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TOXICOLOGY
t
rba
im
nek
ová
emysl Po
kal
Department of Pharmacology (M.., O.P., V.G.), Department of Histology and Embryology (Y.M.), and Department of Physiology (A.P., M.A.), Faculty of Medicine in Hradec Králové and Department of Biochemical Sciences, Faculty of Pharmacy (T.., H.K.), Charles University in Prague, Hradec Králové, Czech Republic; and Lady Davis Institute for Medical Research, Departments of Physiology and Medicine, McGill University, Montreal, Quebec, Canada (P.P.)
Received July 24, 2006; accepted September 25, 2006.
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Abstract |
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; Minotti et al., 2004). Both the chronic (Von Hoff et al., 1979) and delayed (Lipshultz et al., 1991) types of ANT cardiotoxicity are associated with cardiomyopathy and irreversible damage of left ventricular myocardium, which functionally manifests itself as congestive heart failure.
Although the precise mechanisms involved in the chronic ANT cardiotoxicity still remain to be determined, there is a general agreement that reactive oxygen species (ROS) play an important role there (Hrdina et al., 2000). Therefore, numerous experimental cardioprotective interventions have been focused on ROS scavengers, including the "classic" antioxidants like vitamin E or acetylcysteine. After some promising initial experience, obtained mostly in acute experimental settings, mixed, contradictive, or solely negative outcomes were reported from both chronic experimental models and clinical studies (Legha et al., 1982; Myers et al., 1983; Herman et al., 1985; Berthiaume et al., 2005). From the numerous agents tested so far, only very few are currently in further development (Iliskovic et al., 1999; Abou-El-Hassan et al., 2003; Oliveira et al., 2004; Fisher et al., 2005). At present, the only drug with a well evidenced cardioprotective effect, in both experimental and clinical settings, is dexrazoxane (ICRF-187), prodrug yielding metal-chelating metabolites (Herman and Ferrans, 1986; Speyer et al., 1992; Swain et al., 1997; Marty et al., 2006). These active metabolites supposedly shield the so-called "labile iron pool" inside the cardiomyocytes and/or replace iron from complexes with ANTs and thereby prevent excessive production of ROS and particularly hydroxyl radicals (Hasinoff et al., 1998). Importantly, in most of recent clinical studies, dexrazoxane did not interfere with anticancer efficacy of ANTs (Swain and Vici, 2004; Marty et al., 2006), which is in agreement with a recent experimental study showing that ROS are not among the main mediators of their anticancer effect (Wu and Hasinoff, 2005). Thus, intracellular iron chelation is the only well established and successful strategy for cardioprotection in patients treated with higher cumulative doses of ANTs (Cvetkovic and Scott, 2005). Unfortunately, because of the myelosuppressive potential and high costs, the use of dexrazoxane is limited to selected groups of patients, such as those given more than 300 mg/m2 doxorubicin (or equivalent). It is estimated that only 6 to 7% of patients receiving ANTs are treated with dexrazoxane in Europe (Swain and Vici, 2004).
Apart from dexrazoxane, the data on possible cardioprotective properties of other iron chelators are surprisingly limited. Deferoxamine, the most widely used iron chelator for the treatment of iron overload, failed as a cardioprotectant in a chronic in vivo model of ANT cardiotoxicity (Herman et al., 1994). This observation is explainable by a hydrophilic nature of this drug, which is responsible for a limited entry of this agent into the cardiomyocytes. In vitro, bidentate iron chelator deferiprone was shown to have a cardioprotective potential (Barnabe et al., 2002), whereas another strong novel chelator ICL670 was ineffective under similar conditions (Hasinoff et al., 2003). In part, iron chelation may be also involved in the cardioprotective effects of flavonoid monoHER (Bruynzeel et al., 2006). We have previously reported that pyridoxal isonicotinoyl hydrazone (PIH), an aroylhydrazone iron chelator (Ponka et al., 1979; Baker et al., 1992), is capable of improving survival and slightly ameliorating the cardiotoxicity induced by chronic ANT treatment in rabbits (Simunek et al., 2005b). On the other hand, PIH is nowadays understood to be rather a "parent compound", from which a number of novel analogs are being derived. These advanced chelators are strong, selective for iron, and have improved cell penetration as well as excellent antioxidant properties (Simunek et al., 2005a). Pyridoxal 2-chlorobenzoyl hydrazone (o-108; Fig. 1) is among the most promising candidates (Link et al., 2003), and it was shown to be safe and well tolerated after repeated administration to rabbits (Sterba et al., 2005). Therefore, the main goal of the present study was to assess whether o-108 has cardioprotective properties against chronic daunorubicin (DAU) cardiotoxicity without compromising its antiproliferative efficacy.
