Adenovirus-mediated human topoisomerase IIalpha gene transfer increases the sensitivity of etoposide-resistant human and mouse breast cancer cells.

ABSTRACT

Cellular resistance to chemotherapeutic agents is attributable to several mechanisms, including alteration of topoisomerase IIa gene expression. Our previous studies have shown that transient transfection with a vector containing either Drosophila or human topoisomerase IIalpha gene into drug-resistant tumor cells enhanced their drug sensitivity. Furthermore, we constructed a recombinant adenovirus, Ad-hTopoIIalpha, containing the human topoisomerase IIa gene that was able to selectively increase etoposide sensitivity in drug-resistant tumor cells. We also examined Ad-hTopoIIalpha for therapeutic efficacy in vitro using additional etoposide-resistant cell lines, including a mouse breast cancer cell line and a human leukemia cell line. The etoposide-resistant mouse breast cancer cell line FvP, which is derived from FM3A, and etoposide-resistant human breast cancer cell line, MDA-VP, which derived from MDA-P cells showed increased sensitivity to etoposide as well as increased expression of human Topoisomerase IIa mRNA, but this was not seen in FM3A and MDA-P cells. On the other hand, the etoposide-resistant human leukemia cell line K562/MX2 and the parental cell line K562/P did not show enhanced sensitivity against etoposide or an increase in human Topoisomerase IIa mRNA. Using a recombinant adenovirus containing beta-galactosidase gene (Ad-beta-gal), K562 cells were not transducted by the recombinant adenovirus, while both etoposide-sensitive FM3A cells and etoposide resistant FvP cells were transducted by recombinant adenovirus. Ad-hTOP2alpha and etopside treatment showed reduced inoculated tumor weight in the mice. We concluded that a recombinant adenovirus containing the human Topoisomerase IIalpha gene might be a powerful tool for overcoming drug resistance in breast cancer cells, but not in leukemia cells.