左旋肉碱监测及防治蒽环类抗生素心脏毒性作用

目的 分析急性淋巴细胞白血病患儿血浆游离肉碱浓度的变化与蒽环类药物的关系,同时探讨补充左旋肉碱改善蒽环类药物心脏毒性的疗效.方法 急性淋巴细胞白血病缓解期42例患儿,根据入院时化疗是否含有蒽环类药物分为非蒽环类化疗组(1组)及蒽环类化疗组,后者又分为蒽环类化疗未补充肉碱组(2组)及蒽环类化疗补充肉碱组(3组).每组14例.所有患儿均在化疗后第3天接受常规支持治疗或左旋肉碱治疗,疗程共10 d.监测3组患儿用药前、中、后的血浆游离肉碱浓度及心肌酶、超声心动图、心电图各项指标.另将1组及3组患儿合并后按照蒽环类药物累积量分为蒽环类药物低累积量组(Ⅰ组<150ms/m2)及高累积量组(Ⅱ组≥150mg/m2),分别比较各项监测指标.结果 1组患儿左旋肉碱浓度及心电图异常率较3组患儿低,差异有统计学意义.2组与3组所有指标差异无统计学意义.Ⅰ组肉碱浓度明显高于Ⅱ组,心电图异常率亦较Ⅱ组增高,差异有统计学意义.结论 使用蒽环类抗生素短期内可能使左旋肉碱浓度代偿性增高,同时左旋肉碱浓度与蒽环类药物累积量呈负相关,监测其下降程度可以比超声心动图更早反映患儿出现慢性心肌损害的可能性.     

蒽环类药物治疗儿童恶性肿瘤所致心脏毒性的评价研究进展

蒽环类药物是一类来源于波赛链霉菌青灰变种的化疗药物,是细胞周期非特异性的细胞毒性药物,作为目前治疗儿童白血病、淋巴瘤及多种实体肿瘤的一线化疗药物,具有广泛的抗肿瘤效应.但蒽环类药物引起的不良反应如心脏毒性、骨髓抑制、脱发等,尤其是心脏毒性,往往呈进展性且具有不可逆性,极大地影响了患儿的远期生活质量.对蒽环类药物心脏毒性早期发现、诊断及相应干预是目前临床心脏损害的研究热点.临床上用于监测蒽环类药物心脏毒性的方法很多,如何有效监测葸环类药物所致心脏毒性显得尤为重要.该文针对蒽环类药物所致心脏毒性评价方面的研究进展作一综述.     

蒽环类药物心脏毒性机制的研究进展

蒽环类药物治疗白血病及实体瘤作用显著,但伴随而来的心脏毒性作用,是目前临床待解决的难题之一。早前认为心毒性主要与氧化应激损伤有关,新研究发现:线粒体生物生成、细胞能量代谢、神经调节蛋白、降钙素、"C13醇"代谢物等机制共同参与致心脏毒性,本文现就蒽环类药物心毒性机制的研究进展做一综述。     

右雷佐生对心肌保护作用研究进展

右雷佐生作为抗蒽环类心肌损害的保护剂,已成为研究热点。右雷佐生对蒽环类药物心肌损害的保护作用在许多动物实验及成人临床得到证实。有研究证实右雷佐生不但不干扰蒽环类药物的抗肿瘤效应,而且有协同作用。现就右雷佐生对心肌保护作用研究进展做一综述,以期为探讨右雷佐生对幼年患者的心肌保护作用提供参考。     

活性氧在化疗药物抗白血病中的研究进展

随着活性氧(ROS)研究的深入,它在肿瘤细胞凋亡中的作用不断被肯定,目前临床上的许多传统化疗药物的抗肿瘤作用与ROS密切相关,并且许多正在临床或实验研究阶段的药物成分都是通过产生ROS而发挥抗肿瘤作用.肿瘤细胞对ROS的易感性及肿瘤细胞本身高浓度的ROS这两个因素,决定了在胞内同样浓度的ROS作用下,肿瘤细胞能够发生凋亡而正常细胞则耐受.白血病化疗药物如柔红霉素、长春新碱等抗肿瘤作用与ROS有关,抑制ROS的产生则化疗药物的活性受到抑制.     

