylnorspermine (DENSpm) daily for five days every 21 days in patients with previously treated metastatic breast cancer. Clin. Cancer Res. 9, 5922-5928 (2003).
23. Giardiello, F. M. et al. Ornithine decarboxylase and polyamines in familial adenomatous polyposis. Cancer Res. 57, 199-201 (1997). Showed that colonic ODC activity and polyamine levels were increased in patients with FAP, a genetic form of colon cancer.
24. Groden, J. et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66, 589-600 (1991).
25. Kinzler, K. W. et al. Identification of FAP locus genes from chromosome 5q21. Science 253, 661-665 (1991).
26. Iwamoto, M., Ahnen, D. J., Franklin, W. A. & Maltzman, T. H. Expression of β-catenin and full-length APC protein in normal and neoplastic colonic tissues. Carcinogenesis 21, 1935-1940 (2000).
27. He, T. C. et al. (1998) Identification of c-MYC as a target of the APC pathway. Science 281, 1509-1512.
28. Boyd, K. E. & Farnham, P. J. Identification of target genes of oncogenic transcription factors. Proc. Soc. Exp. Biol. Med. 222, 9-28 (1999).
29. Hermeking, H. The MVC oncogene as a cancer drug target. Curr. Cancer Drug Targets 3, 163-175 (2003).
30. Bello-Fernandez, C., Packham, G. & Cleveland, J. L. The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc. Natl Acad. Sci. USA 90, 7804-7808 (1993). Showed that ODC is a transcriptional target of the MYC oncogene
31. Pena, A. et al. Regulation of human ornithine decarboxylase expression by the c-Myc.Max protein complex. J. Biol. Chem. 268, 27277-27285 (1993).
32. Erdman, S. H. et al. APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the Min mouse. Carcinogenesis 20, 1709-1713 (1999). Demonstrated that ODC RNA was unregulated, OAZ RNA was downregulated and intestinal polyamine content increased as a consequence of loss of wildtype APC in a mouse model.
33. Fultz, K. E. & Gerner, E. W. APC-dependent regulation of omithine decarboxylase in human colon tumor cells. Mol. Carcinog. 34, 10-18 (2002).
34. Shantz, L. M. & Pegg, A. E. Ornithine decarboxylase induction in transformation by H-Ras and RhoA. Cancer Res. 58, 2748-2753 (1998).
35. 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).
36. Ignatenko, N. A., Babbar, N., Mehta, D., Casero, R. A. Jr & Gerner, E. W. Suppression of polyamine catabolism by activated Ki-ras in human colon cancer cells. Mol. Carcinog. 39, 91-102 (2004).
37. Babbar, N., Ignatenko, N. A., Casero, R. A. Jr & Gerner, E. W Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer. J. Biol. Chem. 278, 47762-47775 (2003). Established SSAT as a transcriptional target of the PPARγ tumour suppressor and showed that the sulphone metabolite of the NSAID sulindac induced SSAT transcription by activating PPARγ.
38. Bai, G. et al. Androgen regulation of the human ornithine decarboxylase promoter in prostate cancer cells. J. Androl. 19, 127-135 (1998).
39. De Benedetti, A. & Harris, A. L. elF4E expression in tumors: its possible role in progression of malignancies. Int. J. Biochem. Cell Biol. 31, 59-72 (1999).
40. Martinez, M. E. et al. Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene. Proc. Natl Acad. Sci. USA 100, 7859-7864 (2003). Showed that an SNP in the ODC promoter was associated, with reduced risk of colon-polyp recurrence in people reporting aspirin use. Provided evidence that the ODC SNP reduced polyamine synthesis, while aspirin induced polyamine catabolism and export, thereby reducing polyamine levels.
41. Ignatenko, N. A. et al. The chemopreventive agent α- difluoromethylornithine blocks K-ras dependent tumor formation and specific gene expression in Caco-2 cells. Mol. Carcinog. 39, 221-233 (2004).
42. Brzozowski, T., Konturek, S. J., Drozdowicz, D., Dembinski, A. & Stachura, J. Healing of chronic gastric ulcerations by L-arginine. Role of nitric oxide, prostaglandins, gastrin and polyamines. Digestion. 56, 463-471 (1995).
43. Xie, X., Tome, M. E. & Gerner, E. W. Loss of intracellular putrescine pool-size regulation induces apoptosis. Exp. Cell Res. 230, 386-392 (1997).
