Polyamine-containing etoposide derivatives as poisons of human type II topoisomerases: Differential effects on topoisomerase II? and II?.

ABSTRACT: Etoposide is an anticancer drug that acts by inducing topoisomerase II-mediated DNA cleavage. Despite its wide use, etoposide is associated with some very serious side-effects including the development of treatment-related acute myelogenous leukemias. Etoposide targets both human topoisomerase II? and II?. However, the contributions of the two enzyme isoforms to the therapeutic vs. leukemogenic properties of the drug are unclear. In order to develop an etoposide-based drug with specificity for cancer cells that express an active polyamine transport system, the sugar moiety of the drug has been replaced with a polyamine tail. To analyze the effects of this substitution on the specificity of hybrid molecules toward the two enzyme isoforms, we analyzed the activity of a series of etoposide-polyamine hybrids toward human topoisomerase II? and II?. All of the compounds displayed an ability to induce enzyme-mediated DNA cleavage that was comparable to or higher than that of etoposide. Relative to the parent drug, the hybrid compounds displayed substantially higher activity toward topoisomerase II? than II?. Modeling studies suggest that the enhanced specificity may result from interactions with Gln778 in topoisomerase II?. The corresponding residue in the ? isoform is a methionine.

SUBMITTER: Oviatt AA 

PROVIDER: S-EPMC6097886 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature