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Adenovirus-mediated Human Topoisomerase II Gene Transfer Increases the Sensitivity of Etoposide-resistant Human Breast Cancer Cells¹

Departments of Cancer Biology [Z. Z., Y. K., T. A., E. S. K.] and Pediatrics [C. H., E. S. K.] and Division of Medicine [L. A. Z.], The University of Texas M. D. Anderson Cancer Center, and Department of Cell Biology, Baylor College of Medicine [K. K.], Houston, Texas 77030

Cellular resistance to chemotherapeutic agents is attributable to several mechanisms, including alteration of topoisomerase II (topo II) gene expression. Etoposide-resistant MDA-VP human breast cancer cells express lower amounts of enzymatically active and drug-sensitive topo II than do MDA parent cells, suggesting that the low level of topo II is the mechanism of resistance. To determine whether transfer of a normal topo II gene into MDA-VP cells can increase topo II gene expression, topo II protein production, and cell sensitivity to etoposide, a recombinant adenovirus, Ad-hTopoII, containing the human topo II gene, was constructed. The shuttle vector pAvCvSv-hTopII was constructed and cotransfected with the pBHG10 packaging vector into 293 cells. Infectious recombinant adenovirus plaques were isolated and purified. Presence of the topo II gene was confirmed by PCR and restriction enzyme digestion. After infection with Ad-hTopoII, topo II mRNA expression in MDA-VP cells increased 7.4-fold, topo II protein production increased 5.9-fold, and sensitivity to etoposide was enhanced 4.5-fold compared with control transfected cells. Infection of normal human embryonic lung cells and human fibroblast cells with Ad-hTopoII did not enhance the expression of topo II or sensitivity to etoposide. Viral uptake was comparable in the MDA-VP and normal cell lines. These data suggest that topo II gene transfer using an adenoviral vector can selectively increase etoposide sensitivity in drug-resistant tumor cells and may enhance the therapeutic index of etoposide.

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