Dexrazoxane HCl (ICRF-187, ADR-529)

Dexrazoxane Hydrochloride is the hydrochloride salt of a bisdioxopiperazine with iron-chelating, chemoprotective, cardioprotective, and antineoplastic activities. After hydrolysis to an active form that is similar to ethylenediaminetetraacetic acid (EDTA), dexrazoxane chelates iron, limiting the formation of free radical-generating anthracycline-iron complexes, which may minimize anthracycline-iron complex-mediated oxidative damage to cardiac and soft tissues. This agent also inhibits the catalytic activity of topoisomerase II, which may result in tumor cell growth inhibition.

The use of dexrazoxane for the prevention of anthracycline extravasation injury.[Pubmed:18230055]

Expert Opin Investig Drugs. 2008 Feb;17(2):217-23.

BACKGROUND: The use of the anthracycline anticancer drugs doxorubicin, daunorubicin, epirubicin and idarubicin sometimes results in accidental extravasation injury and can be a serious complication of their use. OBJECTIVE: The object of this review was to evaluate the preclinical and clinical literature on the use of dexrazoxane in preventing anthracycline-induced extravasation injury. METHODS: A review of the literature was carried out using PubMed. RESULTS/CONCLUSIONS: Dexrazoxane, which is clinically used to reduce doxorubicin-induced cardiotoxicity, has been shown in two clinical studies and in several case reports to be highly efficacious in preventing anthracycline-induced extravasation injury. Dexrazoxane is a prodrug analog of the metal chelator EDTA that likely acts by removing iron from the iron-anthracycline complex, thus preventing formation of damaging reactive oxygen species.

Utility of dexrazoxane for the reduction of anthracycline-induced cardiotoxicity.[Pubmed:19018683]

Expert Rev Cardiovasc Ther. 2008 Nov;6(10):1311-7.

Dexrazoxane is a derivative of the powerful metal-chelating agent ethyl enediamine tetra acetic acid. Its cardioprotective effect is thought to be due to its ability to chelate iron and reduce the number of metal ions complexed with anthracycline and, consequently, decrease the formation of superoxide radicals. Preclinical studies have confirmed that dexrazoxane has significant activity as a cardioprotective agent against anthracycline-induced cardiotoxicity. Dexrazoxane is well-tolerated, with myelosuppression being the dose-limiting toxicity in Phase I trials. The cardioprotective utility of dexrazoxane has been further illustrated in a number of randomized trials. In addition no significant difference in survival has been observed between the dexrazoxane and control arms of these trials but, in one, a significantly lower response rate was observed in the dexrazoxane compared to placebo arm. Further trials are required to evaluate the efficacy of dexrazoxane in hematological malignancies as well as the adjuvant treatment of breast cancer. Its use in the paediatric setting and in the management of elderly patients with cardiac comorbidity also requires investigation. Recently, interest has focused on the use of dexrazoxane as an antidote for anthracycline extravasation. In addition the general cytoprotective activity of this drug requires further assessment, as well as selectivity in this context.

Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial.[Pubmed:20850381]

Lancet Oncol. 2010 Oct;11(10):950-61.

BACKGROUND: Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment. METHODS: Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m(2) doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m(2) dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087. FINDINGS: 100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: -0.82, 95% CI -1.31 to -0.33; end-systolic dimension: 0.57, 0.21-0.93) but not for those who also received dexrazoxane (-0.41, -0.88 to 0.06; 0.15, -0.20 to 0.51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0.47, 0.46-0.48) and thickness-to-dimension ratio (0.66, 0.64-0.68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0.04) for left ventricular fractional shortening at 5 years in girls (1.17, 0.24-2.11), but not in boys (-0.10, -0.87 to 0.68). Similarly, subgroup analysis showed dexrazoxane protection (p=0.046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1.15, 0.44-1.85), but not in boys (0.19, -0.42 to 0.81). With a median follow-up for recurrence and death of 8.7 years (range 1.3-12.1), event-free survival was 77% (95% CI 67-84) for children in the doxorubicin-alone group, and 76% (67-84) for children in the doxorubicin plus dexrazoxane group (p=0.99). INTERPRETATION: Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys. FUNDING: US National Institutes of Health, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.