44. Erez, O., Goldstaub, D., Friedman, J. & Kahana, C. Putrescine activates oxidative stress dependent apoptotic death in ornithine decarboxylase overproducing mouse myeloma cells. Exp. Cell Res. 281, 148-156 (2002).
45. Takigawa, M. et al. Tumor angiogenesis and polyamines: á-difluoromethylomithine, an irreversible inhibitor of ornithine decarboxylase, inhibits B16 melanoma-induced angiogenesis in ovo and the proliferation of vascular endothelial cells in vitro. Cancer Res. 50, 4131-4138 (1990).
46. Takahashi, Y., Mai, M. & Nishioka, K. α-difluoromethylomithine induces apoptosis as well as anti-angiogenesis in the inhibition of tumor growth and metastasis in a human gastric cancer model. Int. J. Cancer 85, 243-247 (2000).
47. Bauer, P. M., Buga, G. M., Fukuto, J. M., Pegg, A. E. & Ignarro, L. J. Nitric oxide inhibits ornithine decarboxylase via S-nitrosylation of cysteine 360 in the active site of the enzyme. J. Biol. Chem. 276, 34458-34464 (2001).
48. Buga, G. M., Wei, L. H., Bauer, P. M., Fukuto, J. M. & Ignarro, L. J. (1998) NG-hydroxy-L-arginine and nitric oxide inhibit Caco-2 tumor cell proliferation by distinct mechanisms. Am. J. Physiol. 275, R1258-R1264.
49. Itoh, M. & Bissell, M. J. The organization of tight junctions in epithelia: implications for mammary gland biology and breast tumorigenesis. J. Mammary Gland Biol. Neoplasia 8, 449-462 (2003).
50. Trosko, J. E. The role of stem cells and gap junctional intercellular communication in carcinogenesis. J. Biochem. Mol. Biol. 36, 43-48 (2003).
51. Guo, X. et al. Regulation of adherens junctions and epithelia paracellular permeability: a novel function for polyamines. Am. J. Physiol. Cell Physiol. 285, C1174-C1187 (2003).
52. Shore, L., McLean, P., Gilmour, S. K., Hodgins, M. B. & Finbow, M. E. Polyamines regulate gap junction communication in connexin 43-expressing cells. Biochem. J. 357, 489-495 (2001).
53. Pegg, A. E. et al. Transgenic mouse models for studies of the role of polyamines in normal, hypertrophic and neoplastic growth. Biochem. Soc. Trans. 31, 356-360 (2003).
54. Williams-Ashman, H. G. & Schenone, A. Methyl glyoxal bis(guanylhydrazone) as a potent inhibitor of mammalian and yeast S-adenosytmethionine decarboxylases. Biochem. Biophys. Res. Commun. 46, 288-295 (1972).
55. Mamont, P. S. et al. α-methyl ornithine, a potent competitive inhibitor of ornithine decarboxylase, blocks proliferation of rat hepatoma cells in culture. Proc. Natl Acad. Sci. USA 73, 1626-1630 (1976).
56. Bey, P. et al. Analogues of ornithine as inhibitors of ornithine decarboxylase. New deductions concerning the topography of the enzyme's active site. J. Med. Chem. 21, 50-55 (1978).
57. Doua, F. & Yapo, F. B. Human trypanosomiasis in the Ivory Coast: therapy and problems. Acta Trop. 54, 163-168 (1993).
58. Seiler, N. Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 1. Selective enzyme inhibitors. Curr. Drug Targets 4, 537-564 (2003).
59. Bitonti, A. J. et al. Bis(benzyl)polyamine analogs as novel substrates for polyamine oxidase. J. Biol. Chem. 265, 382-388 (1990).
60. Seiler, N., Duranton, B. & Paul, F. The polyamine oxidase inactivator MDL 72527. Prog. Drug Res. 59, 1-40 (2002).
61. Mamont, P. S., Claverie, N. & Gerhart, F. Fluorine-containing polyamines: biochemistry and potential applications. Adv. Exp. Med. Biol. 250, 691-706 (1988).
62. McCann, P. P. & Pegg, A. E. Ornithine decarboxylase as an enzyme target for therapy. Pharmacol. Ther. 54, 195-215 (1992).
63. McCann, P. P., Pegg, A. E. & Sjoerdsma, A. Inhibition of Polyamine Metabolism, Biological Significance and Basis for New Therapies (Academic, Orlando, 1987).