小儿白血病化疗药物的毒性反应及处理

小儿白血病主要的治疗方法是化疗,由于化疗方法的改进,使小儿急性白血病的治疗效果明显提高,尤其是小儿急性淋巴细胞性白血病。同时不可忽视的是,随着化疗药物的不断增多,与化疗药物相关的并发症也不断涌现,除由骨髓抑制所致的最常见的感染并发症外,还有一些其他常见且严重的化疗药物所致的毒性反应,特别是心脏损害,主要见于蒽环类药物;肝脏毒性,主要由甲氨蝶呤引起;肾脏毒性主要由环磷酰胺所致,这些毒性反应如未予充分重视,亦可导致小儿白血病治疗的失败。     

蒽环类药物致心脏毒性的研究进展

蒽环类药物是一类对造血系统肿瘤和实体肿瘤具有高效作用的抗癌药物 ,在临床化疗方案中 ,蒽环类药物的作用呈现出明显的剂量 效应关系 ,但随着剂量的增加 ,其不良反应也愈加突出。但引起学者最多关注的是蒽环类药物引起的心脏毒性。蒽环类药物致心脏毒性的研究最早始于 2 0世纪     

不同方案诱导治疗儿童急性早幼粒细胞白血病的临床分析

目的比较全反式维甲酸(ATRA)和三氧化二砷(As2O3)联合与不联合蒽环类药物诱导治疗儿童急性早幼粒细胞白血病(APL)的疗效和不良反应。方法回顾性分析2002年1月1日至2012年12月31日初治的46例APL患儿的临床资料,并根据不同诱导化疗方案和初始白细胞高低进行分组和对比分析。结果 30例不加蒽环组患儿中有2例早期死亡,而16例加蒽环组患儿无一早期死亡。加蒽环组与不加蒽环组的完全缓解率、达分子学缓解时间和诱导化疗结束时微小残留病定量分析的差异均无统计学意义(P0.05)。加蒽环组的高白细胞持续时间明显短于不加蒽环组,差异有统计学意义(P0.05)。全体加蒽环组和不加蒽环组的凝血异常时间、肝脏毒性、感染率差异无统计学意义(P均0.05)。结论儿童APL诱导化疗中联合蒽环类药物可减少高白细胞持续时间,降低白细胞峰值,有助于减少早期死亡。     

急性早幼粒细胞性白血病的治疗及主要并发症的处理

自从应用全反式维A酸（ATRA）及三氧化二砷（As2O3）后,急性早幼粒细胞性白血病（APL）的预后大为改观,成为急性非淋巴细胞性白血病（ANLL）中治疗效果最好的一种。APL化疗方案与其他白血病化疗用药的方式不同,其不是数种药物同时联合用药,而是单药序贯应用。现就ATRA、As2O3及蒽环类药物的应用,巩固维持治疗的化疗方案,及最主要的并发症——弥散性血管内凝血的诊治作一介绍。     

蒽环类药物致心脏毒性的研究进展

蒽环类药物是一类对造血系统肿瘤和实体肿瘤具有高效作用的抗癌药物，在临床化疗方案中，蒽环类药物的作用呈现出明显的剂量．效应关系．但随着剂量的增加，其不良反应也愈加突出。但引起学者最多关注的是蒽环类药物引起的心脏毒性。     

Late cardiotoxicity of anthracyclines in children with acute leukemia.

Congestive heart failure is one the most severe late complications of cancer therapy with anthracyclines. The function of the heart muscle was evaluated in 50 children (30 boys and 20 girls), aged from 5 years 6 months to 20 years 7 months, treated in the past for lymphoblastic or nonlymphoblastic acute leukemia. The total dose of the administrated anthracyclines was 120-550 mg/m2. The circulatory system was evaluated on the basis of history, physical examination, ECG, exercise test and echocardiography. Impaired contractility of the heart muscle was found in 32% of cases. The degree of impairment was related to the total dose of anthracyclines and to the period from discontinuation of therapy. Heart muscle function disorders were present also in children, in whom the cumulative dose of anthracycline antibiotics did not exceed 400 mg/m2. In the majority of patients the evidence of heart damage was subclinical.     

