Effects of angiotensin II receptor blocker (candesartan) in daunorubicin-induced cardiomyopathic rats

BACKGROUND: Daunorubicin is an anthracycline anti-tumor agent; anthracycline chemotherapy in cancer can cause severe cardiomyopathy leading to a frequently fatal congestive heart failure; the first-line treatment is diuretics and digoxin. Recently, angiotensin-converting enzyme inhibitors have been shown to be effective in the treatment of such toxicity. The purpose of this study was to investigate the effects of angiotensin II type-1 receptor antagonist (candesartan) in a rat model of daunorubicin-induced cardiomyopathy. METHODS: Rats were treated with a cumulative dose of 9 mg/kg body weight daunorubicin (i.v.). 28 days later, after the development of cardiomyopathy, animals were randomly assigned to candesartan-treated (5 mg/kg/day, p.o.) or vehicle-treated groups; age-matched normal rats were used as the control group. Candesartan treatment was continued for 28 days. Hemodynamic and echocardiographic parameters were measured, cardiac protein and mRNA were analyzed, and histopathological analyses of myocardial fibrosis, cell size and apoptosis were conducted. RESULTS: Following cardiomyopathy, left ventricular end diastolic pressure and left ventricular systolic dimension were significantly elevated; while % fractional shortening and Doppler E/A ratio were significantly reduced. Cardiomyopathic hearts showed significant increases in % fibrosis, % apoptosis, and myocyte diameter/body weight ratio; candesartan treatment reversed these changes. Fas-L protein overexpression in myopathic hearts was significantly suppressed by treatment with candesartan. Moreover, SERCA2 mRNA and protein expression were both down-regulated in myopathic hearts and restored to normal by candesartan treatment, significantly. CONCLUSIONS: Our findings suggest that candesartan treatment significantly improved the left ventricular function and reversed the myocardial pathological changes investigated in this model of daunorubicin-induced cardiomyopathy; suggesting its potentials in limiting daunorubicin cardiotoxicity.     

Doxorubicin and cyclophosphamide followed by weekly docetaxel as neoadjuvant treatment of early breast cancer: analysis of biological markers in a GEICAM phase II study

Introduction  To evaluate the sequential administration of doxorubicin (A) and cyclophosphamide (C) followed by weekly docetaxel in women with stage II to IIIA breast cancer. Patients and methods  Patients received 60 mg/m² of A and 600 mg/m² of C every three weeks for four cycles followed by 12 infusions of weekly docetaxel at a dose of 36 mg/m² and with a 2-week resting period. Results  Sixty-three women were included. On an intentionto-treat basis, clinical response rate was 90% (95% CI: 83–98), with 46% complete responses. Breast-conserving surgery could be performed in 43 patients (68%). Complete pathological responses in the breast were confirmed in 17% of patients. No correlations between levels of expression of topoisomerase II alpha, survivin or p27 and the pathological response were detected. The study treatment was generally well tolerated. Conclusion  Neoadjuvant AC followed by weekly docetaxel is a feasible regimen for patients with early-stage breast cancer.     

Ultrasound Myocardial Tissue Characterization by Integrated Backscatter in Children Treated with Anthracyclines

The objective of our study was to evaluate integrated backscatter (IBS) measurement, an ultrasound method of myocardial tissue characterization, in children receiving cardiotoxic anthracyclines for malignancy. Myocardial injury is known to diminish the normal cyclic variation of IBS (CVIBS) during the cardiac cycle. We used a cross-sectional, case-controlled study of children receiving anthracyclines and serial, prospective observation in a subgroup of children. The study took place in a university-affiliated, tertiary referral center for pediatric cardiology and oncology. Children undergoing routine echocardiograms before, during, and after anthracycline treatment participated in this study. Children evaluated in the cardiology clinic for innocent murmurs participated as controls. There was no intervention. CVIBS was measured using specialized echocardiographic software which quantitates the intensity of backscattered echoes returning from myocardial cells within a user-defined region of interest. Standard echocardiographic measures of left ventricular function were also made. The results indicated that abnormal CVIBS was prevalent during anthracycline treatment (17%) and at late follow-up (20%). In serial studies, CVIBS decreased in all children after anthracycline treatment. Anthracycline dose and time since last dose did not predict which children would have abnormalities of left ventricular function or of CVIBS. This report provides preliminary evidence that CVIBS may be a useful supplement to the noninvasive, echocardiographic assessment of the heart during anthracycline treatment in children.     