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Chemicals
Pyridoxal 2-chlorobenzoyl hydrazone (o-108) was synthesized inhouse by a Schiff-base condensation of pyridoxal and 2-chlorobenzoylhydrazide as described previously (Link et al., 2003). The structure and purity of the compound was confirmed employing 1H and 13C NMR, infrared spectroscopy, and high-performance liquid chromatography with UV detection (Kovarikova et al., 2004). Cremophor EL (Sigma-Aldrich, Prague, Czech Republic), daunorubicin (Daunoblastina; Pharmacia, Nerviano, Italy), ketamine (Narketan inj.; Gedeon Richter, Budapest, Hungary), Aqua pro injectione (Biotika, Martin, Slovakia), saline (Natrium Chloratum; Biotika), and pentobarbital (Nembutal sodium; Abbott Laboratories, Abbott Park, IL) were used in the experiment.
Experimental Design
First, a study addressing potential effects of o-108 on the antiproliferative properties of DAU was performed, as this compound may only have value when it does not compromise the anticancer effect of anthracyclines. Thereafter, chronic anthracycline cardiomyopathy was induced in rabbits in a standard and previously validated schedule (DAU 3 mg/kg i.v., once weekly for 10 weeks, n = 15) (Gersl and Hrdina, 1994; Simunek et al., 2004). Control animals received saline (1 ml/kg i.v., n = 11), and another group was injected with the vehicle for the chelator (10% Cremophor EL i.p., n = 5) in the same scheme. The investigated iron chelator o-108 was partially dissolved in 10% Cremophor EL and administered intraperitoneally either alone (25 mg/kg i.p., n = 5) or in two doses (10 or 25 mg/kg, n = 8 each) 30 min before each DAU administration (3 mg/kg i.v.).
Body weight was recorded weekly, whereas mortality, general appearance, and behavior were observed daily. Noninvasive echocardiographic measurements were performed at the beginning of the study, later in weeks 9 and 10, and finally at the end of experiment (5–7 days after the last administration of drugs). Blood for cardiac troponin T determination was sampled before the 1st, 5th, 8th, and 10th administration, as well as at the end of the study. Standard biochemical and hematological parameters were determined from blood sampled before the 1st and 5th administrations and at the end of study. Five to seven days after the last administration, invasive hemodynamic measurements were performed. Thereafter, the animals had been overdosed with pentobarbital, and autopsy was performed. Heart and selected organs were excised and prepared for histological examination.
Proliferation Studies with HL-60 Cells
HL-60 human acute promyelocytic leukemia cell line was obtained from ATCC (Manassas, VA). Cells were maintained in RPMI 1640 medium (Sigma-Aldrich) supplemented with 10% heat-inactivated fetal bovine serum (Sigma-Aldrich), 1% penicillin/streptomycin (PAA, Pasching, Austria), and grown in humidified atmosphere at 37°C in 5% CO2. Medium was renewed every 2 to 3 days. For proliferation studies, the cells were seeded at a density of 105 cells/ml. Tested substances (o-108 and/or DAU) had been added, and cells were allowed to proliferate under standard conditions. The test concentrations of o-108 were chosen after pilot experiments and ranged from 0.1 to 300 µM. For combination assays, 2.5 nM DAU concentration was used, which was shown in our previous experiments to induce partial growth inhibition. To dissolve o-108, dimethyl sulfoxide (0.2%, v/v) was used, and it was present in the culture medium of all groups. At this concentration, dimethyl sulfoxide had no effect on cellular proliferation. To quantify the number of viable cells after each treatment, at 48 and/or 72 h of incubation, trypan blue unstained cells were counted using a Bürker's hemocytometer under a light microscope.
