Relationship of DNA Topoisomerase IIα and β Expression to Cytotoxicity of Antineoplastic Agents in Human Acute Lymphoblastic Leukemia Cell Lines

Abstract

The levels of expression of topoisomerase IIα and topoisomerase IIβ were investigated in six established cell lines of human childhood acute lymphoblastic leukemia (ALL) as a function of doubling time, cell cycle distribution, and of sensitivity to the antineoplastic agents Adriamycin and etoposide. The slowest growing cell line, ALL-G, was most sensitive to both drugs, whereas the fastest growing cell line, ALL-C, was 15.3- and 6.4-fold more resistant than ALL-G to Adriamycin and etoposide, respectively. Furthermore, ALL-W, the second most rapidly dividing cell line, was most resistant to both Adriamycin (22.8-fold) and etoposide (14.1-fold). Expression of topoisomerase IIα varied inversely with doubling time, whereas no correlation was found between topoisomerase IIβ levels and doubling time. Expression of topoisomerase IIβ varied inversely with that of topoisomerase IIα. The level of topoisomerase IIα correlated directly with the percentage of cells in S and G₂-M phases, whereas topoisomerase IIβ expression varied directly with the number of cells in G₁. An inverse correlation was found between the level of expression of topoisomerase IIβ and resistance to Adriamycin, whereas a direct correlation was observed between the level of expression of topoisomerase IIα and resistance to Adriamycin. Studies with etoposide, although not statistically significant, were consistent with the pattern observed with Adriamycin. These findings suggest that in ALL cells, cytocidal activity of Adriamycin and etoposide may be mediated, at least in part, by topoisomerase IIβ.