Evidence from studies with intact mammalian cells that merbarone and bis(dioxopiperazine)s are topoisomerase II poisons.

A Chinese hamster V79 cell-based assay for detection of topoisomerase II (topo II) poisons and catalytic inhibitors has been applied to study two bis(dioxopiperazine)s (ICRF-187 and ICRF-154) and a structurally distinct but related compound, merbarone. All three compounds have been previously characterized as being catalytic inhibitors of DNA topo II based primarily on in vitro studies with purified enzymes. The present studies indicate, to the contrary, that all three compounds are very potent DNA clastogens in V79 cells, by virtue of their ability to produce micronuclei, the formation of which is strongly antagonized under conditions in which DNA topo II is rendered catalytically inactive. None of the compounds could be demonstrated to possess catalytic inhibitory activity in intact V79 cells under the conditions tested. These studies provide biological evidence that bis(dioxopiperazine)s are capable of functional topo II poisoning in intact mammalian cells.