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

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A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIα in vivo. / Grauslund, Morten; Vinding, Annemette; Füchtbauer, Annette C.; Hoflander, Kenneth Francis; Hjorth, Peter Hansen; Jensen, Peter B.; Sehested, Maxwell; Füchtbauer, Ernst-Martin; Jensen, Lars H.

In: Molecular Pharmacology, Vol. 72, No. 4, 2007, p. 1003-1014.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Grauslund, M, Vinding, A, Füchtbauer, AC, Hoflander, KF, Hjorth, PH, Jensen, PB, Sehested, M, Füchtbauer, E-M & Jensen, LH 2007, 'A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIα in vivo', Molecular Pharmacology, vol. 72, no. 4, pp. 1003-1014. https://doi.org/10.1124/mol.107.036970

APA

Grauslund, M., Vinding, A., Füchtbauer, A. C., Hoflander, K. F., Hjorth, P. H., Jensen, P. B., Sehested, M., Füchtbauer, E-M., & Jensen, L. H. (2007). A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIα in vivo. Molecular Pharmacology, 72(4), 1003-1014. https://doi.org/10.1124/mol.107.036970

CBE

Grauslund M, Vinding A, Füchtbauer AC, Hoflander KF, Hjorth PH, Jensen PB, Sehested M, Füchtbauer E-M, Jensen LH. 2007. A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIα in vivo. Molecular Pharmacology. 72(4):1003-1014. https://doi.org/10.1124/mol.107.036970

MLA

Vancouver

Grauslund M, Vinding A, Füchtbauer AC, Hoflander KF, Hjorth PH, Jensen PB et al. A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIα in vivo. Molecular Pharmacology. 2007;72(4):1003-1014. https://doi.org/10.1124/mol.107.036970

Author

Grauslund, Morten ; Vinding, Annemette ; Füchtbauer, Annette C. ; Hoflander, Kenneth Francis ; Hjorth, Peter Hansen ; Jensen, Peter B. ; Sehested, Maxwell ; Füchtbauer, Ernst-Martin ; Jensen, Lars H. / A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIα in vivo. In: Molecular Pharmacology. 2007 ; Vol. 72, No. 4. pp. 1003-1014.

Bibtex

@article{71327bb0cf4111dcabe4000ea68e967b,
title = "A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIα in vivo",
abstract = "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 IIα to the effects of bisdioxopiperazines. A tyrosine 165 to serine mutation (Y165S) in topoisomerase IIα, 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 TOP2AY165S/+ 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 TOP2AY165S/+ mice, highlighting the role of topoisomerase IIα in this process. The biological and pharmacological implications of these findings are discussed, and areas for further investigations are proposed",
author = "Morten Grauslund and Annemette Vinding and F{\"u}chtbauer, {Annette C.} and Hoflander, {Kenneth Francis} and Hjorth, {Peter Hansen} and Jensen, {Peter B.} and Maxwell Sehested and Ernst-Martin F{\"u}chtbauer and Jensen, {Lars H.}",
note = "Paper id:: 17622580",
year = "2007",
doi = "10.1124/mol.107.036970",
language = "English",
volume = "72",
pages = "1003--1014",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "4",

}

RIS

TY - JOUR

T1 - A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIα in vivo

AU - Grauslund, Morten

AU - Vinding, Annemette

AU - Füchtbauer, Annette C.

AU - Hoflander, Kenneth Francis

AU - Hjorth, Peter Hansen

AU - Jensen, Peter B.

AU - Sehested, Maxwell

AU - Füchtbauer, Ernst-Martin

AU - Jensen, Lars H.

N1 - Paper id:: 17622580

PY - 2007

Y1 - 2007

N2 - 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 IIα to the effects of bisdioxopiperazines. A tyrosine 165 to serine mutation (Y165S) in topoisomerase IIα, 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 TOP2AY165S/+ 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 TOP2AY165S/+ mice, highlighting the role of topoisomerase IIα in this process. The biological and pharmacological implications of these findings are discussed, and areas for further investigations are proposed

AB - 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 IIα to the effects of bisdioxopiperazines. A tyrosine 165 to serine mutation (Y165S) in topoisomerase IIα, 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 TOP2AY165S/+ 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 TOP2AY165S/+ mice, highlighting the role of topoisomerase IIα in this process. The biological and pharmacological implications of these findings are discussed, and areas for further investigations are proposed

U2 - 10.1124/mol.107.036970

DO - 10.1124/mol.107.036970

M3 - Journal article

C2 - 17622580

VL - 72

SP - 1003

EP - 1014

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 4

ER -