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Polyamine Metabolism and Its Importance in Neoplastic Growth and as a Target for Chemotherapy¹

Departments of Physiology and Pharmacology and Cancer Research Center, Milton S. Hershey Medical Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

The polyamine-biosynthetic pathway represents an inviting target for the development of agents inhibiting carcinogenesis and tumor growth. Polyamines play an essential role in the proliferation and development of mammalian cells. Deranged polyamine metabolism may be an important factor in carcinogenesis. Depletion of polyamines inhibits growth of neoplastic cells in vitro and in animal models. Several different classes of other anticancer agents may under some conditions exert enhanced effects when polyamine levels are depleted. Some suitable inhibitors of polyamine production are currently available and other promising compounds are presently being tested. It should soon prove possible to block polyamine biosynthesis at every step in the pathway. The use of these inhibitors alone and combined either with each other or with other antitumor agents will enable a full examination of the potential of this approach.

¹ Research on polyamines in the author's laboratory was supported by Grants CA-18138, GM-26290, and CA-37606 from the NIH.

Received 10/14/87. Accepted 11/10/87.

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				L. Y. Y. Fong, V. T. Nguyen, A. E. Pegg, and P. N. Magee {{alpha}}-Difluoromethylornithine Induction of Apoptosis: A Mechanism Which Reverses Pre-established Cell Proliferation and Cancer Initiation in Esophageal Carcinogenesis in Zinc-deficient Rats Cancer Epidemiol. Biomarkers Prev., March 1, 2001; 10(3): 191 - 199. [Abstract] [Full Text]

				W. Durante, L. Liao, S. V. Reyna, K. J. Peyton, and A. I. Schafer Transforming Growth Factor-{beta}1 Stimulates L-Arginine Transport and Metabolism in Vascular Smooth Muscle Cells : Role in Polyamine and Collagen Synthesis Circulation, February 27, 2001; 103(8): 1121 - 1127. [Abstract] [Full Text] [PDF]

				H. A. Hahm, V. R. Dunn, K. A. Butash, W. L. Deveraux, P. M. Woster, R. A. Casero Jr., and N. E. Davidson Combination of Standard Cytotoxic Agents with Polyamine Analogues in the Treatment of Breast Cancer Cell Lines Clin. Cancer Res., February 1, 2001; 7(2): 391 - 399. [Abstract] [Full Text]

				O. Erez and C. Kahana Screening for Modulators of Spermine Tolerance Identifies Sky1, the SR Protein Kinase of Saccharomyces cerevisiae, as a Regulator of Polyamine Transport and Ion Homeostasis Mol. Cell. Biol., January 1, 2001; 21(1): 175 - 184. [Abstract] [Full Text]

				D. S. Alberts, R. T. Dorr, J. G. Einspahr, M. Aickin, K. Saboda, M. J. Xu, Y.-M. Peng, R. Goldman, J. A. Foote, J. A. Warneke, et al. Chemoprevention of Human Actinic Keratoses by Topical 2-(Difluoromethyl)-dl-ornithine Cancer Epidemiol. Biomarkers Prev., December 1, 2000; 9(12): 1281 - 1286. [Abstract] [Full Text]

				Y. Takatsuka, Y. Yamaguchi, M. Ono, and Y. Kamio Gene Cloning and Molecular Characterization of Lysine Decarboxylase from Selenomonas ruminantium Delineate Its Evolutionary Relationship to Ornithine Decarboxylases from Eukaryotes J. Bacteriol., December 1, 2000; 182(23): 6732 - 6741. [Abstract] [Full Text]

				J. Moffatt, M. Hashimoto, A. Kojima, D. O. Kennedy, A. Murakami, K. Koshimizu, H. Ohigashi, and I. Matsui-Yuasa Apoptosis induced by 1'-acetoxychavicol acetate in Ehrlich ascites tumor cells is associated with modulation of polyamine metabolism and caspase-3 activation Carcinogenesis, December 1, 2000; 21(12): 2151 - 2157. [Abstract] [Full Text] [PDF]

				A. Paasinen-Sohns, M. Kielosto, E. Kaariainen, T. Eloranta, A. Laine, O. A. Janne, M. J. Birrer, and E. Holtta C-Jun Activation-Dependent Tumorigenic Transformation Induced Paradoxically by Overexpression or Block of S-Adenosylmethionine Decarboxylase J. Cell Biol., November 13, 2000; 151(4): 801 - 810. [Abstract] [Full Text] [PDF]

				K. Limsuwun and P. G. Jones Spermidine Acetyltransferase Is Required To Prevent Spermidine Toxicity at Low Temperatures in Escherichia coli J. Bacteriol., October 1, 2000; 182(19): 5373 - 5380. [Abstract] [Full Text]