Cardioprotection Studies in Rabbits
Echocardiography. Noninvasive LV systolic function measurements were carried out in rabbits using a GE Vingmed CFM 800A echocardiograph (GE Vingmed Ultrasound, Horten, Norway) equipped with a pediatric 7.5-MHz probe. The LV long axis view was obtained through the left parasternal approach, and a guided M-mode measurement at the tips of the mitral valve was performed. The left ventricular ejection fraction (LVEF) was calculated from the LV end-diastolic and end-systolic dimensions determined from at least four heart cycles in each measurement. Individual LVEF values were determined as means of at least three independent examinations.
Invasive Hemodynamic Measurements. In pentobarbital anesthesia, the left carotid artery was prepared and a polyethylene catheter (length 300 mm, inner diameter 1.0 mm), filled-in with heparinized (10 IU/ml) saline, was introduced into the left heart ventricle. After a 15 min-equilibration period, the maximum of the first derivative of LV pressure rise in the isovolumic phase of the systole (dP/dtmax, an index of LV contractility) was obtained together with heart rate. For the arterial blood pressure measurement, a polyethylene cannula was inserted into the right femoral artery. The ADI PowerLab/8SP (ADInstruments Pty Ltd., Castle Hill, Australia) with appropriate transducers and the software Chart for Windows 3.4.11 were used for pressure measurements, their differentiation, and recording.
Cardiac Troponin T Determination. Cardiac troponin T, as a selective and sensitive marker of heart damage induced by chemotherapeutics (Adamcova et al., 2005), was determined in heparinized plasma using an Elecsys Troponin T STAT Immunoassay (Roche, Basel, Switzerland) and an Elecsys 2010 (Roche) immunoassay analyzer with the detection limit of 0.010 ng/ml. The values below this detection limit were considered to be zero.
Standard Biochemical and Hematological Analyses. Routine biochemical parameters were determined in plasma/serum using an automatic analyzer (Hitachi 737; Hitachi, Tokyo, Japan) at the Institute of Clinical Biochemistry and Diagnostics; hematological parameters were measured using an automatic analyser Coulter T890 (Beckman Coulter, Fullerton, CA) at the Institute of Clinical Hematology, University Teaching Hospital in Hradec Králové.
Histological Examination. Tissue blocks of the transversely sectioned left and right cardiac ventricles, left kidney, left liver lobule, left caudal lung lobule, and duodenum (
3 cm below the pyloric sphincter) were fixed by immersion in 4% neutral formaldehyde for 5 to 7 days. Paraffin sections (6-µm thick) were stained with hematoxylin-eosin and Masson's blue trichrome. Photomicrographs were made with a Lucia G software version 4.51 (Laboratory Imaging, Prague, Czech Republic) at the Department of Medical Biology and Genetics, Faculty of Medicine in Hradec Králové.
Statistical Analysis
The statistical software SigmaStat for Windows 3.0 (SPSS Inc., Chicago, IL) was used in this study. All data are expressed as mean ± S.E.M. Significances of the differences were estimated using one-way ANOVA unpaired test (comparison between groups) or paired t test (comparison with the initial value within each group). Data without a normal distribution were evaluated using the nonparametric tests: Kruskal-Wallis ANOVA on Ranks and Wilcoxon Signed Rank Test. Correlation analysis was performed using Spearman's method and regression analysis. P 
0.05 was used as the level of statistical significance unless indicated otherwise.
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Results |
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30 µM. Further dose escalation resulted in pronounced cytotoxic action. DAU (2.5 nM) significantly inhibited proliferation of HL-60 cell to 62% of control values. At low doses (0.1–10 µM), o-108 did not significantly influence the DAU action, whereas at higher concentrations, an additive antiproliferative effect was detected (Fig. 2B).
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) in the group treated with a combination of o-108 in the higher dose, the mortality occurred earlier, around the middle of the study. The details on survival during the study are shown in Fig. 3.
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Echocardiography. Echocardiographically determined LVEF revealed a progressive decline in LV systolic function in DAU-treated animals (Fig. 5). In contrast, there was no significant change in this parameter during the whole study in the o-108 (10 mg/kg) + DAU group. Furthermore, LVEF values in this group did not statistically differ from those determined in controls, and the LVEF was mostly also significantly higher than in the daunorubicin group. On the other hand, administration of o-108 (25 mg/kg) + DAU led to a fall in the LVEF resembling the administration of DAU alone.
