Received for publication April 10, 2007.
Revised June 27, 2007.
Accepted for publication July 10, 2007.

A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase II in vivo

Abstract

The bisdioxopiperazines such as ICRF-187 (dexrazozane) ICRF-154 and ICRF-193 are agents which inhibit eukaryotic topoisomerase II, while their ring opened hydrolysis products are strong iron chelators. The clinically approved analogue ICRF-187 is a pharmacological modulator of to-poisomerase II poisons such as etoposide in preclinical animal models. ICRF-187 is also used to protect against anthracycline-induced cardiomyopathy, and has recently been approved as an anti-dote for alleviating tissue damage and necrosis following accidental anthracycline extravasation. This dual modality of bisdioxopiperazines, including ICRF-187, raises the question whether their pharmacological in vivo effects are mediated through interaction with topoisomerase II, or via their intracellular iron chelating activity. In an attempt to distinguish between these possibilities, we here present a transgenic mouse model aimed at identifying the contribution of topoisomerase II to the effects of bisdioxopiperazines. A tyrosine 165 to serine mutation (Y165S) in topoisom-erase II previously demonstrated to render the human orthologue of this enzyme highly resistant towards bisdioxopiperazines was introduced at the TOP2A locus in mouse embryonic stem cells by targeted homologous recombination. These cells were used for the generation of transgenic TOP2A^Y165S/+ mice which were demonstrated to be resistant towards the general toxicity of both ICRF-187 and ICRF-193. Hematological measurements indicate that this is most likely caused by a decreased ability of these agents to induce myelosuppression in TOP2A^Y165S/+ mice, highlighting the role of topoisomerase II in this process. The biological and pharmacological implications of these findings are discussed, and areas for further investigations proposed.

Key words: Genetics, Metals and chelators, Resistance, Topoisomerases

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