				L. Lan, C. Trempus, and S. K. Gilmour Inhibition of Ornithine Decarboxylase (ODC) Decreases Tumor Vascularization and Reverses Spontaneous Tumors in ODC/Ras Transgenic Mice Cancer Res., October 1, 2000; 60(20): 5696 - 5703. [Abstract] [Full Text]

				P. P. Carbone, J. A. Douglas, J. Thomas, K. Tutsch, M. Pomplun, M. Hamielec, and D. Pauk Bioavailability Study of Oral Liquid and Tablet Forms of {{alpha}}-Difluoromethylornithine Clin. Cancer Res., October 1, 2000; 6(10): 3850 - 3854. [Abstract] [Full Text]

				R. J. Bergeron, R. L. Merriman, S. G. Olson, J. Wiegand, J. Bender, R. R. Streiff, and W. R. Weimar Metabolism and Pharmacokinetics of N ,N11-Diethylnorspermine in a Cebus apella Primate Model Cancer Res., August 1, 2000; 60(16): 4433 - 4439. [Abstract] [Full Text]

				W. W. and C. M. Higuchi Dietary Soy Protein Is Associated with Reduced Intestinal Mucosal Polyamine Concentration in Male Wistar Rats J. Nutr., July 1, 2000; 130(7): 1815 - 1820. [Abstract] [Full Text]

				R. Singh, S. Pervin, A. Karimi, S. Cederbaum, and G. Chaudhuri Arginase Activity in Human Breast Cancer Cell Lines: N{{omega}}-Hydroxy-L-arginine Selectively Inhibits Cell Proliferation and Induces Apoptosis in MDA-MB-468 Cells Cancer Res., June 1, 2000; 60(12): 3305 - 3312. [Abstract] [Full Text]

				F. A. L. M. Eskens, G. A. Greim, C. van Zuylen, I. Wolff, L. J. Denis, A. S. Th. Planting, F. A. Muskiet, J. Wanders, N. C. Barbet, L. Choi, et al. Phase I and Pharmacological Study of Weekly Administration of the Polyamine Synthesis Inhibitor SAM 486A (CGP 48 664) in Patients with Solid Tumors Clin. Cancer Res., May 1, 2000; 6(5): 1736 - 1743. [Abstract] [Full Text] [PDF]

				M. A. Hoyt, M. Broun, and R. H. Davis Polyamine Regulation of Ornithine Decarboxylase Synthesis in Neurospora crassa Mol. Cell. Biol., April 15, 2000; 20(8): 2760 - 2773. [Abstract] [Full Text]

				B. S. Reddy Novel Approaches to the Prevention of Colon Cancer by Nutritional Manipulation and Chemoprevention Cancer Epidemiol. Biomarkers Prev., March 1, 2000; 9(3): 239 - 247. [Abstract] [Full Text]

				R. M. Ray, M. J. Viar, Q. Yuan, and L. R. Johnson Polyamine depletion delays apoptosis of rat intestinal epithelial cells Am J Physiol Cell Physiol, March 1, 2000; 278(3): C480 - C489. [Abstract] [Full Text] [PDF]

				P. H. M. Hoet and B. Nemery Polyamines in the lung: polyamine uptake and polyamine-linked pathological or toxicological conditions Am J Physiol Lung Cell Mol Physiol, March 1, 2000; 278(3): L417 - L433. [Abstract] [Full Text] [PDF]

				D. E. Graham, C. L. Bock, C. Schalk-Hihi, Z. J. Lu, and G. D. Markham Identification of a Highly Diverged Class of S-Adenosylmethionine Synthetases in the Archaea J. Biol. Chem., February 11, 2000; 275(6): 4055 - 4059. [Abstract] [Full Text] [PDF]

				E. I. Salim, H. Wanibuchi, K. Morimura, S. Kim, Y. Yano, S. Yamamoto, and S. Fukushima Inhibitory effects of 1,3-diaminopropane, an ornithine decarboxylase inhibitor, on rat two-stage urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine Carcinogenesis, February 1, 2000; 21(2): 195 - 203. [Abstract] [Full Text] [PDF]

				M. Ketteler, R. Westenfeld, A. Gawlik, E. de Heer, and A. Distler Acute glomerular upregulation of ornithine decarboxylase is not essential for mesangial cell proliferation and matrix expansion in anti-Thy-1-nephritis Nephrol. Dial. Transplant., January 1, 2000; 15(1): 16 - 22. [Abstract] [Full Text] [PDF]

				B. Saverio, D. Pierpaola, A. Serenella, C. Cesare, M. Bruno, T. Auro, and C. Arnaldo Tumor Progression Is Accompanied by Significant Changes in the Levels of Expression of Polyamine Metabolism Regulatory Genes and Clusterin (Sulfated Glycoprotein 2) in Human Prostate Cancer Specimens Cancer Res., January 1, 2000; 60(1): 28 - 34. [Abstract] [Full Text]