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Cardiac Troponin T Plasma Concentrations. Repeated treatment with DAU induced a significant elevation in plasma concentration of cardiac troponin T commencing with the 8th week (Fig. 8). Cardiac troponin T elevations were also determined in the combination group treated with 25 mg/kg o-108. On the other hand, markedly suppressed elevation of this marker was observed in the group treated with daunorubicin together with o-108 in the lower dose. At the end of the experiment, slightly increased levels of troponin T were detectable in animals treated with o-108 alone; nevertheless, these values did not reach the significance with respect to either the control or vehicle groups.
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Biochemical and Hematological Analyses. The follow-up of serum biochemistry (Table 2) in the DAU group revealed a significant elevation in creatinine, cholesterol, and triglycerides, whereas a significant decrease was observed in total protein, ALP, and serum iron. The coadministration of either dose of o-108 mostly did not significantly change the trends observed in the group receiving DAU alone, although with the 10 mg/kg dose, most of changes were generally slightly less pronounced.
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With respect to hematological parameters, repeated administration of DAU induced significant decreases in the counts of leukocytes and erythrocytes, hematocrit, and hemoglobin, whereas, at the same time, the mean cell volume and red cell distribution width tended to increase (Table 3). Cotreatment with either dose of o-108 led to similar results; the only significant difference appeared in the value of the mean cell volume, which increased at the end of experiment in the o-108 (10 mg/kg) + DAU group.
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Post Mortem Examination. Pleural effusion (hydrothorax), often accompanied with pericardial effusion (hydropericardium), was present in 10 of 15 (67%) daunorubicin-receiving animals, whereas ascites were less frequent (4/15, i.e., 27%) and usually also less severe. The combination of DAU with 10 mg/kg o-108 caused hydrothorax in only 25% of animals (2/8), and no ascites was observed. The same treatment employing the higher dose of the chelator induced hydrothorax in 75% animals surviving until the end of experiment (3/4), whereas no distinguishable effusion was apparent in four prematurely dying animals. No other abnormalities were observed.
Histological Examinations. In comparison with control animals (Fig. 9a), as well as other groups under study (Fig. 9, b, c, e, and f), DAU treatment induced a massive focal damage of the left-ventricular myocardium (Fig. 9d). The large groups of degenerating to necrotic cells frequently accompanied with a mononuclear infiltration were observed (Fig. 9d). The resulting damage was so profound that the extent of healing process (gradual replacement of necrotic cells by the fibrotic tissue) was insufficient, which resulted into the partial disintegration of myocardium in these areas.
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With respect to the biochemical changes (namely the increased creatinine level), suggesting impaired glomelular filtration, our interest was also directed to the histopathological examination of the kidney. In comparison with controls (Fig. 10a), a severe damage of parenchyma was found in the kidney of group treated with DAU alone (Fig. 10d). Toxic damage developed, particularly in the cortical tubules, mostly in the form of tubular nephritis. The whole range of changes, i.e., from hyaline degeneration to the necrosis of the epithelial cells of many proximal and distal convoluted tubules in the cortex, less of the collecting tubules in the medulla were found, which documented the subsequent development of the damage. The volume of hyaline casts within the lumina of tubules varied from case to case (Fig. 10d).
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Discussion |
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), does not have potential to blunt the extensive antiproliferative efficacy of DAU. Moreover, o-108 itself was shown to have moderate antiproliferative potential, which is in line with previous observations (Richardson et al., 1995). It should be noted that some other aroylhydrazones (particularly those derived from salicylaldehyde, 2-hydroxy-1-naphthylaldehyde or di-2-pyridylketone) has been shown to be significantly more efficient from this point of view (Richardson et al., 1995; Le and Richardson, 2004; Yuan et al., 2004; Kalinowski and Richardson, 2005). The present findings are in concert with latest experimental and clinical data, which conclude that chelator-based cardioprotective approach employing dexrazoxane does not have an impact on the anticancer efficacy of ANTs (Swain and Vici, 2004; Wu and Hasinoff, 2005; Marty et al., 2006), despite some previous concerns (Swain et al., 1997). With this in mind, o-108 certainly remains to be a very good candidate for further cardioprotective studies.
