MolPharm Over 1500 Individual Drug Articles!

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on May 18, 2005; DOI: 10.1124/mol.105.013326

0026-895X/05/6802-538-550$20.00
Mol Pharmacol 68:538-550, 2005

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.105.013326v1
68/2/538    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
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 Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Locatelli, G. A.
Right arrow Articles by Maga, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Locatelli, G. A.
Right arrow Articles by Maga, G.

Diketo Hexenoic Acid Derivatives Are Novel Selective Non-Nucleoside Inhibitors of Mammalian Terminal Deoxynucleotidyl Transferases, with Potent Cytotoxic Effect against Leukemic Cells

Giada A. Locatelli, Roberto Di Santo, Emmanuele Crespan, Roberta Costi, Alessandra Roux, Ulrich Hübscher, Igor Shevelev, Giuseppina Blanca, Giuseppe Villani, Silvio Spadari, and Giovanni Maga

Istituto di Genetica Molecolare IGM-CNR, Pavia, Italy (G.A.L., E.C., S.S., G.M.); Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università di Roma "La Sapienza", Roma, Italy (R.D.S., R.C., A.R.); Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich-Irchel, Zürich, Switzerland (U.H., I.S.); and Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Toulouse Cedex, France (G.B., G.V.)

Mammalian terminal deoxyribonucleotidyl transferase (TDT) catalyzes the non–template-directed polymerization of deoxyribonucleoside triphosphates and has a key role in V(D)J recombination during lymphocyte and repertoire development. More than 90% of leukemic cells in acute lymphocytic leukemia and approximately 30% of leukemic cells in the chronic myelogenous leukemia crisis show elevated TDT activity. This finding is connected to a poor prognosis and response to chemotherapy and reduced survival time. On the other hand, recent data indicated that TDT is not the only terminal deoxyribonucleotidyl transferase in mammalian cells. Its close relative, DNA polymerase {lambda}, can synthesize DNA both in a template-dependent (polymerase) and template-independent (terminal deoxyribonucleotidyl transferase) fashion. DNA polymerase {lambda} might be involved in the nonhomologous end-joining recombinational repair pathway of DNA double-strand breaks. In this work, we report the characterization of the mechanism of action of three diketo hexenoic acid (DKHA) derivatives, which proved to be extremely selective for the terminal deoxyribonucleotidyl transferase activity of DNA polymerase {lambda} and TDT. They seem to be the first non–nucleoside-specific inhibitors of mammalian terminal transferases reported. Moreover, the DKHA analog 6-(1-phenylmethyl-1H-indol-3-yl)-2,4-dioxo-5-hexenoic acid (RDS2119) was not toxic toward HeLa cells (CC50 > 100 µM), whereas it showed significant cytotoxicity against the TDT+ leukemia cell line MOLT-4 (CC50 = 14.9 µM), thus having the potential to be further developed as a novel antitumor agent.

Received March 30, 2005; accepted May 18, 2005

Address correspondence to: Dr. Giovanni Maga, Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy. E-mail: maga{at}igm.cnr.it






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2005 by the American Society for Pharmacology and Experimental Therapeutics