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Research Articles: Therapeutics, Targets, and Development

Activation of clinically used anthracyclines by the formaldehyde-releasing prodrug pivaloyloxymethyl butyrate

¹ Department of Biochemistry, La Trobe University, Bundoora, Victoria, Australia; ² Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Beilinson Campus, Petach Tikva, Israel; and ³ Department of Chemistry, Bar Ilan University, Ramat Gan, Israel

Requests for reprints: Suzanne M. Cutts, Department of Biochemistry, La Trobe University, Bundoora, Victoria 3086, Australia. Phone: 61-3-94791517; Fax: 61-3-94792467. E-mail: S.cutts{at}latrobe.edu.au

Abstract

The anthracycline group of compounds is extensively used in current cancer chemotherapy regimens and is classified as topoisomerase II inhibitor. However, previous work has shown that doxorubicin can be activated to form DNA adducts in the presence of formaldehyde-releasing prodrugs and that this leads to apoptosis independently of topoisomerase II–mediated damage. To determine which anthracyclines would be useful in combination with formaldehyde-releasing prodrugs, a series of clinically relevant anthracyclines (doxorubicin, daunorubicin, idarubicin, and epirubicin) were examined for their capacity to form DNA adducts in MCF7 and MCF7/Dx (P-glycoprotein overexpressing) cells in the presence of the formaldehyde-releasing drug pivaloyloxymethyl butyrate (AN-9). All anthracyclines, with the exception of epirubicin, efficiently yielded adducts in both sensitive and resistant cell lines, and levels of adducts were similar in mitochondrial and nuclear genomes. Idarubicin was the most active compound in both sensitive and resistant cell lines, whereas adducts formed by doxorubicin and daunorubicin were consistently lower in the resistant compared with sensitive cells. The adducts formed by doxorubicin, daunorubicin, and idarubicin showed the same DNA sequence specificity in sensitive and resistant cells as assessed by -exonuclease–based sequencing of -satellite DNA extracted from drug-treated cells. Growth inhibition assays were used to show that doxorubicin, daunorubicin, and idarubicin were all synergistic in combination with AN-9, whereas the combination of epirubicin with AN-9 was additive. Although apoptosis assays indicated a greater than additive effect for epirubicin/AN-9 combinations, this effect was much more pronounced for doxorubicin/AN-9 combinations. [Mol Cancer Ther 2007;6(4):1450–9]

Grant support: Australian Research Council (S.M. Cutts and D.R. Phillips) and Israel Science Foundation grant 542/00-4 (A. Rephaeli and A. Nudelman).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: S.M. Cutts and L.P. Swift contributed equally to this work and are first authors.

⁴ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 9/ 7/06; revised 1/31/07; accepted 2/22/07.

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