The main aim of the present study was to explore possible cardioprotective effects of o-108 against anthracycline-induced chronic cardiac toxicity. The model used in the present study was previously analyzed and has been shown as appropriate and suitable for this purpose (Simunek et al., 2004). The use of DAU instead of doxorubicin is based on our previous study, in which DAU administered weekly to rabbits was shown to induce less severe extracardiac toxicity and mortality along with well reproducible cardiac injury (Klimtova et al., 2002). Dexrazoxane, as a positive control, was previously capable of affording effective cardioprotection in our model that again supports its relevance. Furthermore, it was recently pointed out that, in rabbits, the cardiomyocyte calcium handling and structure and function of myocardial sarcomere reflect, both in normal and failing heart, the human system more accurately than in rodents (Marian, 2005).
In this study, the chelator o-108 was administered to rabbits in two doses (10 and 25 mg/kg) 30 min before each DAU injection. The timing and route of administration was adopted from previous successful studies with dexrazoxane, whereas the dosage was derived from the study on the safety and tolerability of the repeated administration of this drug (Sterba et al., 2005). The results of the present study showed that 10 mg/kg o-108, administered before DAU, was able to completely abolish the daunorubicin-induced mortality. The well being of the animals in this group was evidenced by significant body weight gain similar to that determined in the vehicle group and without significant differences compared with controls. Furthermore, the echocardiographically determined LVEF showed no significant drop in the LV systolic function during the whole study. These values were significantly improved compared with the group treated with DAU alone. The even more sensitive invasive measurement of the cardiac contractility (dP/dtmax), performed at the end of experiment, clearly revealed significantly better LV performance in the o-108-treated (10 mg/kg) animals. These findings are even more encouraging in the light of 100% survival in this group, because all animals under study were invasively examined, including those with potential cardiac deterioration. This is not the case of the DAU-only group in which those animals with the most severe cardiac failure died prematurely. Furthermore, at the end of study, both parameters of systolic function (LVEF and dP/dtmax) have shown a very good correlation. Cardiac troponin T plasma rise, as a result of myocardial injury, was also less pronounced in the group treated with the chelator, which corresponds with the lower extent and intensity of the LV myocardial damage, as assessed by histological examination.
With this in mind, rather surprising, however, unequivocal results were obtained when the same cotreatment was realized with the 2.5-fold higher dose (25 mg/kg) of the chelator. First, the mortality was worse than in animals treated with DAU alone. However, the early timing of the premature mortality (in relatively low cumulative doses of DAU) is unlikely to be attributed to cardiac damage. This hypothesis was also evidenced by the absence of marked histopathological changes in myocardium together with the minimal levels of troponin T determined before the death cases. The most conspicuous biochemical finding in the o-108 (25 mg/kg) + DAU group was progressively increasing creatininemia, particularly at the end of the study—more pronounced than in DAU alone and even more marked in comparison with combination of DAU with the lower dose of the chelator. Surprisingly, these biochemical changes were not followed by corresponding morphological findings in surviving animals (only modest to medium changes of the similar pattern as in the DAU group). Unfortunately, the kidneys, as well as most of other organs, could not be appropriately examined in prematurely dead animals due to the autolysis. Therefore, it is not feasible to draw definitive conclusions on the cause of the mortality observed in this group from the present study, and this is supposed to be addressed in further experiments designed for this purpose.
Although the occurrence of premature deaths unrelated to heart injury was quite surprising, the absence of marked cardioprotection with an increased dose of the chelator caused even more curiosity. With respect to these findings, it should be noted that repeated administration of o-108 alone to rabbits in the same schedule had no distinct impact on either the morphology or function of the heart or other organs, even in the dose of 100 mg/kg (Sterba et al., 2005). The findings from the present study cannot be attributed to interindividual or seasonal variability, because these animals were randomized for o-108 cotreatment and the same experimental conditions were employed. Moreover, the model used in this study is experienced to be well reproducible (Gersl and Hrdina, 1994; Simunek et al., 2004). The authors rather suggest that it is a causal observation, because a similarly unusual pattern of dose-response relationship was also witnessed previously during an extension of our study of cardioprotective effect of another aroylhydrazone iron chelator, PIH. Whereas 25 mg/kg PIH in our model seemed to have positive effects on DAU-induced mortality and cardiac function (Simunek et al., 2005b), further escalation of the PIH dose to 50 mg/kg resulted in negative outcomes in terms of both overall mortality and cardioprotective effects (Gersl et al., 2004).
