| INTRODUCTION: Since 1960s',anthracycline opens up a broad prospect for chemotherapy. From biosynthesis to structure modification, scientists had found a series of anthracyclines, such as daunorubicin, doxorubicin (also called adriamycin), epirubicin, THP, pirarubicin, adarubicin, idarubicin etc. It has already been affirmed that they are all have some effects against human malignancies.Doxorubicin (14-hydroxy-daunomycin,DOX) is considered to be one of the most potent, broad-spectrum drugs against a wide range of tumor. Dox is highlyeffective against hematological malignancies and solid tumors. In 1968, dox was originally isolated form a mutant streptomyces peucetius obtained from daunorubicin-producing organism, S.peucetius. Dox showed grearter antitumor activity than daunorubicin against some murine cancers and also had a better therapeutic index. However, its clinical usage is often limited by the undesirable acute and chronic side-effects. The acute side-effects such as myelosuppression , nausea, vomiting and arrhythmias are either reversible or clinically manageable. The chronic side effects represented by the development of cardiomyopathy and ultimately congestive heart failure, which are irreversible and have bad prognosis. In a retrospective study of patient records, these cardiotoxic effects have been found to correlate with the total amount of the drug administered. Consequently, once the cumulative dose exeeds 500mg/m2, the cancer patients often were conflicted with doxombicin-induced cardiotoxicity, so, if we couldn't protect the heart from doxombicin, it will be excluded from many chemotherapentic regimens. Thus, people would have a good way to protect the heart, but not alter the antitumor activity of doxombicin.AIM: This study aims to determine the effects of amifostine on the doxombicin-induced rat cardiotoxicity, The activity of SOD and GSH-Px, the change rat left ventricular function and cardiomyopathy are observed to explore its possible mechanism.METHODS: SD rats weighing 250?0g were divided into three groups. Control group: NS(n=6,3mg/kg) were injected ip, twice a day, cumulative dose was 18mg/kg. Dox group: DOX(n=8, 3mg/kg). were injected ip, twice a day, cumulative dose was 18mg/kg. Amifostine adding Dox group: injecting amifostine (n=8,200mg/kg,ip) before Dox administered 30 min, twice a day, from d7 to dll,it meaned started injection of amifostine after Dox cumulative dose was given 9mg/kg. After 24h at the last injection, killed rats and detected SOD and GSH-Px, left ventricular function and observed the pathological change of cardiac tissue.RESULT: (l)Hymodynamic effects:We found no significant hemody-namic effect for amifostine adding doxorubicin. LVDP, 眃p/dtmax and LVDPxHR did not differ from control values when the rats ofamifostine+dox group were perfused. However amifostine+dox could significant enhancing hemodynamic effects(n=6, LVDP89.53 + 10.04 mmHg p<0.05, +dp/dtmax 1972.30 ?413.78mmHg/min p<0.01,-dp/dtmax -1498.98 ?294.90mmHg/min p<0.01,LVDP X HR15266.79 ?3606.85mmHg 'times/min P<0.05) as compared with dox group(n=6, 51.71 + 17.47mmHg, 1126.14 + 467.79mmHg/min,-821.30 + 292.62mmHg/min,9516.71+4677.15mmHg ?times/min respectively).(2) Effect on GSH-Px activities: The activities of GSH-Px of heart and hepatic tissue were enhanced significantly in pretreatment of amifostine (n=6, 143.93?9.50U and 213.08?7.99U,about 49% and 26% increment) compared with doxirubicin group (n=6, 38.69?.24U and 99.89 ?6.13U,p<0.05).(3) Effect on SOD activities:The activities of SOD of heart and Rbc extraction were increased significantly (p<0.05 and p<0.01 respectively) in amifostine+doxorubicin group(n=6, 349.35?137.21NU/mg ?prot and 34527.00?6398.50NU/gHb, about 59% and 35% increment) compared with dox (n=6,211.48?8.58 NU/mg ?prot and 23553.31?186.58 NU/g Hb respectively).(4) Pathological observation:The changes of pathologic was observed.Dox group was diffuse cells damage with vacuolization, mergence, frank necrosis. Amifostine+doxorubicin was a... |
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