Theoretical ground for adsorptive therapy of anthracyclines cardiotoxicity (name not amended)
Anthracyclines (doxorubicin, daunorubicin, epirubicin and others) are highly effective in treating various tumors and also are the most demanded class of chemopreparations applied in oncological practice as well as pediatric oncology [3, 24, 118, 130].
The chemical structure of these preparations can be represented the following way: hydrotetracenequinone chromophores with three planar hexatomic rings that are linked with one or several sugar residues. The distinctions between separate preparations relate to the state of aglycone or hydrocarbon part of the molecule (Fig. 1) .
The spectrum of therapeutic action of the anthracyclines varies significantly:
- DNA intercalation and suppression of macromolecules synthesis;
- production of free radicals with the following activation of lipid peroxidation (LPO);
- binding with DNA molecule and its alkylation;
- straightforward action toward membranes;
- initiation of DNA damage by inhibition of topoisomerase II;
- induction of apoptosis.
Anthracyclines imply strong radiomimetic properties. It is clear from the example of the dynamics of dysfunctions of blood system showing resemblance with the case observed upon ionizing radiation injury [6, 26]. Anthracyclines assist in reducing activity of DNA reparation enzymes.
As matter of fact the synthetic phase of cell mitosis and the point when presynthetic phase transits into synthetic are the most sensitive to polychemotherapy. Anthracycline antibiotics direct the cytotoxic capacity simultaneously at various phases of mitotic cycle that ensures their significant therapeutic effect, but at the same time – strong side effects.
Doxorubicin (DOX, Adriamycin, a derivative of Rubomycin — 14-hydrorubomycin) is nowadays one of the most efficient agents of the medication group. It is a vital and unique compound of Breast cancer treatment protocols, adjuvant and neoadjuvant chemotherapy of solid tumors in children, soft tissue sarcomas, aggressive lymphomas and hemoblastoses .
When present in the body DOX transforms into 13–dihydrodoxorubicinol (DOXol) by dint of cytochrome Р450 system and at the end — into free radical state of semiquinone type. Free radicals of the mentioned anticancer antibiotic immediately go in reaction with molecular oxygen and cause an accumulation of LPO products and destroy the cells at their structural, functional and organization levels .
The major side effects after taking anthracyclines treatment are exemplary for the majority of antineoplastic preparations and cause nausea and vomiting, bone marrow depression, intestinal epithelium and other mucosal surfaces damage (as well as hair follicles), repression or mortification of reproductive function, etc. .
The distinctive feature of DOX and other anthracyclines is the high cardiotoxic action. That is why the dosage and limits of use of the preparation strongly relates to the injury of cardiac muscle [34, 37].
Acute and particularly chronic DOX cardiotoxicity may result in fatal dilated cardiomyopathy (DCMP), lead to serious clinical manifestations. The complications may develop into congestive heart failure (CHF) when the mortality rate equals 60% .
The latest systems of side effects control for anthracycline chemotherapy recommend a special monitoring and evaluation of left ventricular ejection fraction.
The evaluation is supposed to be applied before the treatment and after a half of cumulative dose is achieved. The index must be measured after each next anthracyclines treatment and controlled on 3rd, 6th and 12th months after therapy is terminated .
Statistically 50% of patients who experienced anthracycline chemotherapy die from CHF for the reason of cardiotoxicity. It happens within two years from the moment of diagnosis of anthracycline cardiomyopathy despite the applied therapy [41, 113].
There is a number of possible risk factors of cardiac lesion development:
- cumulative dose of the preparations > 550 mg/m2 and more (after an achievement of cumulative dose, predominantly DCMP develops within a year);
- age group (under 3 and after 65 years old);
- radiotherapy of mediastinum;
- administration of other cardiotoxic agents at the same time;
- female gender;
- concomitant cardiac pathology;
- bolus administration of the preparation .
There are cases known, that CHF occurred and developed with a number of patients who obtained cumulative dose two times lower than the critical [62, 114].
