A murine experimental anthracycline extravasation model: pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage
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A murine experimental anthracycline extravasation model : pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage. / Thougaard, Annemette V; Langer, Seppo W; Hainau, Bo; Grauslund, Morten; Juhl, Birgitte Ravn; Jensen, Peter Buhl; Sehested, Maxwell.
I: Toxicology, Bind 269, Nr. 1, 28.02.2010, s. 67-72.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - A murine experimental anthracycline extravasation model
T2 - pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage
AU - Thougaard, Annemette V
AU - Langer, Seppo W
AU - Hainau, Bo
AU - Grauslund, Morten
AU - Juhl, Birgitte Ravn
AU - Jensen, Peter Buhl
AU - Sehested, Maxwell
N1 - (c) 2010 Elsevier Ireland Ltd. All rights reserved.
PY - 2010/2/28
Y1 - 2010/2/28
N2 - The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found to be similar to findings in humans: massive necrosis in the subcutis, dermis and epidermis followed by sequestration and healing with granulation tissue, and a graft-versus-host-like reaction with hyperkeratotic and acanthotic keratinocytes, occasional apoptoses, epidermal invasion by lymphocytes and healing with dense dermal connective tissue. The extension of this fibrosis was quantified, and dexrazoxane intervention resulted in a statistically significant decrease in fibrosis extension, as also observed in the clinic. Several mechanisms have been proposed in anthracycline extravasation cytotoxicity, and we tested two major hypotheses: (1) interaction with topoisomerase II alpha and (2) the formation of tissue damaging reactive oxygen species following redox cycling of an anthracycline Fe(2+) complex. Dexrazoxane could minimise skin damage via both mechanisms, as it stops the catalytic activity of topoisomerase II alpha and thereby prevents access of anthracycline to the enzyme and thus cytotoxicity, and also acts as a strong iron chelator following opening of its two bisdioxopiperazine rings. Using the model of extravasation in a dexrazoxane-resistant transgenic mouse with a heterozygous mutation in the topoisomerase II alpha gene (Top2a(Y165S/+)), we found that dexrazoxane provided a protection against anthracycline-induced skin wounds that was indistinguishable from that found in wildtype mice. Thus, interaction with topoisomerase II alpha is not central in the pathogenesis of anthracycline-induced skin damage. In contrast to dexrazoxane, the iron-chelating bisdioxopiperazine ICRF-161 do not inhibit the catalytic cycle of topoisomerase II alpha. This compound was used to isolate and test the importance of iron in the wound pathogenesis. ICRF-161 was found ineffective in the treatment of anthracycline-induced skin damage, suggesting that iron does not play a dominant role in the genesis of wounds.
AB - The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found to be similar to findings in humans: massive necrosis in the subcutis, dermis and epidermis followed by sequestration and healing with granulation tissue, and a graft-versus-host-like reaction with hyperkeratotic and acanthotic keratinocytes, occasional apoptoses, epidermal invasion by lymphocytes and healing with dense dermal connective tissue. The extension of this fibrosis was quantified, and dexrazoxane intervention resulted in a statistically significant decrease in fibrosis extension, as also observed in the clinic. Several mechanisms have been proposed in anthracycline extravasation cytotoxicity, and we tested two major hypotheses: (1) interaction with topoisomerase II alpha and (2) the formation of tissue damaging reactive oxygen species following redox cycling of an anthracycline Fe(2+) complex. Dexrazoxane could minimise skin damage via both mechanisms, as it stops the catalytic activity of topoisomerase II alpha and thereby prevents access of anthracycline to the enzyme and thus cytotoxicity, and also acts as a strong iron chelator following opening of its two bisdioxopiperazine rings. Using the model of extravasation in a dexrazoxane-resistant transgenic mouse with a heterozygous mutation in the topoisomerase II alpha gene (Top2a(Y165S/+)), we found that dexrazoxane provided a protection against anthracycline-induced skin wounds that was indistinguishable from that found in wildtype mice. Thus, interaction with topoisomerase II alpha is not central in the pathogenesis of anthracycline-induced skin damage. In contrast to dexrazoxane, the iron-chelating bisdioxopiperazine ICRF-161 do not inhibit the catalytic cycle of topoisomerase II alpha. This compound was used to isolate and test the importance of iron in the wound pathogenesis. ICRF-161 was found ineffective in the treatment of anthracycline-induced skin damage, suggesting that iron does not play a dominant role in the genesis of wounds.
KW - Animals
KW - Anthracyclines/toxicity
KW - Antigens, Neoplasm/physiology
KW - DNA Topoisomerases, Type II/physiology
KW - DNA-Binding Proteins/physiology
KW - Extravasation of Diagnostic and Therapeutic Materials/metabolism
KW - Female
KW - Iron/physiology
KW - Mice
KW - Mice, Transgenic
KW - Models, Animal
KW - Organ Specificity/drug effects
KW - Poly-ADP-Ribose Binding Proteins
KW - Skin/drug effects
KW - Subcutaneous Tissue/drug effects
U2 - 10.1016/j.tox.2010.01.007
DO - 10.1016/j.tox.2010.01.007
M3 - Journal article
C2 - 20079798
VL - 269
SP - 67
EP - 72
JO - Toxicology
JF - Toxicology
SN - 0300-483X
IS - 1
ER -
ID: 247891257