Several hypotheses might be proposed to explain the findings described above; e.g., a very recent study on the pharmacokinetics of o-108 (Kovarikova et al., 2006) and salicylaldehyde isonicotinoyl hydrazone (another aroylhydrazone iron chelator with high antioxidative potential) (Simunek et al., 2005a) suggested that these chelators generally possess relatively short terminal half-lives of elimination (Kovarikova et al., 2005). This might be a limitation in the light of the relatively long stay of anthracyclines and their metabolites in myocardium (Cusack et al., 1995). Our results suggest that the chelator administered at the optimal dose may chelate the intracellular labile iron pool inside the cardiomyocytes and thereby afford meaningful cardioprotection. Nevertheless, further boosting of the cardioprotective efficacy might rather require a longer intracellular half-life instead of its higher peak concentrations; as in this case, some perturbations in the cellular iron metabolism in the cardiomyocytes already compromised with an anthracycline may appear.
Recent studies suggest that anthracyclines (and/or their 13-OH metabolites) are able to significantly impair cellular iron homeostasis (Kwok and Richardson, 2004; Xu et al., 2005). Kwok and Richardson (2003) demonstrated that anthracyclines are capable of causing marked perturbations in iron storage in ferritin and its subsequent release. It is plausible that very intensive chelation, such as that induced with ICL670 treatment (Hasinoff et al., 2003) or with high doses of aroylhydrazones, might "overshoot" the optimal degree of chelation and subsequently contribute to the iron metabolism misbalance caused by anthracyclines. As this effect might be associated with the peak concentrations, perhaps it could be helpful to administer aroylhydrazones by longer infusions or in smaller doses before and possibly also after anthracyclines. Furthermore, even better might be to improve the pharmacokinetic properties of o-108 through mild modification of its chemical structure.
In conclusion, the present study has shown that the novel iron chelator o-108 does not have any negative impact on the antiproliferative efficacy of daunorubicin. Moreover, the chelator itself has moderate antiproliferative effects that are additive to those of DAU. Furthermore, besides dexrazoxane, this study is the first to support the iron chelation concept as an effective cardioprotective strategy against chronic type of anthracycline cardiotoxicity; administration of o-108 (10 mg/kg) was able to completely overcome the daunorubicin-induced mortality along with marked improvement in cardiac function and morphology. However, the surprising dose dependence experienced in this study suggests that the role of iron in this process might be more complex than originally supposed. Hence, further studies of iron chelation-based cardioprotection are needed to determine the potential of this approach and to obtain deeper insight into the pathogenesis of the anthracycline cardiotoxicity.
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Acknowledgements |
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eluhová for skillful technical assistance during the whole study and Associate Professor Bohuslav Mánek for the kind review of English grammar. We also thank Shan Soe-Lin and Alex D. Sheftel for reading the manuscript and helpful suggestions. |
Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: ANT, anthracycline; DAU, daunorubicin; LV, left ventricular; ROS, reactive oxygen species; ICRF-187, dexrazoxane; o-108, pyridoxal 2-chlorobenzoyl hydrazone; PIH, pyridoxal isonicotinoyl hydrazone; LVEF, left ventricular ejection fraction; ICL670, deferasirox.
Address correspondence to: Dr. Martin trba, Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, imkova 870, Hradec Králové 1, 500 38, Czech Republic. E-mail address: sterbam{at}lfhk.cuni.cz
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) a statistically significant decrease or (i) an insignificant body weight change in comparison with the initial values. Where no symbol is given, a significant increase is meant. Statistical significance (ANOVA, P < 0.05) in comparison with: c, control group; v, vehicle group; o, o-108 alone (25 mg/kg); d, daunorubicin group; and 1, o-108 (10 mg/kg) + daunorubicin.