Currently there is not enough studies done on reasons and particular details of anthracycline cardiomyopathy heart damage. Supposedly cardiotoxicity is caused by production of free radicals by “anthracycline-iron” complex and LPO products resulting in dysfunction of myocardium [45, 67].
EPR-studies proved that in this process mitochondrial, nuclear and microsomal reductases catalyze an attachment of electron to quinone residue of tetracycline ring of anthracyclines causing development of semiquinone free radical that produces superoxide anion radical О2•– and hydrogen peroxide H2O2.
Toxic properties of the H2O2 significantly increases along with the reaction with low molecular weight iron (LMW Fe). Ferritin becomes to be a physiologic protector that acts as a secure storage of cytosol source of high molecular weight iron particles in soluble and nontoxic form. However, LMW Fe could be replaced from this transport form by О2•– radical and anthracycline semiquinone radicals .
With most cases of cells defence enzymes of antioxidant system (superoxide dismutase, catalase and glutathione peroxidase) drop down to minimum the injuring action of the mentioned factors. From the other point, the volume of endogenous antioxidants of cardiomyocytes is strictly limited and is not able to supply necessary reaction to anthracycline-induced oxidative stress. Eventually it causes degeneration and descent of cardiac muscle contractility (Fig. 2).
According to existing professional opinion, “Metabolic theory” is an alternative to the theory stating that free radicals result in the cardiomyocytes damage [37, 62, 67].
DOX cardiotoxicity reasons may be the following: the cardiac muscle accumulates the highly reactive alcoholic metabolite doxorubicinol (DOXol) that inhibits Са2+, Mg2+-dependent ATPase of sarcoplasmic reticulum, f0-f1 proton pomp of mitochondria and transport of Na+-Ca2+ in sarcolemma, therefore it disturbs intracellular energetic metabolism, ion gradients and balance of Ca2+ [62, 66].
Mitochondrion is the major supplier of ATP to cells, and is the 30% of the total myocardium weight. The principal factor that contributes in toxic action of DOX on cardiomyocytes, is its strong affinity to cardiolipin — anionic phospholipid which is particular for mitochondrial membrane and vital constituent that supports mitochondrial structural and functional aspects as well as overal metabolism od energy and survival of cells [28, 42, 73]. The other possible reason for cardiotoxicity because of DOX is the disturbance of mitochondrial membrane penetrability .
Various studies show a close relation and particular prognostic value of significantly high level of proinflammatory cytokines, especially tumor necrosis factor-α (TNF-α), Interleukin-1β (IL–1β), Interleukin-6 (IL-6), and their soluble receptors with the risk of heart failure (HF) and regression of left ventricular ejection fraction. High volume of cytokines’ in case of HF signals immune activation, i.e. epiphenomenon of complicated course of disease. At the same time it influences the development of myocardial dysfunction and remodeling of left ventricle in direct way [65, 126].
According to current state of research about the effects of TNF–α include negative inotropic action, myocardial remodeling, and myocardial fibrosis, reinduction of fetal phenotype of myocardium, apoptosis of cardiomyocytes, endothelial dysfunction, skeletal muscle myopathy, myocardium cachexia .
Elevated indications of Interleukin-8 cause insulin resistance to develop as well as diabetes mellitus in patients with DCMP .
Below there is a brief representation of a recent widely-discussed theory of cardiomyopathy development as a consequence of endotoxicosis (Fig. 3). Colon acts as the major depot of bacterial endotoxins (LPS) and is sensuous to harmful action of antiblastoma preparations. The damage of colon mucosa, edema and ischemia of enteric wall cause bacterial translocation that leads for LPS to be released as well as immuno-inflammatory activation and cytokines release [47, 107].
The substantial fact is that averagely 30% of DOX is distinguished with bile in unaltered form and causes more of the cytotoxic action directed to intestinal mucosa .
Similarly to all genotoxic drugs, DOX promotes р53–mediated cell death . As a matter of fact, p53 gene plays a significant role in cell division and death processes. It has shown that its chemical suppression stops DOX-induced cell death and the damage of mitochondrial membrane .
