Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity

The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs). Based on the obtained results, the bis(2-aminoacetoxymethyl)-type prodrug GK-667 was selected for advanced investigations due to its straightforward synthesis, sufficient solubility, low cytotoxicity and favorable ICRF-193 release. Upon administration of GK-667 to NVCMs, the released ICRF-193 penetrated well into the cells, reached sufficient intracellular concentrations and provided effective cytoprotection against anthracycline toxicity. The pharmacokinetics of the prodrug, ICRF-193 and its rings-opened metabolite was estimated in vivo after administration of GK-667 to rabbits. The plasma concentrations of ICRF-193 reached were found to be adequate to achieve cardioprotective effects in vivo. Hence, GK-667 was demonstrated to be a pharmaceutically acceptable prodrug of ICRF-193 and a promising drug candidate for further evaluation as a potential cardioprotectant against chronic anthracycline toxicity.

Abstract 13508: Left Ventricular Contractile and Kinetic Changes in Failing Human Myocardium Due to Anthracycline Toxicity

Introduction: Anthracyclines are used effectively to treat many cancers. However, cumulative and irreversible cardiotoxicity can limit anthracyclines’ clinical benefit. Mechanisms of cardiotoxicity have been assessed in murine models, but no studies directly assess human heart contractility. Our objective was to assess left ventricular contractile force, kinetics of contraction and relaxation, and frequency-dependent activation in anthracycline-induced failing human myocardium. Methods: From 2009-2019, we assessed live tissue-level contractile forces and kinetics in isolated left ventricular intact trabeculae from failing and non-failing human hearts. After the trabeculae were transferred to and stabilized in a custom setup, baseline contractile force and kinetic parameters were assessed at 1 Hz (normal resting in vivo heart rate), followed by frequency-dependent activation (0.5-3.0 Hz) under near-physiological conditions. Retrospectively, we analyzed muscles from three cohorts of individuals: (1) with non-ischemic cardiomyopathy due to anthracycline toxicity (NICM-AC; n =14), (2) with NICM and history of cancer without anthracycline or known cardiotoxic treatments (NICM; n =14), and (3) with non-failing myocardium and no history of cancer (NF; n =14). Results: At stimulation of 1 Hz, active developed force (Fdev) of NICM-AC trabeculae was significantly lower than NF and NICM trabeculae. NICM-AC trabeculae exhibited prolonged 90% relaxation time (RT90), significantly slower maximal rate of force decay (-dF/dt), and slower maximal kinetic rate of relaxation (-dF/dt/Fdev). In addition, frequency-dependent activation and relaxation were markedly impaired in both failing groups. Conclusions: Human myocardium failing due to anthracycline toxicity had significantly decreased force and slower relaxation kinetics compared to non-ischemic failing myocardium. With increase in stimulation frequency, anthracycline treated myocardium exhibited impaired activation and relaxation kinetics. These findings suggest that cardio-protection strategies should aim to improve not only contractile force, but also kinetics of relaxation.

Transfusional Iron Overload: An Underappreciated Danger in AML Patients?

Abstract 4133 The survival rate for childhood cancer has improved steadily over the last 3 decades creating an increasing population of survivors. Though this is one of the great successes in medicine, there is a growing awareness that survivors are at increased risk for late therapy related adverse effects including cardiovascular toxicity. The Childhood Cancer Survivor Study showed that the standardized mortality ratio for cardiac causes was > 8 times higher than expected and cumulative probability of cardiac death increased 15-25 years after cancer diagnosis.[i] The cardiotoxic effects of anthracyclines are well documented in the literature. They are an essential component of treatment for AML. However, their use is limited by dose-related cardiomyopathy. An important factor in anthracycline toxicity is iron's role in promoting the formation of toxic oxygen species. Cardiac tissue is recognized to be especially vulnerable to free radical damage. Anthracyclines cause altered expression of iron-regulated genes and change intracellular iron trafficking. It is known that, dexrazoxane-an iron chelator, is an effective cardioprotective agent against doxorubicin effects in animal models. The American Society of Clinical Oncology recommends its use in metastatic breast cancer patients receiving a doxorubicin dose of >300 mg/m2.[ii] Dexrazoxane was found to prevent or reduce cardiac injury associated with doxorubicin use in childhood ALL without compromising the anti-leukemic effect.[iii] We hypothesize that cardiomyocytes damaged by anthracyclines are more susceptible to iron accumulation, potentiating anthracycline toxicity in patients with a heavy transfusion burden. Consecutive adolescent patients with AML admitted to our institution were reviewed. These patients received a cumulative anthracycline dose of 200 to 300 mg/m2. Iron loading was estimated from the number of red cell units given. The iron content of a single red cell unit is approximately 200 mg. 10 AML patients received 24-59 units of blood (median 35) over a median of 222 days. This equates to 65-235 mg of iron/kg (median of 129 mg/kg). Iron loading was identified in AML patients due to transfusion. The iron load is less than seen in children with thalassemia but in AML patients, who are known to have increased adverse cardiac events, it is possible that anthracycline induced cardiomyopathy could have been exacerbated by transfused iron. To prove the hypothesis the next step is to investigate T2* MRI detectable myocardial iron deposition and cardiac dysfunction and markers of myocardial injury in AML patients. These observations may provide evidence for using iron chelation therapy in the treatment of AML. [i] Lipshultz S, Alvarez JA, Scully RE. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 2008; 94: 525-533 [ii] Carver JR, Shapiro CL, Ng A, et al. ASCO Cancer Survivorship Expert Panel. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cance survivors: cardiac and pulmonary late effects. J Clin Oncol 2007; 25: 3991-4008 [iii] Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 2004; 351: 145-53 Disclosures: No relevant conflicts of interest to declare.