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¹ University of Texas Health Science Center, San Antonio, Texas and ² University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Jan M. Woynarowski, Department of Radiation Oncology, University of Texas Health Science Center, 14960 Omicron Drive, San Antonio, TX 78245. Phone: 210-677-3832; Fax: 210-677-0058. E-mail: jmw1{at}idd.org

Targeting topoisomerase II (topo II) is regarded as an important component of the pleiotropic mechanism of action of anthracycline drugs. Here, we show that 4-demethoxy analogues of doxorubicin, including annamycin, exhibit a greater ability to trap topo II cleavage complexes than doxorubicin and some other 4-methoxy analogues. In leukemic CEM cells with wild-type topo II, annamycin induced substantial levels of topo II–mediated DNA-protein cross-links (15-37% of total DNA for 0.5-50 µmol/L drug), whereas doxorubicin-induced DNA-protein cross-links were marginal (0-4%). In CEM/VM-1 cells that harbor mutated, drug-resistant topo II, both 4-methoxy and 4-demethoxy drugs produced marginal DNA-protein cross-links. Annamycin, but not doxorubicin, formed topo II–mediated DNA-protein cross-links also in isolated CEM nuclei. In disparity with the unequal DNA-protein cross-link induction, both drugs induced comparable levels of DNA strand breaks in CEM cells. Compared with CEM, drug cytotoxicity against CEM/VM-1 cells was reduced 10.5- to 13.8-fold for 4-demethoxy analogues but only 3.8- to 5.5-fold for 4-methoxy drugs. Hence, growth inhibition by 4-demethoxy analogues seems more dependent on the presence of wild-type topo II. The enhanced topo II targeting by 4-demethoxy analogues was accompanied by a profound induction of apoptotic DNA fragmentation in leukemic CEM cells. Normal WI-38 fibroblasts, however, were markedly more resistant to annamycin-induced DNA-protein cross-links, apoptosis, and growth inhibition. The enhanced topo II targeting by 4-demethoxy doxorubicin analogues underscores the mechanistic diversity of anthracycline drugs. This diversity needs to be recognized as a factor in responses to drugs such as annamycin and doxorubicin.

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Received 1/14/04; revised 7/16/04; accepted 9/ 8/04.

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