Protective Effect Of Dexrazoxane On Cardiotoxicity Induced By Trastuzumab And Anthracycline And Its Mechanism

Objective:1. To monitor the cardiac function of women breast cancer patients who received anthracycline and who rececived anthracycline in combination with dexrazoxane.To distinguish differences between the two groups above in order to observe adverse reactions to chemotherapy and to understand the protective effect of dexrazoxane on cardiotoxicity caused by anthracycline chemotherapy drugs.To evaluate the conjunction security of dexrazoxane with anthracycline in combination with anthracycline.2. To monitor the cardiac function of F344rats that received anthracycline in combination with trastuzumab and rececived anthracycline, trastuzumab in combination with dexrazoxane. To test the protective effect of dexrazoxane on cardiotoxicity caused by anthracycline and trastuzumab.To evaluate the conjunction security of dexrazoxane with anthracycline in combination with anthracycline.To study the rational application of dexrazoxane dose in the type of cardiac toxicity model.Methods:1. A total of122invasive breast cancer patients after operation were randomly divided into two groups:Experimental group of61cases treated with EPI plus DEX(DEX:EPI10:1) as adjuvant chemotherapy regimen; Control group of61cases treated with EPI but without DEX. To record adverse reaction and general conditions before chemotherapy and after chemotherapy. To observe changes of specific cardiac functional status (LVEF).To compare the change differences of two groups of cardiac function (BNP, cTnT) in double antibody sandwich method and to observe non-cardiac toxicity of dexrazoxane in combination with anthracycline.2. The rats were randomly divided into blank control group(n=5) treated nothing, DOX/Doc/Her group treated with chemotherapy plus trastuzumab and experimental group (n=15)(three subgroup depending on the dose of dexrazoxane,n=5) treated with chemotherapy plus trastuzumab in combination with dexrazoxane.To observe rats’ general conditions and changes of specific cardiac functional status(ANP、BNP、cTnI) in double antibody sandwich method and the levels of MDA in TBA method and levels of SOD in xanthinoxidase method.To observe myocardial tissue myocardial pathological changes on electron microscope after HE staining.To detect cardiac myocyte apoptosis in TUNEL analysis.Results:1. Protective effect of dexrazoxane on cardiotoxicity for women breast cancer patients who received anthracycline-containing. Brain natriuretic peptide (brain, natriuretic peptide BNP), cardiac troponin T(cTnT) after four cycles of chemotherapy were significantly higher than those before chemotherapy in control group respectively,with statistically significant difference observed(P<0.05).While those levels above were no statistically significant difference observed(P>0.05) in experimental group. Heart rate(HR) after four cycles of chemotherapy was significantly more quickly than that before chemotherapy in control group, with statistically significant difference observed(P<0.05).While that level above was no statistically significant difference observed(P>0.05) in experimental group. Left ventricular ejection fraction(LVEF) after four cycles of chemotherapy was reduced significantly more than that before chemotherapy in control group, with statistically significant difference observed(P<0.05).While that level above was no statistically significant difference observed(P>0.05) in experimental group. Absolute neutrophil count after four cycles of chemotherapy was reduced a little more than that before chemotherapy in control group, with no statistically significant difference observed(P>0.05).While that level above was statistically significant difference observed(P<0.05) in experimental group. Non-cardiac and hematologic toxicity had no statistically significant difference in both control group and experimental group between before chemotherapy and after four cycles of chemotherapy.The incidence of Ⅰ～Ⅳ degree of bone marrow suppression were21.3%、16.4%、24.6%、4.9%in experimental group;While they were16.4%、11.5%、9.8%、5.5%respectively,which had statistically significant difference(P<0.05).2. The protective effect of dexrazoxane on cardiotoxicity induced by trastuzumab in combination with anthracycline:The weight three group before administration had no difference.The rats became gradually lazily moving， eating less and diarrheaing both DOX/Doc/Her group and DOX/Doc/Her+DZR group. The weight loss between two groups above had no statistically significant difference observed(P>0.05). The levels of MDA and cTnI were significantly increased in DOX/Doc/Her+DZR group,while the increased amplitude was not as high as the DOX/Doc/Her group,which had statistically significant difference. Left ventricular ejection fraction (LVEF) in DOX/Doc/Her+DZR group was significantly higher than that in DOX/Doc/Her+DZR group(P<0.05). The myocardial histopathological in the electron microscope have some difference among groups and subgroupsn except control group. The incidence of apoptosis was the significantly lower than the other groups; The apoptosis index in DOX/Doc/Her+DZR group was significantly lower than DOX/Doc/Her group,which had statistically significant difference(P<0.05).Conclusions:1. In clinical trials, dexrazoxane has a protective effect on cardiotoxicity induced by anthracycline without increasing non-cardiac and non-hematologic toxicity.But dexrazoxane may increase bone marrow suppression of the anthracycline chemotherapeutic drug. We should pay attention to this adverse reactions in the clinical application process.2. In zoology experiments, dexrazoxane has a protective effect on cardiotoxicity induced by anthracycline in combination with trastuzumab to some extent. Dexrazoxane can reduce the levels of serum MDA, cTnI, and cardiac myocyte apoptosis.