The recent researches describe the transformation of vasoactive mediator generation upon HF development, particularly, of endothelin-1 and nitric oxide [15, 23, 104]. Vasoconstrictive cytokines, endothelin-1 and big endothelin-1, which account for contractility, arrhythmogenesis and remodeling of myocardium, relate to the group of prognostic signals of the level of patients that survive ill with HF [43, 61, 95] and have an important meaning in pathogenesis and progression of cardiomyopathy.
Several studies relate CHF progression to oxidant-dependent activation of heat shock factors by DOX followed with expressed heat shock proteins (Hsp): Hsp25 leading to actin degradation , and Hsp60, mostly functioning in mitochondria .
Another important point is the processes of enzymatic activation of binding of DOX with nuclear DNA , selective alteration of cardiac mRNA coding significant protein of myocardium as αС–actin , and increase of phospholipase activeness controlled by LPO . Some authors consider important the malfunction of calcium channels , proteolysis of titin (binding that plays a vital role in contractility of muscles), and decomposition of cardiac transcription factors concordance [19, 33].
Subclinical myocardial injury reasoned by anthracyclines is possible to diagnose using ECG, Holter monitoring, high resolution ECG, evaluation of heart rhythm variability, echocardiography, radionuclide ventriculography, myocardium scintigraphy, magnetic resonance tomography, analysis of concentrations of cardiac enzymes and other biochemical screenings of cardiomyocyte issue . On the other hand, most of the standard diagnosis methods show insufficient prognostic ability and myocardial biopsy is an invasive approach, technically complicated and not safe [4, 89].
For that reason, biochemical markers for monitoring of anthracycline based chemotherapy as well as prophylaxis of cardiomyopathy development for patients with no manifestations of myocardial damage appears more favourable and reasonable. At the moment, the application of lactate dehydrogenase (LDG) and creatinphosphokinase (CPK) ia considered to give low results in specification.
That is why in the current situation natriuretic peptides (atrial natriuretic peptide — ANP and brain natriuretic peptide — BNP) are considered more efficient from the point of informativeness. These neurohormones play predominant role while supporting the compensated state in patients with primary CHF signs, first of all, for the reason of the their effect on renal homeostasis, water-electrolytic balance and renin-angiotensin-aldosterone system at the sircumstances of decreased cardiac ejection.
Terminal fragment of BNP precursor — NT-proBNP (N-terminal prohormone of brain natruretic peptide) — has longer half-life period, so the recent researches have been completed with NT-proBNP which is secreted in heart ventricles responding to quantity and pressure overloads . Blood plasma proportion of NT-proBNP and BNP increases during the first year after chemotherapy with below-medium anthracycline dosage .
The important fact is that currently there is no essential evidence of prognostic importance of natriuretic peptide levels, but an elevation of their blood plasma concentration may be reasonable to be applied for patients with higher risks of heart malfunction development in late-term. Such patients demand more intense and supportive therapy. It has been found that concentration of carnitine, lipid peroxidase level in blood plasma is related to myocardial dysfunction [11, 50].
Regardless the spectrum of suggested biochemical markers, the most safe and reliable approach of myocardial malfunction forecasting is supposed to be specification of level of cardiac troponin T (cTnT) which is excreted in blood for the reason of cardiomyocyte membrane destruction . In many studies it has been shown that even moderate rise of cTnT inducted by DOX, is connected to histological symptoms of myocardial damage .
According to clinically applied patterns acute and chronic cardiotoxicity is possible to be distinguished [37, 50, 129]. Acute form evolves when the preparations course is started or several hours after. The symptoms show transitory arrhythmia and hypotension curable with available treatments. Chronic cardiotoxicity causes congestive HF that is refractory to average inotropic agents .
