Anthracycline-induced cardiotoxicity: Overview of studies examining the roles of oxidative stress and free cellular iron

The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance. Anthracyclines may promote the formation of ROS through redox cycling of their aglycones as well as their anthracycline-iron complexes. This proposed mechanism has become particularly popular in light of the high cardioprotective efficacy of dexrazoxane (ICRF-187). The mechanism of action of this drug has been attributed to its hydrolytic transformation into the iron-chelating metabolite ADR-925, which may act by displacing iron from anthracycline-iron complexes or by chelating free or loosely bound cellular iron, thus preventing site-specific iron-catalyzed ROS damage. However, during the last decade, calls for the critical reassessment of this “ROS and iron” hypothesis have emerged. Numerous antioxidants, although efficient in cellular or acute animal experiments, have failed to alleviate anthracycline cardiotoxicity in clinically relevant chronic animal models or clinical trials. In addition, studies with chelators that are stronger and more selective for iron than ADR-925 have also yielded negative or, at best, mixed outcomes. Hence, several lines of evidence suggest that mechanisms other than the traditionally emphasized “ROS and iron” hypothesis are involved in anthracycline-induced cardiotoxicity and that these alternative mechanisms may be better bases for designing approaches to achieve efficient and safe cardioprotection.     

阿霉素不同剂量静脉注射的药动学及其临床意义

采用ＨＰＬＣ法测定１４例肿瘤患者使用不同剂量阿霉素的血药浓度，并计算药代参数。４０ｍｇ／ｍ２和２５ｍｇ／ｍ２两组的血药峰浓度、ＡＵＣ、Ｖｃ差异有显著性。阿霉素的药代动力学存在明显的个体差异，血药峰浓度、Ｖｃ、Ｋ１２与疗效相关。     

Results of a randomized study of early stage Hodgkin's disease using ABVD,EBVD, or MBVD

From January 1986 to December 1989, 157 previously untreated patients, with Hodgkin's disease stage I or II without bulky disease, were enrolled in a clinical comparative study. The objectives of the study were to compare the efficacy and safety of using epirubicine or mitoxantrone instead of adriamycin in the combination chemotherapy regimen ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine). The complete response rate was better in the patients treated with the ABVD or EBVD regimens compared to the MBVD arm. Also, differences in overall survival and relapse-free survival were better in the patients who received ABVD or EBVD compared to the MBVD regimen. Hematological, gastrointestinal and cardiac toxicity were similar in the three groups. Dose intensity, delays and complications were also similar in the three groups. The mitoxantrone-containing regimen was found to have less efficacy in comparison to the other regimens tested in the present study in patients with favorable stage I or II Hodgkin's disease. © 1995 Wi1ey-Liss Inc.     

茯苓对阴虚水肿模型大鼠及其热象的影响

目的 观察茯苓对阴虚水肿模型大鼠的影响,研究茯苓利水作用特点及机制,并评价茯苓对阴虚水肿所表现出热象的影响。方法 尾iv阿霉素联合ig甲状腺片复制阴虚水肿模型大鼠,给予茯苓水煎液或六味地黄丸干预4周,观察大鼠水肿情况和一般生长状态,检测24 h尿量和尿蛋白,测量肛温,进行冷热板实验计算热板停留时间比;检测血清总蛋白（total cholesterol,TP）、白蛋白（albumin,Alb）、尿素氮（blood urea nitrogen,BUN）、肌酐（creatinine,Cr）、环磷酸腺苷（cyclic adenosine monophosphate,c AMP）、环磷酸鸟苷（cyclic guanosine monophosphate,c GMP）水平;测定肾组织超氧化物歧化酶（superoxide dismutase,SOD）活性及活性氧（reactive oxygen species,ROS）、丙二醛（malondialdehyde,MDA）水平;苏木素-伊红（HE）染色观察肾组织病理变化;Western blotting检测肾脏组织Klotho和棕色脂肪组织中解偶联蛋白1...     

