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64 Mustafa Yatin enhanced rates of PA uptakes that leads to elevated levels of PA. ODC also exhibits properties of oncogens, like c-myc, c-fos, c-jun, and expression of oncogens like src, neu, and Ha-ras result in significant increases of ODC activity. Similarly, inhibition of polyamine biosynthetic enzymes by specific inhibitors and depletion of PA levels is strongly associated with decreased transcription of the c-myc, c-fos and ODC gene. Inserting a partial cDNA coding for ODC under the control of a strong viral promoter and by transfecting the plasmid to cells caused to stable ODC over-expression (Thomas and Thomas, 2001; Janne et al., 1991; Marton and Pegg, 1995). These transfected ODC over-expressed cells showed malignant transformation and upon inoculation to nude mice, they produced extensively vascularized, aggressive tumors (Thomas and Thomas, 2001). Thus, these evidences from in vitro and in vivo studies suggested that oncogenes may enhance the transcription of the ODC gene and certain oncogens induce ODC and enhance the formation of PA, and vice versa, PA induce expression of oncogens. Polyamine synthesis inhibitors Blockade of ODC enzyme activity by DFMO causes a time dependent decrease of the cellular Put level, followed by a decrease of Spd, in contrast, Spm concentrations are usually not much effected and even may increase. The decreases in Put concentration is obvious due to impairment of its producing enzyme ODC. The depletion of Spd has mainly three reasons: first, decreased formation due the limited availability of Put as substrate of Spd synthase. Second, dilution of PA pool due to cell division and decrease in the amount per cell. Third, enhanced formation of Spm due to elevation in AdoMetDC activity. The reason for the induction of AdoMetDC in DFMO treated cells (thus Spd depleted) is the unavailability of Put as substrate. This consequently causes to excessive availability of dcAdoMet and leads to accumulation of Spm in the cells. AdoMetDC is effectively inhibited by methylglyoxal bis (guanylhydrazone) (MGBG) and this drug can be also be to inhibit PA synthesis (to decline Spd and Spm levels) in vivo. However, MGBG is not specific to AdoMetDC, it also inhibits diamine oxidase (DAO) and has chemical structre with considerable resemblance to PA and is taken up by the same transport system as PA. Therefore, it is difficult to prove the antiproliferative effects of MGBG are due to PA depletion as its effects can be reversed by exogenous addition of Spd could simply be due to displacement of MGBG from intracellular sites by structuraly similar Spd or competitive interference with drug transport. Additionaly, therapeutic combination of MGBG with DFMO causes to abnormal accumulation in the cells and non-specific cytoxicities. In recent years, industrial research programs (Ciba-Geigy) developed structural derivatives of MGBG to minimize non-specific effects. The bicyclic analog of MGBG, 4-(aminoiminomethyl)-2,3-dhydro-1 Hinden-1-onediaminomethylenehydrazone (CGP-48664) fulfilled this criterion, eliminating the severe toxicities associated with parent compound. Mutant cell lines lacking PA transport are resistant to MGBG, but they remain sensitive to CGP-48644 (Thomas and Thomas, 2001). Thus, CGP-48644, not like MGBG, does not share the same uptake mechanism with PA, allowing combination with DFMO to deplete all three PA levels, has a much broader therapeutic window than MGBG. The back conversion of Spm to Spd and to Put is mediated by dual actions of N1-acetylation (SSAT) followed by oxidative removal acetamidopropanal by polyamine oxidase (PAO) to maintain the proper balance of PA pools to ensure cell growth (Figure 1). Although no inhibitor is developed to specifically inactivate SSAT, a series of compounds have been designed to inhibit PAO very potently and efficiently (Bolkenius et al., 1985). The most widely used of these inhibitors is the polyamine analogue, N1-N2-bis (2,3-butadienyl)-1,4-butanediamine (MDL-72527). Cells treated with MDL-72527 alone are not growth inhibited, indicating that the back conversion pathway is not a critical step for cell growth under normal conditions. However, when MDL-72527 was administered in combination with other PA enzyme inhibitors (i.e. DFMO) or PA analogues, a much greater depletion of PA pools were achieved and caused significant growth inhibition than either agent given alone (Claveria et al., 1987; Prakash et al., 1990). Polyamine analogues Porter and Bergeron(1988) were the first to suggest the use of polyamine analogues as a new approach in