There is an opinion distinguishing early forms (which occur within the first year) and late form (evolving from 1st till 30th years with the critical points between 7–10th years) . Creutzig U. et al.  notes likelier chronic cardiomyotoxicity development in young patients who already experienced cardiomyotoxicity acute form or undertaken several courses with anthracyclines. The risk remains high with lighter dosages of preparation.
It is important to note, that for patients with survival higher than 5 years after anthracyclines anticancer treatment have a risk to future heart pathologies 10 fold higher comparing to overal population . Similarly around 60% of patients survived after childhood cancer go under prescription of the treatments exactly from the same medical group .
Therefore the research for finding efficient approaches of prophylaxis and mitigation of cardiotoxic influences of anthracyclines is considered of a vital significance. Firstly, it is the diagnosis for risks factors possibilities in the patients, amendment of cumulative dose of anthracyclines, and constant observation and control of subclinical myocardial injury . The creation of new preparations with milder cardiotoxic action as well as their liposomal forms becomes an important task for scientists [13, 38, 97, 105, 119].
It makes good sense to apply active curative-prophylactic usage of cardioprotectors with antioxidant characteristics, particularly organic amifostine thiosulphate , L-carnitine , N-acetylcysteine, vitamin Е , thiotriazoline , flavonoid rutoside , etc. the other agents that arebeing applied are: cholesterol-depletion agent probucol [49, 58], beta-blockers , calcium channel inhibitors [69, 122] and combined with activators of ATP-sensitive potassium channels .
Rovustatin and probucol has good antiapoptotic potential against cardiomyocytes and represent the classics within lipid-lowering medication group [84, 106]. Cardioprotective effect of adenosine is fairly familiar to oncologists. It increases intracellular ATP concentration and overall adenylate potential . As for Cardinale D. et al., if a patient takes immediately the ACE-blocker enalapril, that almost completely stops the evolving of HF in the risk-groups . Still, the statistics show that the preparation gave moderate positive effect in children who have taken intense chemotherapy .
Several experiments were undertaken regarding the usage of erythropoietin, thromboplastin, and synthetic prostacyclin iloprost as cardioprotectors [53, 55, 71]. According to professional point of view, the application of granulocyte colony stimulates prophylaxis of DOX-induced DCMP and appears to show positive improvements. The mentioned cytokine is at the same time the most potent myeloprotective agent.
Iron-chelating component cardioxane shows positive outcomes in prophylaxis of acute and chronic DOX-induced cardiomyopathy. Yhus it should be considered that the effect on the action of cytostatic anthracycline-based treatment is individual and may be instable [29, 32, 57]. Cardioxane application is limited by its causes of myelotoxicity, nausea and diarrhea .
Regardless intense research in the field, the action of cardiotoxicity development upon anthracycline-based chemotherapy stay incomplete in terms of information and the possibilities of today preventive and curative approaches remain limited. The lack of safe methods of prophylaxis and cure of anthracycline cardiomyopathy encourages the search of new solutions. Therefore nowadays approaches of sorption therapy is gives perspectives and appears promising.
Sorption technologies are believed to be efficient curative measures for removing of toxic components of endogenous and exogenous origin from organism liquids . The major sorption detoxification approaches are purification of blood and its components via hemosorptive procedures. Patients are administered high doses of sorption products.
Cancer patients experience endogenous intoxication caused by tumorogenous process as well as by treating means directed to destruct malignant lesions . The “tumor disposition” (the condition occurred during the course of malignant pathology) depends on stable LPO activation, oxidative stress , and “metabolic intoxication” connected with malfunctioning of excretory organs, i.e. collecting extra volumes of toxic intermediate and terminal metabolites .
Detoxification products and methods are very important in treating oncology. For instance, upon DMCP positive improvements of plasmaimmunosorption occurred expressing in the decrease of а NT-pro BNP marker and sufficient increase of ejection fraction from 25.5 to 30.9% . Enteropsorption can be considered efficient detoxification approach a noninvasive method opposite to hemosorption, and plasmapheresis.
Clinical term “enterosorption” has been applied in the medical field since 1982 .
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