Jaw. Byl et al., DNA topoisomerase II as the target for the anticancer drug TOP-53: Mechanistic basis for drug action, BIOCHEM, 40(3), 2001, pp. 712-718
TOP-53 is a promising anticancer agent that displays high activity against
non-small cell lung cancer in animal tumor models [Utsugi, T., et al. (1996
) Cancer Res. 56, 2809-2814]. Compared to its parent compound, etoposide, T
OP-53 is considerably more toxic to non-small cell lung cancer cells, is mo
re active at generating chromosomal breaks, and displays improved cellular
uptake and pharmacokinetics in animal lung tissues. Despite the preclinical
success of TOP-53, several questions remain regarding its cytotoxic mechan
ism. Therefore, this study characterized the basis for drug action. Results
indicate that topoisomerase II is the primary cytotoxic target for TOP-53.
Furthermore, the drug kills cells by acting as a topoisomerase II poison.
TOP-53 exhibits a DNA cleavage site specificity that is identical to that o
f etoposide. Like its parent compound, the drug increases the number of enz
yme-mediated DNA breaks by interfering with the DNA religation activity of
the enzyme. TOP-53 is considerably more efficient than etoposide at enhanci
ng topoisomerase II-mediated DNA cleavage and exhibits high activity agains
t human topoisomerase II alpha and II beta in vitro and in cultured cells.
Therefore, at least in part, the enhanced cytotoxic activity of TOP-53 can
be attributed to an enhanced activity against topoisomerase II. Finally, TO
P-53 displays nearly wild-type activity against a mutant yeast type II enzy
me that is highly resistant to etoposide, This finding suggests that TOP-53
can retain activity against systems that have developed resistance to etop
oside, and indicates that substituents on the etoposide C-ring are importan
t for topoisomerase II-drug interactions.