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

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 , can synthesize DNA both in a template-dependent (polymerase) and template-independent (terminal deoxyribonucleotidyl transferase) fashion. DNA polymerase 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 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 for publication March 30, 2005.

Accepted for publication 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

This article has been cited by other articles:

				G. Maga, E. Crespan, U. Wimmer, B. van Loon, A. Amoroso, C. Mondello, C. Belgiovine, E. Ferrari, G. Locatelli, G. Villani, et al. Replication protein A and proliferating cell nuclear antigen coordinate DNA polymerase selection in 8-oxo-guanine repair PNAS, December 30, 2008; 105(52): 20689 - 20694. [Abstract] [Full Text] [PDF]