64. Lawson, K. R., Ignatenko, N. A., Piazza, G. A., Cui, H. & Gerner, E. W. Influence of K-ras activation on the survival responses of Caco-2 cells to the chemopreventive agents sulindac and difluoromethylornithine. Cancer Epidemiol. Biomarkers Prev. 9, 1155-1162 (2000).
65. Weeks, C. E., Herrmann, A. L., Nelson, F. R. & Slaga, T. J. α-Difluoromethylomithine, an irreversible inhibitor of ornithine decarboxylase, inhibits tumor promoter-induced polyamine accumulation and carcinogenesis in mouse skin. Proc. Natl Acad. Sci. USA 79, 6028-6032 (1982). Demonstrated that DFMO inhibited chemically induced skin carcinogenesis by a mechanism affecting tumour promotion. Provided the first evidence from animal models supporting the rationale for DFMO as a chemopreventive agent
66. Meyskens, F. L. Jr et al. Effect of α-difluoromethylornithine on rectal mucosal levels of polyamines in a randomized, double-blinded trial for colon cancer prevention. J. Natl Cancer Inst. 90, 1212-1218 (1998). Demonstrated the safety of DFMO and its potent biochemical effect on polyamine content in human colon tissue over a 1-year period; a critical study for planning of Phase III trials.
67. Rao, C. V., Tokumo, K., Rigotty, J., Zang, E., Keloff, G. & Reddy, B. S. Chemoprevention of colon carcinogenesis by dietary administration of piroxicam, α-difluoromethylomithine, 16α-fluoro-5-androsten-17-one, and ellagic acid individual and in combination. Cancer Res. 51, 4528-4534 (1991).
68. Croghan, M. K., Aickin, M. G. & Meyskens, F. L. Dose-related α-difluoromethylomithine ototoxicity. Am. J. Clin. Oncol. 14, 331-335 (1991).
69. Pasic, T. R., Heisey, D. & Love, R. R. α-difluoromethylomithine ototoxicity. Chemoprevention clinical trial results. Arch. Otolaryngol. Head Neck Surg. 123, 1281-1286 (1997).
70. Doyle, K. J., McLaren, C. E., Shanks, J. E., Galus, C. M. & Meyskens, F. L. Effects of difluoromethylomithine Chemoprevention on audiometry thresholds and otoacoustic emissions. Arch. Otolaryngol. Head Neck Surg. 127, 553-558 (2001).
71. Mitchell, M. F. et al. Phase I dose de-escalation trial of α-difluoromethylomithine in patients with grade 3 cervical intraepithelia neoplasia. Clin. Cancer Res. 4, 303-310 (1998).
72. Carbone, P. P. et al. Phase I chemoprevention study of difluoromethylornithine in subjects with organ transplants. Cancer Epidemiol. Biomarkers Prev. 10, 657-661 (2001).
73. Love, R. R. et al. Randomized phase I chemoprevention dose-seeking study of α-difluoromethylomithine. J. Natl Cancer Inst. 85, 732-737 (1993).
74. Alberts, D. S. et al. Chemoprevention of human actinic keratoses by topical 2-(difluoromethyl)-di-omithine. Cancer Epidemiol. Biomarkers Prev. 9, 1281-1286 (2000). Clinical study showing efficacy of DFMO in the treatment of actinic keratoses in humans.
75. Boyle, J. O., Meyskens, F. L. Jr, Garewal, H. S. & Gerner, E. W. Polyamine contents in rectal and buccal mucosae in humans treated with oral difluoromethylornithine. Cancer Epidemiol. Biomarkers Prev. 1, 131-135 (1992).
76. Simoneau, A. R., Gerner, E. W., Phung, M., McLaren, C. E. & Meyskens, F. L. Jr. α-difluoromethylomithine and polyamine levels in the human prostate: results of a phase IIa trial. J. Natl Cancer Inst. 93, 57-59 (2001).
77. Fabian, C. J. et al. A phase II breast cancer Chemoprevention trial of oral α-difluoromethylornithine: breast tissue, imaging, and serum and urine biomarkers. Clin. Cancer Res. 8, 3105-3117 (2002).
78. Meyskens, F. L. Jr et al. Dose de-escalation chemoprevention trial of α-difluoromethylomithine in patients with colon polyps. J. Natl Cancer Inst. 86, 1122-1130 (1994). Clinical study that used a novel dose de-escalation design to identify the lowest does of DFMO that still caused the desired biochemical effect (polyamine depletion) in the target tissue.