Toxicity of magnetic albumin microspheres bearing adriamycin

Magnetic albumin microspheres entrappingadriamycin ( ADM- MAM) is a novel chemothera-peutic compound with site- specific drug delivery,which was exploited and developed in 1 970 's[1] .However,there wasno detailinformation indexed onits toxicity[2 ] . In recentyears,we studied the toxici-ty of the compounds macroscopically and microscopi-cally and also gotits value of LD50 .1　METHODSAND RESULTSBased on the method previously reported[1] ,thecompound of ADM- MAM was synthesized[14 ]…     

生脉注射液对阿霉素致心脏损伤保护作用的实验研究

用Wister大鼠模型研究生脉注射液对阿霉素致心脏损伤的保护作用。结果：使用生脉注射液比单纯使用阿霉素,血清SOD活性升高,MDA、GOT、LDH、HBDH、LDH1／LDH2比值及心肌病理计分下降。表明;生脉注射液对阿霉素导致的心脏损伤具有保护作用,其机理与其清除氧自由基,保护SOD活性有关。     

丹参及生脉液对阿霉素所致大鼠肾小球硬化的实验性治疗作用

观察丹参及生脉液对阿霉素所致 Ｓ Ｄ 大鼠肾小球硬化实验性治疗作用。摘除大鼠左肾７ ｄ 后,尾静脉注射阿霉素（６ ｍ ｇ·ｋｇ － １） 。隔日腹腔注射丹参及生脉液,８ 周后处死大鼠。观察血红蛋白（ Ｈｂ） 、血尿素氮（ Ｂ Ｕ Ｎ） 、胆固醇（ Ｃｈ） 及２４ ｈ 尿蛋白含量; Ｅ Ｌ Ｉ Ｓ Ａ 法测定肾皮质Ⅳ型胶原（ Ⅳｃｏｌ ．） 及层粘连蛋白（ Ｌ Ｎ） ;用免疫组化法,计算机图象分析肾小球系膜区Ⅳｃｏｌ ．及 Ｌ Ｎ 含量。结果显示：模型丹参及模型生脉液组肾皮质、肾小球系膜区Ⅳｃｏｌ．及 Ｌ Ｎ 含量明显低于模型对照组（ Ｐ ＜ ０ ．０５） ,高于正常对照组（ Ｐ ＜ ０ ．０１） 。提示丹参及生脉液能减轻阿霉素所致肾小球硬化的程度。     

Osteoclastome-like giant cell thyroid carcinoma controlled by intensive radiation and adriamycin,in a patient with meningioma and multiple myeloma treated by radiation and cytoxan

The eighth case of osteoclastome-like giant cell carcinoma of the thyroid, and the first one to be treated with adriamycin in addition to surgery and radiation, is reported. This rare variant of anaplastic thryoid carcinoma appeared in a patient operated on for meningioma and treated for multiple myeloma with cranial radiation and chronic administration of cytoxan.     

含诺维本的联合化疗对47例中晚期肺癌的近期疗效

目的：探讨含诺维本的联合化疗治疗中晚期肺癌的近期疗效及毒副反应。方法：应用以诺维本为主，与顺铂及阿霉素联合治疗47例中晚期肺癌有效率及毒副反应。结果：47例中晚期肺癌总有效率为48．9％。其中非小细胞肺癌有效率为56．8％（肺鳞癌为57．8％，肺腺癌为55．6％），小细胞肺癌有效率为20％.两组差异显著（P＜0．05），而鳞癌和腺癌疗效无明显差别（P＞0．05）。本方案毒副反应主要是骨髓抑制、神经毒性，胃肠道反应则较少。结果提示含有诺维本的联合化疗不仅对非小细胞肺癌有较好疗效，且毒副反应较轻。结论：含有诺维本的联合化疗，是一个值得临床更深入研究及应用的治疗非小细胞肺癌方案。     

抑制生存传导路径可增加肿瘤细胞化疗敏感性

目的：研究抑制磷酸酰肌醇3激酶(PI3K)／Akt生存传导路径是否可增加肿瘤细胞对一些化疗药物的敏感性。方法：采用Akt亚型特异抑制剂结合多柔比星(阿霉素ADM)或喜树碱治疗各种肿瘤细胞系；检测细胞凋亡蛋白激酶3活性，来定量评估细胞凋亡程度；免疫沉淀 Werstern印迹法测定药物对磷酸化各类Akt亚型的抑制作用。结果：①各类Akt亚型抑制剂可阻断Akt1或Akt2蛋白序列上的第308位点苏氨酸(pAkt^308)和第473位点丝氨酸(pAkt^473)磷酸化，并表现出相应的Akt亚型抑制特异性；②单独抑制某一类Akt亚型并不足以增加肿瘤细胞对化疗药物的敏感性，只有同时抑制Akt1和Akt2才能增敏药物对肿瘤细胞的杀灭效应；③药物的增敏效应可能和肿瘤细胞内源性PTEN脱磷酸酶的表达有一定的关联。结论：临床应用化疗结合PI3K／Akt生存传导路径抑制剂应选择具有阻断2种Akt亚型功能的药物以达到最大的肿瘤杀灭效应。