chemotherapy and lead to a very large number of structural analogues and homologs with the general formula: R1-NH-(CH2)a-NH-(CH2)b-NH-(CH2)-NH- R2, where R1 and R2 are alkyl residues, and a and b is any integer number. In general, polyamine analogues competitively use the same transport system with PA to incorporate cells, interferes with PA metabolism, lacks the necessary physiological functions of PA in normal cellular functions, but suppress ODC and AdoMetDC activities and induce SSAT activities, leads to rapid depletion of PA levels (Bergeron et al., 1997). Starting in mid 1980s efforts to synthesize and identify specific PA inhibitors have began in several academic and industrial laboratories. The structural characteristics of these PA transport inhibitors (i.e. compounds which deter or compete with natural PA for transport) have been analyzed by QSAR and by COMFA (comparative molecular field analysis) as well as simple charge to chain length correlation produced a preliminary theoretical predictive model to design new analogues (Xia et al., 1997; Li et al., 1997; Burns et al., 2001). References Albensi BC, Alasti N and Mueller AL. Long-term potentiation of in the presence of NMDA receptor antagonist arylalkylamine spider toxins. J Neurosci Res. 62: 177-185, 2000. Austin TX, Moulinoux JP, Quemener V, Delcros JG and Cippolla B. Circulating polyamines as biological markers for cancer. In: Polyamines in Cancer: Basic Mechanisms and Clinical Approaches. Nishioka K (Ed). Chapman Hill. 233-249, 1996. Aziz SM, Olson JW and Gillespie M. Multiple polyamine transport pathways in cultured pulmonary artery smooth muscle cells: Regulation by hypoxia. Am J Respir Cell Mol Biol. 10:160-166, 1994. Bergeron R J, Feng Y, Weimar WR, Mcmannis JS, Dimova H, Porter C, Raisler B and Phanstiel O. A comparison of structure-activity relationships between spermidine and spermine analogue antineoplastics. J Med Chem. 40: 1475-1494, 1997. Bergeron RJ, McManis JS, Weimar WR, Scherier KM, Gao F, Wu Q, Ortiz-Ocasio J, Luchetta GR, Porter C and Vinson JRT. The role of charge in polyamine analogue recognition. J Med Chem. 38: 2278-2285, 1995. Bolkenius F, Bey P and Seiler N. Specific inhibition of polyamine oxidase in vivo is a method for the elucidation of its physiological role. Biochem Biophys Acta. 828: 69-76, 1985. Polyamines 65 Burns MR, Carlson CL, Vanderwerf SM, Ziemer JR, Weeks RS, Cai F, Webb HK and Graminski GF. Amino acid/spermine conjugates: Polyamine amides as a potent spermidine uptake inhibitors. J Med Chem. 44: 3632-3644, 2001. Byers TL and Pegg AE. Properties and physiological function of the polyamine transport system. Am J Physiol (Cell Physiol 26). 257: C545-C553, 1989. Canellakis E and Hayashi SI. Ornithine decarboxylase antizymes. In: Ornithine Decarboxylase Biology, Enzymology and Molecular Genetics. Shin-‹chi Hayashi (Ed). Pergamon Press. 1989. Claveria N, Wagner J and Knogden B. Inhibition of polyamine oxidase improves the antitumor effect of ornithine decarboxylase inhibitors. Cancer Res. 7: 765-772, 1987. Coffino P. Regulation of cellular polyamines by antizyme. Nature Reviews Molecular Cell Biology. 2: 188-194, 2001. Coffino P. Antizyme, a mediator of ubiquitin-independent proteasomal degradation. Biochimie. 83: 319-323, 2001. Feuerestein BG, Williams LD, Basu HS and Marton LJ. Implications and concepts of polyamine - nucleic acid interactions. J Cell Biochem. 46: 37-47, 1991. Gilad GM and Gilad VH. Novel polyamine derivatives as neuroprotective agents. J Pharmacol Exp Therap. 291: 39-43, 1999. Hayashi S and Murakami Y. Rapid and regulated degradation of ornithine decarboxylase. Biochem J. 306: 1-10, 1995. Hayashi S, Murakami Y and Matsufuji S. Ornithine decarboxylase antizyme: A novel type regulatory protein. Trends Biochem Sci. 21: 27-30, 1996. He Y, Suzuki T, Kashiwagi K and Igarashi K. Antizyme delays the restoration by spermine of growth of polyamine-deficient cells through its negative regulation of polyamine transport. Biochem Biophys Res Com. 203:608-614, 1994. Hebby O. Role of Polyamines in the control of cell proliferation and differentiation. Differentiation. 19: 1-20, 1981. Heller JS, Fong WF and Cannelakis ES. Induction of a protein inhibitor to ornithine decarboxylase by the end products of its reaction. Proc Natl Acad Sci USA. 73: 1858-1862, 1976. Hoet PHM and Nemery B. Polyamines in the lung: polyamine uptake and polyamine-linked pathological or toxicological conditions. Am J Phsiol Lung Cell Mol Physiol. 278: L417-L433, 2000. http://www.ucmp.berkeley.edu/history/leeuwenhoek.html Hyvonen T, Seiler N and Persson L. Characterization of a COS cell line deficient polyamine transport. Biochim Biophys Acta. 1221, 279-285, 1994. Igarashi K and Kashiawagi K. Polyamines: Mysterious modulators of cellular functions. Bioche Biophys Res Com. 271: 559-564, 2000. Janne J, Alhonen L and Leinonen. Polyamines: From molecular biology to clinical applications. Trends in Mol Med. 23: 241-259, 1991.
Page 1 and 2: STANBUL 1998 VOLUME 1 • NO. 2 •
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Page 5 and 6: 46 Gülriz Bayçu Cd Contamination
Page 7 and 8: 48 Gülriz Bayçu Figure 2: Optimiz
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Page 11 and 12: 52 Gülriz Bayçu plants and fungi
Page 13 and 14: 54 Gülriz Bayçu References Abraha
Page 17 and 18: cells (cancer), inflammatory sites
Page 19 and 20: 1991, Russel and Synder, 1968; Pegg
Page 21: Figure 3: Several sources of PAs ar
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Page 27 and 28: 70 Tülin Aktaç and Elvan Bakar Ma
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Page 31 and 32: 74 Seyhan Altun et al. Altun (1996)
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