79. Levy, G. N. Prostaglandin H syntheses, nonsteroidal anti-inflammatory drugs, and colon cancer. FASEB J. 11, 234-247 (1997).
80. Oshima, M. et al. Suppression of intestinal polyposis in Ape δ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell, 87, 803-809 (1996).
81. Phillips, R. K. et al. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenornatous polyposis. Gut 50, 857-860 (2002).
82. Bishop-Bailey, D., Calatayud, S., Warner, T. D., Hla, T. & Mitchell, J. A. Prostaglandins and the regulation of tumor growth. J. Environ. Pathol. Toxicol. Oncol. 21, 93-101 (2002).
83. Hughes, A., Smith, N. I. & Wallace, H. M. Polyamines reverse non-steroidal anti-inflammatory drug-induced toxicity in human colorectal cancer cells. Biochem. J. 374, 481-488 (2003).
84. Jacoby, R. F. et al. Chemopreventive efficacy of combined piroxicam and difluoromethylornithine treatment of Apc mutant Min mouse adenomas, and selective toxicity against Apc mutant embryos. Cancer Res. 60, 1864-1870 (2000).
85. Meyskens, F. L. Jr et al. Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial. J. Natl Cancer Inst. 86, 539-543 (1994).
86. Hong, W. K. et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 323, 795-801 (1990).
87. Fisher, B. et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 90, 1371-1388 (1998).
88. Mitchell, J. L., Hoff, J. A. & Bareyal-Leyser, A. Stable omithine decarboxylase in a rat hepatoma cell line selected for resistance to α-difluoromethylornithine. Arch. Biochem. Biophys. 290, 143-152 (1991).
89. Meyskens, F. L. Jr & Szabo, E. How should we move the field of chemoprevention agent development forward in a productive manner. Eur. J. Cancer (in the press).
90. Levin, V. A. et al. Phase III randomized study of postradiotherapy chemotherapy with combination α-difluoromethytornithine-PCV versus PCV for anaplastic gliomas. Clin. Cancer Res. 9, 981-990 (2003).
91. Lux, G. D., Marton, L. J. & Baylin, S. B. Omithine decarboxylase is important in intestinal mucosal maturation and recovery from injury in rats. Science 210, 195-198 (1980). Showed the importance of polyamines in normal intestinal development and repair of damage.
92. Yarrington, J. T. et al. Intestinal changes caused by DL-α-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase. Exp. Mol. Pathol. 39, 300-316 (1983).
93. Wang, J. Y. & Johnson, L. R. Lumina polyamines stimulate repair of gastric mucosal stress ulcers. Am. J. Physiol. 259, G584-G592 (1990).
94. Wang, J. Y. & Johnson, L. R. Polyamines and ornithine decarboxylase during repair of duodenal mucosa after stress in rats. Gastroenterology 100, 333-343 (1991).
95. Babal, P., Manuel, S. M., Olson, J. W. & Gillespie, M. N. Cellular disposition of transported polyamines in hypoxic rat lung and pulmonary arteries. Am. J. Physiol. Lung Cell Mol. Physiol. 278, L610-L617 (2000).
96. Ahuja, V., Tantry, U., Park, J. & Barbul, A. Effect of difluoromethylornitine, a chemotherapeutic agent, on wound healing. J. Surg. Res. 114, 308-309 (2003).
97. Calandra, R. S., Rulli, S. B., Frungieri, M. B., Suescun, M. O. & Gonzalez-Calvar, S. I. Polyamines in the male reproductive system. Acta Physiol. Pharmacol. Ther. Latinoam. 46, 209-222 (1996).
98. Guha, S. K. & Janne, J. Decarboxylation of omithine and adenosymethionine in rat ovary during pregnancy. Acta Endocrinol. (Copenh.) 81, 793-800 (1976).
99. Hoshiai, H., Lin, Y. C., Loring, J. M., Perelle, B. A. & Villee, C. A. Ornithine decarboxylase activity and polyamine content of the placenta and decidual tissue in the rat. Placenta 2, 105-116 (1981).
100. 1-acetyltransferase (SSAT). J. Biol. Chem. 277, 3647-3657 (2002).
101. Humphreys, M. H., Etheredge, S. B., Lin, S. Y., Ribstein, J. & Marton, L. J. Rena ornithine decarboxylase activity, potyamines, and compensatory renal hypertrophy in the rat. Am. J. Physiol. 255, F270-F277 (1988).
