Dexrazoxane pre‐treatment protects skinned rat cardiac trabeculae against delayed doxorubicin‐induced impairment of crossbridge kinetics

Abstract

1 Dexrazoxane (DXR, ICRF-187) has been shown both in animal studies and clinical trials to provide a substantial cardioprotection when co-administered with anthracycline drugs like Doxorubicin (DOX). In a previous study, we showed that chronic DOX treatment in rats is associated with a clear impairment of the crossbridge kinetics and shift in myosin iso-enzymes. 2 The present study was adopted to investigate whether the cardioprotective action of DXR involves preservation of the normal actin-myosin interaction. Rats were treated for 4 weeks with either DOX at a weekly dose of 2 mg kg 71 (i.v.), or were pre-injected with DXR (40 mg kg 71, i.v.) at a 20 : 1 dose ratio 30 min prior to the DOX infusion. Rats receiving saline or DXR alone were included in the experiments. Cardiac trabeculae were isolated 4 weeks after the last infusion and were skinned with detergent. 3 Crossbridge turnover kinetics were studied after application of rapid length perturbations of varying amplitudes in Ca 2+ -activated preparations. DXR treatment oered a signi®cant protection against the DOX-induced impairment of the crossbridge kinetics in isolated cardiac trabeculae. Time constants describing transitions between dierent crossbridge states were restored to normal in both the quick release protocol and the slack-test. DXR prevented the shift from the`high ATPase' amyosin heavy chain (MHC) isoform towards the`low-ATPase' b-MHC isoform in the ventricles. 4 We conclude that pre-administration of DXR in rats greatly reduces the deleterious eects of chronic DOX treatment on the trabecular actin ± myosin crossbridge cycle. Preventing direct deleterious eects on the actin ± myosin crossbridge system may provide a new target for preventing or reducing DOX-related cardiotoxicity and may enable patients to continue the treatment beyond currently imposed limits.

Exercise preconditioning modulates genotoxicity induced by doxorubicin in multiple organs of rats

“…Undamaged cells have an intact nucleus without a tail, whereas damaged cells have the appearance of a comet. To measure DNA damage, two image analysis system parameters were considered: tail intensity (% migrated DNA) and tail moment (the product of the tail length and the fraction of DNA in the comet tail) . Tail moment is a virtual measure calculated by the computerized image analysis system considering both the length of DNA migration in the comet tail and the tail intensity.…”

Anthracycline-Induced Cardiotoxicity

“…Significant protection was shown when dexrazoxane 40 mg/kg was administered immediately before the infusion of 2 mg/kg of DOX. Such protection occurred not only through improvement in the process of coupling and decoupling of actin-myosin, but also because it reduced weight loss, edema and diarrhea in rats [64]. In clinical studies, cancer patients that received dexrazoxane/DOX at a ratio of 10:1 presented improvement of the ejection fraction, when compared to patients that received DOX in isolation.…”

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

“…Others have documented that DEX (40 mg/ kg) markedly reduces deleterious effects of DOX (2 mg/kg, weekly for 4 weeks) on trabecular actin-myosin crossbridge cycle (45). DEX (60 mg/kg weekly) was also able to prevent an increase in myocardial total calcium content induced by chronic DAU treatment (3 mg/kg, weekly for 10 weeks) (241).…”