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DNA crosslinking and biological activity of a hairpin polyamide–chlorambucil conjugate

Wang, Yong-Dong and Dziegielewski, Jaroslaw and Wurtz, Nicholas R. and Dziegielewska, Barbara and Dervan, Peter B. and Beerman, Terry A. (2003) DNA crosslinking and biological activity of a hairpin polyamide–chlorambucil conjugate. Nucleic Acids Research, 31 (4). pp. 1208-1215. ISSN 0305-1048.

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A prototype of a novel class of DNA alkylating agents, which combines the DNA crosslinking moiety chlorambucil (Chl) with a sequence-selective hairpin pyrrole-imidazole polyamide ImPy-beta-ImPy-gamma-ImPy-beta-Dp (polyamide 1), was evaluated for its ability to damage DNA and induce biological responses. Polyamide 1-Chl conjugate (1-Chl) alkylates and interstrand crosslinks DNA in cell-free systems. The alkylation occurs predominantly at 5'-AGCTGCA-3' sequence, which represents the polyamide binding site. Conjugate-induced lesions were first detected on DNA treated for 1 h with 0.1 muM 1-Chl, indicating that the conjugate is at least 100-fold more potent than Chl. Prolonged incubation allowed for DNA damage detection even at 0.01 muM concentration. Treatment with 1-Chl decreased DNA template activity in simian virus 40 (SV40) in vitro replication assays. 1-Chl inhibited mammalian cell growth, genomic DNA replication and cell cycle progression, and arrested cells in the G(2)/M phase. Moreover, cellular effects were observed at 1-Chl concentrations similar to those needed for DNA damage in cell-free systems. Neither of the parent compounds, unconjugated Chl or polyamide 1, demonstrated any cellular activity in the same concentration range. The conjugate molecule 1-Chl possesses the sequence-selectivity of a polyamide and the enhanced DNA reactivity of Chl.

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Additional Information:Copyright © 2003 Oxford University Press. Reprinted with permission. Received as resubmission October 28, 2002; Accepted December 10, 2002. We are very grateful to Loretta Gawron for technical assistance and to Drs Marry M. McHugh and Christine M. White from Roswell Park Cancer Institute for careful reading of this manuscript and insightful comments. This study was supported in part by NIH grants CA80939 and CA16056 to T.A.B., and GM57148 to P.B.D. N.R.W. was supported by predoctoral fellowships from Bristol-Myers Squibb and the Ralph M. Parsons Foundation.
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1641
Deposited By: Tony Diaz
Deposited On:08 Feb 2006
Last Modified:26 Dec 2012 08:45

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