102. Mackintosh, C. A., Feith, D. J., Shantz, L. M. & Pegg, A. E. Overexpression of antizyme in the hearts of transgenic mice prevents the isoprenaline-induced increase in cardiac ornithine decarboxylase activity and polyamines, but does not prevent cardiac hypertrophy. Biochem. J. 350, 645-653 (2000).
103. Park, M. H., Lee, Y. B. & Joe, Y. A. Hypusine is essential for eukaryotic cell proliferation. Biol. Signals 6, 115-123 (1997).
104. Schnier, J., Sohwelberger, H. G., Smit-McBride, Z., Kang, H. A. & Hershey, J. W. Translation initiation factor 5A and its hypusine modification are essential for cell viability in the yeast Saccharomyces cerevisiae. Mol. Cell. Biol. 11, 3105-3114 (1991).
105. Kang, H. A. & Hershey, J. W. Effect of initiation factor elF-5A depletion on protein synthesis and proliferation of Saccharomyces cerevisiae. J. Biol. Chem. 269, 3934-3940 (1994).
106. Tome, M. E., Fiser, S. M., Payne, C. M. & Gerner, E. W. Excess putrescine accumulation inhibits the formation of modified eukaryotic initiation factor 5A (elF-5A) and induces apoptosis. Biochem. J. 328, 847-854 (1997).
107. Bevec, D. & Hauber, J. Eukaryotic initiation factor 5A activity and HIV-1 Rev function. Biol. Signals 6, 124-133 (1997).
108. Zuk, D. & Jacobson, A. A single amino acid substitution in yeast elF-5A results in mRNA stabilization. EMBO J. 17, 2914-2925 (1998).
109. Hayashi, S., Murakami, Y. & Matsufuji, S. Ornithine decarboxylase antizyme: a novel type of regulatory protein. Trends Biochem. Sci. 21, 27-30 (1996).
110. Matsufuji, S., Matsufuji, T., Wills, N. M., Gesteland, R. F. & Atkins, J. F. Reading two bases twice: mammalian antizyme frameshifting in yeast. EMBO J. 15, 1360-1370 (1996).
111. Tsuji, T. et al. Induction of epithelial differentiation and DNA demethylation in hamster malignant oral keratinocyte by omithine decarboxylase antizyme. Oncogene 20, 24-33 (2001).
112. 1-acetyltransferase: the turning point in polyamine metabolism. FASEB J. 7, 653-661 (1993).
113. Thomas, T. & Thomas, T. J. Polyamine metabolism and cancer. J. Cell. Mol. Med. 7, 113-126 (2003).
114. Eimer, S., Lakowski, B., Donhauser, R. & Baumeister, R. Loss of spr-5 bypasses the requirement for the C. elegans presenilin sel-12 by derepressing hop-1. EMBO J. 21, 5787-5796 (2002).
115. Hixson, L. J., Emerson, S. S., Shassetz, L. R. & Gerner, E. W. Sources of variability in estimating ornithine decarboxylase activity and polyamine contents in human colorectal mucosa. Cancer Epidemiol. Biomarkers Prev. 3, 317-323 (1994).
116. Xie, X., Gilles, R. J. & Gerner, E. W. Characterization of a diamine exporter in Chinese hamster ovary cells and identification of specific polyamine substrates. J. Biol. Chem. 272, 20484-20489 (1997).
117. Wang, Y. et al. Properties of purified recombinant human potyamine oxidase, PAOh1/SMO. Biochem. Biophys. Res. Commun. 304, 605-611 (2003).
118. Cornbleet, M. A. et al. Phase I study of methylacetylenic putrescine, an inhibitor of polyamine biosynthesis. Cancer Chemother. Pharmacol. 23, 348-352 (1989).
119. Gastaut, J. A. et al. Treatment of acute myeloid leukemia and blastic phase of chronic myeloid leukemia with combined eflornithine (α difluoromethylornithine) and methylglyoxal-bis-guanyl hydrazone (methyl-GAG). Cancer Chemother. Pharmacol. 20, 344-348 (1987).
120. Wilding, G. et al. Phase I trial of the polyamine analog N1,N14-diethylhomospermine (DEHSPM) in patients with advanced solid tumors. Invest. New Drugs 22, 131-138 (2004).
121. Thompson, I. M. et al. The influence of finasteride on the development of prostate cancer. N. Engl. J. Med. 349, 215-224 (2003).