Skip Navigation



Journal of Biochemistry Advance Access published online on September 23, 2006
Journal of Biochemistry, doi:10.1093/jb/mvj193
This Article
Right arrow Advance Access manuscript (PDF)
Right arrow All Versions of this Article:
140/5/657    most recent
mvj193v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Petros, L. M.
Right arrow Articles by Weeks, R. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Petros, L. M.
Right arrow Articles by Weeks, R. S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2006 The Japanese Biochemical Society.
Received August 8, 2006
Accepted September 14, 2006

Regular Paper

Polyamine Analogs with Xylene Rings Induce Antizyme Frameshifting, Reduce ODC Activity, and Deplete Cellular Polyamines

Lorin M. Petros 1 {dagger}, Gerard F. Graminski 2 {dagger}, Susan Robinson 2, Mark R. Burns 2, Nicholas Kisiel 3, Raymond F. Gesteland 1, John F. Atkins 1, Debora L. Kramer 3, Michael T. Howard 1 *, and Reitha S. Weeks 2

1 Department of Human Genetics, University of Utah, 15 N 2030 E, Rm 7410, Salt Lake City, UT 84112-5330
2 MediQuest Therapeutics, Inc., 22322 20th Avenue SE, Ste. 100, Bothell, WA 98021
3 Pharmacology and Therapeutics Dept., Roswell Park Cancer Institute, Buffalo, NY 14263

* To whom correspondence should be addressed.
Michael T. Howard, E-mail: mhoward{at}genetics.utah.edu


  Abstract

Numerous studies have correlated elevated polyamine levels with abnormal or rapid cell growth. One therapeutic strategy to treat diseases with increased cellular proliferation rates, most obviously cancer, has been to identify compounds which lower cellular polyamine levels. An ideal target for this strategy is the protein antizyme - a negative regulator of polyamine biosynthesis and import, and a positive regulator of polyamine export. In this study, we have optimized two tissue-culture assays in 96-well format, to allow the rapid screening of a 750-member polyamine analog library for compounds which induce antizyme frameshifting and fail to substitute for the natural polyamines in growth. Five analogs (MQTPA1-5) containing xylene (1,4-dimethyl benzene) were found to be equal to or better than spermidine at stimulating antizyme frameshifting and were inefficient at rescuing cell growth following polyamine depletion. These compounds were further characterized for effects on natural polyamine levels and enzymes involved in polyamine metabolism. Finally, direct measurements of antizyme induction in cells treated with two of the lead compounds revealed an 8 to 15-fold increase in antizyme protein over untreated cells. The impact of the xylene moiety and the distance between the positively charged amino groups on antizyme frameshifting and cell growth are discussed.

Keywords: polyamine analog; antizyme; frameshift; drug screen; ornithine decarboxylase.
{dagger}These authors contributed equally to the work
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 CarcinogenesisHome page
X. Wang, D. J. Feith, P. Welsh, C. S. Coleman, C. Lopez, P. M. Woster, T. G. O'Brien, and A. E. Pegg
Studies of the mechanism by which increased spermidine/spermine N1-acetyltransferase activity increases susceptibility to skin carcinogenesis
Carcinogenesis, November 1, 2007; 28(11): 2404 - 2411.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.