Treatment of anthracycline extravasation in mice with dexrazoxane with or without DMSO and hydrocortisone

Langer, Seppo W.; Thougaard, Annemette; Sehested, Maxwell; Jensen, Peter Buhl

doi:10.1007/s00280-005-0022-7

Cited by 72 publications

(88 citation statements)

References 11 publications

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“…Although many of these results appeared interesting, the only additional clinical indication for DEX becomes a protection of tissue in accidental ANT extravasation-a rare, but potentially serious, adverse effect associated with long-lasting local damage, ulceration, and necrosis. Langer et al have reported that systemic treatment with DEX (250 mg/kg or triple treatment with 62.5 mg/kg) markedly decreases the area of wound and healing time when started immediately after induction of ANT extravasation in mice (148,149). However, such effects were not achievable with ADR-925, EDTA, N-acetylcystein, vitamin E, merbarone, or aclarubicin, which does not suggest involvement of iron chelation, oxidative stress, or TOP2 inhibition (149).…”

Section: Dex-afforded Tissue Protection Beyond the Ant-induced Cardiomentioning

confidence: 99%

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

Štěrba

Popelová

Vávrová

et al. 2013

Antioxidants & Redox Signaling

276

192

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Section: Dex-afforded Tissue Protection Beyond the Ant-induced Cardiomentioning

confidence: 99%

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

Štěrba

Popelová

Vávrová

et al. 2013

Antioxidants & Redox Signaling

276

192

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“…ICRF-187 can antagonize the effect of these drugs outside the CNS (Hofland et al, 2005b), thereby allowing for a more effective targeting of CNS tumors . Furthermore, ICRF-187 [dexrazoxane (Savene)] has been found to be effective as an antidote against accidental anthracycline extravasation (Langer et al, 2000;Mouridsen et al, 2007). Finally, ICRF-187 (Cardioxane, Zinecard) is also used as a cardioprotectant in anthracycline treatment (Cvetković and Scott, 2005).…”

mentioning

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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“…25 Three animal studies have examined the use of dexrazoxane in mice. [26][27][28] In all 3 studies, injuries caused by subcutaneous anthracycline administration were reduced by intraperitoneal or intravenous dexrazoxane.…”

Section: Literature Reviewmentioning

confidence: 99%

Management of Anthracycline Extravasation Injuries

Reeves

2007

Ann Pharmacother

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Treatment of anthracycline extravasation in mice with dexrazoxane with or without DMSO and hydrocortisone

Cited by 72 publications

References 11 publications

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

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

Management of Anthracycline Extravasation Injuries

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