三维斑点追踪技术评估蒽环类药物对乳腺癌患者右室心肌功能的影响

目的探讨三维斑点追踪(3D-STI)技术评估蒽环类药物对乳腺癌患者右室心肌功能影响的临床应用价值。方法选取行蒽环类药物化疗的乳腺癌患者46例,均于化疗前1 d及化疗2、4、6周期后1 d行3D-STI检查及99mTc-MIBI和18F-FDG双核素显像检查,测量其三尖瓣环收缩期血流速度(S)和位移(TAPSE)、右室面积变化分数(RV-FAC)、左/右室舒张末容积(LV-V/RV-V)、左室射血分数(LVEF)、右室整体纵向应变(RVGLS)、圆周应变(RVGCS)、径向应变(RVGRS)及面积应变(RVGAS),比较不同时间点上述参数的差异。采用Pearson相关分析法分析RVGLS、RVGAS与常规超声心动图指标及3D-STI指标的相关性;绘制受试者工作特征(ROC)曲线评估RVGLS和RVGAS预测右室心肌受损的诊断效能。结果化疗前及化疗2、4、6周期后,S、TAPSE、RV-FAC、RV-V、LV-V及LVEF比较差异均无统计学意义。3D-STI检查显示,与化疗前比较,化疗2、4、6周期后RVGLS均降低,化疗4、6周期后RVGAS均降低(均P<0.05);与化疗2周期比较,化疗4、6周期后RVGLS和RVGAS均降低(均P<0.05);化疗6周期后RVGLS和RVGAS均较化疗4周期降低(均P<0.05)。相关性分析显示,RVGLS与S、TAPSE、RV-FAC、RV-V、LV-V、LVEF、RVGCS、RVGRS、RVGAS均相关(均P<0.05),RVGAS与S、TAPSE、RV-FAC、RV-V、LV-V、LVEF、RVGLS、RVGCS、RVGRS均相关(均P<0.05)。ROC曲线分析显示,以RVGLS<16.99%和RVGAS<20.57%为截断值,其预测右室心肌受损的敏感性、特异性分别为73.1%、96.2%和90.0%、65.0%,曲线下面积分别为0.879、0.830。结论3D-STI评估蒽环类药物对乳腺癌患者右室心肌功能影响有较高价值,可作为临床早期监测右心功能改变的重要方法。     

Menogaril, an Anthracycline Derivative, Inhibits DNA Topoisomerase II by Stabilizing Cleavable Complexes

Menogaril, an anthracycline derivative, has been shown to possess antitumor activity in experimental animal systems, and is now under phase II clinical studies. However, its mechanism of action has not been elucidated. We have found that it inhibits the decatenation activity of purified DNA topoisomerase II using kinetoplast DNA from Crithidia fasciculata , its IC50 being 10 μM, which is comparable to that of etoposide. It does not, however, inhibit topoisomerase I activity at concentrations of up to 400 μM. Binding of topoisomerase II with DNA is not affected, but cleavable complex formation is stimulated by the drug. Cleavage site specificity differes from that of 4'-(9-acridinylamino)methanesulfon- m -anisidide. Menogaril was shown to possess a weak double-helix unwinding activity. These findings allow us to classify menogaril as a cleavable complex-stabilizing topoisomerase II inhibitor.     

新蒽环类抗生素变活霉素A的分离及结构测定

从一株无活性链霉菌1254经诱变后得到的变株113的发酵液中分离到一组新蒽环类抗生素──变活霉素。变活霉素A为其主要成分;其对疱疹病毒Ⅰ、Ⅱ,流感病毒甲及柯萨奇病毒B_6有明显抑制作用,对某些革兰氏阳性菌亦有活性。 基于光谱证据及化学反应,阐明了变活霉素A的结构。通过 CD谱的比较,NOE差谱及~1HNMR数据的分析以及变活霉素A水解产物环状异丙叉醚衍生物的制备,确定了变活霉素A“A”环立体化学为7S、9R,“A”环呈半椅式构象,C-9在蒽醌环平面上方。     

思文霉素对胞外DNA拓扑异构酶介导产生的断裂和松驰反应的影响

思文霉素（Siwenmycin）是最先从我国土壤中的链霉菌培养物中提取的一个新型蒽环类抗生素。研究表明该药是DNA拓扑异构酶抑制剂，以ATP依赖性pBR322 DNA断裂松驰反应，观察思文霉素对从哺乳动物细胞中提取的DNA拓扑异构酶Ⅱ活性的抑制作用后发现该药对此酶的最大抑制浓度为25mmol/L。用思文霉素处理Bel 7402细胞后，从中提取的DNA拓扑异构酶Ⅱ所介导的DNA断裂松驰反应活性比对照组增加5倍，研究还发现，思文霉素可抑制胞外DNA拓扑异构酶Ⅰ活性，碱性洗脱实验证明该药可引起DNA单链断裂。     

Assessment of anthracycline-induced myocardial damage by quantitative indium 111 myosin-specific monoclonal antibody studies

To assess chemotherapeutically induced myocardial damage, myosin-specific antibody scans and ejection fraction measurements were performed in 32 patients with breast cancer and in 9 patients with other tumours. All patients had received chemotherapy including anthracyclines. The ejection fraction decreased by 10% in 14 of 41 (34%) patients after chemotherapy. Antimyosin uptake in the myocardium was observed in 38 of 41 (92%) patients after chemotherapy. Antimyosin uptake was quantified by means of a heart-to-lung ratio, revealing a correlation between the degree of antimyosin uptake in the myocardium and the cumulative dose of anthracycline. Patients with a decreased ejection fraction showed more intense antimyosin uptake, indicating more severe myocardial damage. A higher degree of antimyosin uptake was found in 17 breast cancer patients treated with doxorubicin compared with 15 patients treated with mitoxantrone. We conclude that antimyosin studies provide a sensitive, non-invasive method to monitor myocardial damage in patients treated with anthracyclines. Antimyosin uptake in the myocardium precedes ejection fraction deterioration. This technique may be helpful in the early identification of patients at risk of congestive heart failure during chemotherapy including anthracyclines.This work has been supported by grant DGICYT PM89-0125 and by a research grant from Amersham IbéricaOffprint requests to: I. Carrió     

儿童蒽环类药物心脏毒性研究进展

随着蒽环类药物在儿童血液肿瘤方面的应用,患儿生存率明显提高,监测和诊断蒽环类药物对于儿童心脏毒性的研究越来越受到重视。该文就蒽环类药物对儿童心脏毒性的临床分型、诊断、发病机制、检测手段及预防等方面的研究进展作一综述。