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.