One strategy for inhibiting tumour cell growth is the use of polyamine mimetics to depress endogenous polyamine levels and, ideally, obstruct critical polyamine-requiring reactions. Such polyamine analogues make very unusual drugs, in that extremely high intracellular concentrations are required for growth inhibition or cytotoxicity. Cells exposed to even sub-micromolar concentrations of such analogues can achieve effective intracellular levels because these compounds are incorporated by the very aggressive polyamine uptake system. Once incorporated to these levels, many of these analogues induce the synthesis of a regulatory protein, antizyme, which inhibits both polyamine synthesis and the transporter they used to enter the cell. Thus this feedback system allows steady-state maintenance of effective cellular doses of such analogues. Accordingly, effective cellular levels of polyamine analogues are generally inversely related to their capacity to induce antizyme. Antizyme activity is down-regulated by interaction with several binding partners, most notably antizyme inhibitor, and at least a few tumour tissues exhibit deficiencies in antizyme expression. Our studies explore the role of antizyme induction by several polyamine analogues in their physiological response and the possibility that cell-to-cell differences in antizyme expression may contribute to variable sensitivities to these agents.
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April 2007
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Conference Article|
March 20 2007
Unusual aspects of the polyamine transport system affect the design of strategies for use of polyamine analogues in chemotherapy
J.L.A. Mitchell;
J.L.A. Mitchell
1
1Northern Illinois University, DeKalb, IL 60115, U.S.A.
1To whom correspondence should be addressed (email jmitchell@niu.edu).
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T.K. Thane;
T.K. Thane
1Northern Illinois University, DeKalb, IL 60115, U.S.A.
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J.M. Sequeira;
J.M. Sequeira
1Northern Illinois University, DeKalb, IL 60115, U.S.A.
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R. Thokala
R. Thokala
1Northern Illinois University, DeKalb, IL 60115, U.S.A.
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Publisher: Portland Press Ltd
Received:
October 09 2006
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2007 The Biochemical Society
2007
Biochem Soc Trans (2007) 35 (2): 318–321.
Article history
Received:
October 09 2006
Citation
J.L.A. Mitchell, T.K. Thane, J.M. Sequeira, R. Thokala; Unusual aspects of the polyamine transport system affect the design of strategies for use of polyamine analogues in chemotherapy. Biochem Soc Trans 1 April 2007; 35 (2): 318–321. doi: https://doi.org/10.1042/BST0350318
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