TABLE 1

Preventive/Alleviative strategies for DIC

StrategyMechanism of ActionBenefitsDisadvantagesModela
Altering the dosing regimen of DOXLower peak plasma concentrations and hence lower concentrations in cardiac tissueEasiest way to intervenePatient compliance may be an issue with slow continuous infusion regimens and/or increased dosing frequencyMouse (Pacciarini et al., 1978), rat (Yeung et al., 2002; Kamendi et al., 2015), human (Weiss and Manthel, 1977; Chlebowski et al., 1980; Legha et al., 1982a; Torti et al., 1983)
Dose fractionation and continuous infusion regimens have demonstrated decreased incidence of cardiac events, such as CHF, cardiomyopathy, and LVEF dysfunction
Anticancer efficacy was demonstrated to be uncompromised
Liposomal formulations of DOXReduced circulating concentrations of free DOX in the bloodstream due to liposomal encapsulationLower concentrations of free DOX in cardiac tissue, resulting in reduced intensity of cardiac events as compared with conventional DOX treatmentSkin-related toxicities are commonly observed, such as hand–foot syndrome (palmar–plantar erythrodysesthesia), rashes, melanotic macules, etc., due to the unique pharmacokinetics and tissue distribution properties of PEGylated liposomal DOXMouse (Forssen and Tökès, 1981; Kanter et al., 1993b), beagle dog (Herman et al., 1983; Kanter et al., 1993a; Working et al., 1999), rabbit (Working et al., 1999), human (Berry et al., 1998; Lotem et al., 2000; Lyass et al., 2000; Safra et al., 2000; O’Brien et al., 2004)
Stomatitis is another major toxic effect observed
Use of Cardio-Protective Agentsb
DexrazoxaneIron chelator that prevents ROS generationHas demonstrated long-term cardio-protective effectsSevere myelosuppression due to additive effects with chemotherapeuticsH9c2 rat cardiomyocytes (Lyu et al., 2007; Deng et al., 2014), mouse (Deng et al., 2014), rat (Herman et al., 2000; Lebrecht et al., 2007), rabbit (Popelová et al., 2009), human (Bu’Lock et al., 1993; Wexler et al., 1996; Lipshultz et al., 2010)
Topoisomerase II inhibitor that reduces DOX-induced DNA damageFDA-approved cardio-protective agentRecommended only after receiving >300 mg/m2 cumulative DOX dose, as interference with anticancer activity has been observed when used with chemotherapy initiation
ErythropoietinAnti-atrophic effect on cardiac myocytes and an antifibrotic effect on the myocardiumAttenuates LV dysfunction and enhances LV contractility and cardiac recoveryLack of evidence of long-term cardio-protective effects in humansPerfused isolated rat heart (Ammar et al., 2011), rat (Ammar et al., 2011), neonatal mouse ventricular cardiomyocytes (Kim et al., 2008), mouse (Li et al., 2006b; Kim et al., 2008), AC16 human cardiomyocyte cell line (Cui et al., 2017)
Inhibitory effects on apoptosis of cardiomyocytes
Stimulation of SIRT1 leading to improvement in mitochondrial function and biogenesis
ThrombopoietinInhibitory effects on apoptosis of cardiomyocytesH9c2 rat cardiomyocytes (Li et al., 2006a), primary neonatal rat cardiomyocytes (Li et al., 2006a), mouse (Li et al., 2006a), rat (Chan et al., 2011)
Promotion of cardiomyocyte survival via Akt and ERK pathway activation
Vitamins A, C, and EScavengers of free radicals/ROS and reactive nitrogen species due to antioxidant propertiesReduces short-term cardiotoxicityLong-term cardiotoxicity may not be alleviated due to persistence of mechanisms other than free radical generation in cardiac tissueRat (Tesoriere et al., 1994; Puri et al., 2005; Viswanatha Swamy et al., 2011; Akolkar et al., 2017), rabbit (Milei et al., 1986), isolated rat cardiomyocytes (Ludke et al., 2012; Ludke et al., 2017)
MelatoninMouse (Wahab et al., 2000; Liu et al., 2002), rat (Dziegiel et al., 2002; Oz et al., 2006; Othman et al., 2008), human (Lissoni et al., 1999)
N-acetylcysteineMouse (Doroshow et al., 1981), rat (Arica et al., 2013; Farshid et al., 2014), beagle (Herman et al., 1985), human (Jo et al., 2013)
AmifostineAnticancer efficacy may be compromised due to antagonistic effects with DOXPerfused isolated rat heart (Nazeyrollas et al., 1999), infant rat (Jahnukainen et al., 2001), rat (Herman et al., 2000; Dragojevic-Simic et al., 2004), rabbit (Potemski et al., 2006), human (Gallegos-Castorena et al., 2007)
MangiferinPrevention of OH·radical formation and lipid peroxidation by iron chelationRat (Arozal et al., 2015; Agustini et al., 2016)
Regulates intracellular calcium homeostasis
ProbucolEnhancement of endogenous antioxidants such as glutathione peroxidase and superoxide dismutaseLack of reports on the effect on anticancer efficacy, especially in human studiesRat (Siveski-Iliskovic et al., 1994, 1995; Kumar et al., 2001), mouse (Walker et al., 2011)
CarvedilolInhibition of free radical generation due to antioxidant propertiesH9c2 rat heart cell line (Spallarossa et al., 2004), rat (Santos et al., 2002; Oliveira et al., 2004), human (Tashakori Beheshti et al., 2016; Nabati et al., 2017)
Inhibition of apoptotic pathways in DOX-induced cardiomyocyte death
  • a Refers to experimental models that were used to demonstrate benefits or disadvantages of the respective strategies. The list of references in parantheses is not exhaustive, but representative of the studies conducted.

  • b The list of cardio-protective agents is not exhaustive. Some commonly studied/reported agents are listed in this table.