Separation of bisdioxopiperazine- and vanadate resistance in topoisomerase II

Sørensen, Tina K.; Grauslund, Morten; Jensen, Peter Buhl; Sehested, Maxwell; Jensen, Lars H.

doi:10.1016/j.bbrc.2005.06.177

Cited by 2 publications

(1 citation statement)

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“…The mechanistic basis for this is not clear, but the simplest explanation would be that the level of topoisomerase II␣ catalytic activity in TOP2A Y165S/Y165S embryos is insufficient to meet the requirements during development. Another possibility would be that the embryonic lethality of the homozygous TOP2A Y165S/Y165S mutation is related to the decreased levels of DNA-stimulated ATP hydrolysis seen with the Y165S protein (Sorensen et al, 2005). The DNA transport mechanism of eukaryotic topoisomerase II is directly coupled to ATP hydrolysis (Baird et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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

Grauslund¹,

Thougaard²,

Füchtbauer³

et al. 2007

Mol Pharmacol

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The bisdioxopiperazines such as (ϩ)-(S)-4,4Ј-propylenedi-2,6-piperazinedione (dexrazoxane; ICRF-187), 1,2-bis(3,5-dioxopiperazin-1-yl)ethane , and 4,4Ј-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione 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/ϩ mice, which were demonstrated to be resistant toward the general toxicity of both . Hematological measurements indicate that this is most likely caused by a decreased ability of these agents to induce myelosuppression in TOP2A Y165S/ϩ 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.The nuclear enzyme topoisomerase II is found in all living organisms and possesses the essential activity of cleaving and rejoining DNA by forming a transient protein concealed double-strand break, through which an intact DNA doublestrand helix is transported by a gating mechanism requiring ATP hydrolysis Baird et al., 2001). This activity assists in a number of DNA metabolic processes such as DNA replication, transcription, chromosome condensation and decondensation, and chromosome segregation (Wang, 2002). Higher vertebrates have two isoforms of this enzyme, ␣ and ␤. The topoisomerase II␣ isoform is nuclear, and its expression is highly cell cycle-dependent, peaking at G 2 M , whereas topoisomerase II␤ is located both in the nucleus and cytoplasm and displays a rather constant level during the cell cycle (Austin and Marsh, 1998). Topoisomerase II␣ is essential for cell proliferation (Akimitsu et al., 2003), whereas topoisomerase II ␤ knockout mice die shortly after birth because of developmental defects in the central nervous system (CNS) (Yang et al., 2000).The bisdioxopiperazines such as Morris et al., 2000). This closed-clamp ...

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Section: Discussionmentioning

confidence: 99%