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A Mouse Model for Studying the Interaction of Bisdioxopiperazines with Topoisomerase II in Vivo

Experimental Pathology Unit, Department of Pathology, Copenhagen University Hospital, Copenhagen, Denmark (M.G., M.S., L.H.J.); TopoTarget A/S, Copenhagen, Denmark (M.G., A.V.T., K.F.H., P.B.J., M.S., L.H.J.); Department of Molecular Biology, University of Aarhus, Aarhus, Denmark (A.F., P.H.H., E.-M.F.); and Laboratory for Experimental Medical Oncology, Finsen Center; Copenhagen University Hospital, Copenhagen, Denmark (P.B.J.)

The bisdioxopiperazines such as (+)-(S)-4,4'-propylenedi-2,6-piperazinedione (dexrazoxane; ICRF-187), 1,2-bis(3,5-dioxopiperazin-1-yl)ethane (ICRF-154), and 4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione (ICRF-193) are agents that inhibit eukaryotic topoisomerase II, whereas their ring-opened hydrolysis products are strong iron chelator. The clinically approved analog ICRF-187 is a pharmacological modulator of topoisomerase 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 antidote for alleviating tissue damage and necrosis after accidental anthracycline extravasation. This dual modality of bisdioxopiperazines, including ICRF-187, raises the question of 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 topoisomerase II, demonstrated previously to render the human ortholog of this enzyme highly resistant toward 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 toward 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 are proposed.

Address correspondence to: Dr. Lars Høllund Jensen, Experimental Pathology Unit, Department of Pathology, Rigshospitalet afs. 3731, Biocenter, Bygning 2, 3 sal., Ole Maaløes vej 5, DK-2100 Copenhagen O, Denmark. E-mail: lhj{at}topotarget.com

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