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Cell Cycle, Cell Death, and Senescence

E1A Specifically Enhances Sensitivity to Topoisomerase II Targeting Anticancer Drug by Up-Regulating the Promoter Activity

Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Eugenie S. Kleinerman, Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Unit 87, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-8110; Fax: 713-794-5042. E-mail: ekleiner{at}mail.mdanderson.org

DNA topoisomerases I and II (topo I and II) are nuclear enzymes involved in cellular replication and are targets for several anticancer drugs. We showed previously that E1A gene transfer enhanced the sensitivity of Ewing's sarcoma cells to the topo II targeting agents etoposide and Adriamycin in vitro and in vivo. To determine whether this effect was specific for topo II, we investigated the effect of E1A gene transfer on cell sensitivity to agents that target topo I and IIß. Transfecting TC71 human Ewing's sarcoma cells with an adenoviral vector containing the E1A gene enhanced their sensitivity to the topo II targeting agents etoposide (16-fold) and Adriamycin (8-fold). By contrast, E1A gene transfer did not affect cellular sensitivity to either amsacrine or camptothecin. Western blot analysis indicated that topo II protein levels increased 3.1-fold after E1A gene transfer, but topo I and IIß protein levels did not change. A plasmid containing topo II gene promoter with luciferase reporter gene was constructed to determine the effects of E1A gene transfer on the activity of the topo II promoter. E1A increased the activity of the topo II gene promoter by 3.5-fold relative to that of cells transfected with Ad-ß-gal. These results suggest that elevated topo II protein levels and enhanced sensitivity to topo II targeting agents were secondary to a direct effect of E1A on the topo II promoter. Combining E1A gene therapy with topo II targeting anticancer drugs may therefore have therapeutic benefit by increasing tumor cell sensitivity.

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