蒽环类药所致儿童心功能损害及其监测

目的 指导临床使用蒽环类药,减少药物毒性所致心功能损害。方法 超声心动图、心电图、心肌酶谱及胸部X线片,检测白血病、淋巴瘤患儿化疗前后的心功能状态。结果 85例患儿131次超声心动图测定,异常率38.82％,化疗前异常率20.93％(9／43),化疗后异常率50％(21／42),蒽环类药累积计量≥350mg/M2者,异常率明显增高。2例死于心肌病者药物累积量为100mg/M2和454.35mg/M2。结论 对白血病、淋巴瘤患儿作化疗前后心功能监测十分必要,临床应根据葸环类药物累积总量及心功能状态调整化疗用药;超声心动图监测心功能敏感且实用。     

Evaluation of anthracycline-induced early left ventricular dysfunction in children with cancer: a comparative study with echocardiography and multigated radionuclide angiography

The study aimed to compare diastolic and systolic dysfunctions detected by echocardiography (ECHO) and multigated radionuclide angiography (MUGA) in patients with cancer in the first 3 months after anthracycline-comprising chemotherapy. Children with leukemia and solid tumors who had anthracycline-comprising chemotherapy were enrolled in the study. ECHO and MUGA were performed in all patients before the first chemotherapy course and in the first 3 month of completing anthracycline-comprising chemotherapy. Cumulative anthracycline doses per body surface were calculated. Left ventricular systolic and diastolic functions were measured by both techniques. Twenty-one patients with a median age of 6.9 ± 3.6 years were enrolled in the study. Mean cumulative anthracycline doses were equivalent to 276 ± 83 mg/m² doxorubicin. After anthracycline chemotherapy, cardiac dysfunction was detected in 14 and 48% of the patients by ECHO and MUGA, respectively. All dysfunctions detected by ECHO were systolic, whereas 29% of the patients had diastolic and 38% of the patients had systolic dysfunction in MUGA study. Although the study group is small, MUGA seems more sensitive in detecting anthracycline-induced systolic and diastolic cardiac dysfunctions compared to ECHO.     

All-trans-retinoic acid and arsenic trioxide as initial therapy for acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML). Treatment of pediatric APL is based on the combination of all-trans-retinoic acid (ATRA), an anthracycline and cytosine arabinoside. Arsenic trioxide (ATO) has been studied in adults with newly diagnosed or relapsed APL with excellent response rates both when used as a single agent or in combination with ATRA or ATRA plus chemotherapy. There is little data on combination therapy with ATRA and ATO in pediatric APL. We present a case of an adolescent male with APL who was treated using ATRA and ATO without conventional chemotherapy agents.     

The results of treatment with idarubicin in childhood acute nonlymphoblastic leukemia

Anthracycline and cytosine arabinoside are used in combination as the standard therapy for remission induction of acute nonlymphoblastic leukemia. Idarubicin, a synthetic daunorubicin analogue, shows an improved spectrum activity and diminishes acute or chronic toxicity when compared with the other anthracyclines. This study has been carried out in our clinic in order to evaluate the efficiency of the acute nonlymphoblastic leukemia protocol which includes idarubicin. Thirty-eight patients admitted to our Department between 1992-1999 and diagnosed as acute nonlymphoblastic leukemia (ANLL) were included in the study. Their median age was 7 years 6 months (range, 8 months to 14 years). Induction therapy consisted of idarubicin plus cytosine arabinoside and etoposide. Consolidation therapy consisted of two courses, followed by maintenance therapy with thioguanine, cytosine arabinoside, vincristine and cyclophoshamide. The complete remission rate was found to be 71%. The overall survival estimate was found to be 40% for one year and 23% for three years. We established that the protocol with idarubicin reached a higher remission ratio when compared with the other protocols with anthracycline. However, the degree of the hematologic toxicity ratios related to the therapy increased the complication ratios, which affected the long-term life analyses directly. Therefore this protocol may be revised according to socioeconomical conditions, especially in the developing countries.     

白血病干细胞蛋白质组学研究进展

白血病干细胞(LSCs)是存在于白血病患者体内极少数具有自我更新和增殖能力的细胞,是白血病复发的根源.其具有自身独特的生物学性质,如某些特殊的细胞表面标志,及其自身的细胞周期特点.近年来,许多学者对LSCs的靶向治疗策略进行了探索,为彻底清除LSCs、达到临床长期稳定缓解提供了新的方向.蛋白质组是指细胞或组织基因组所表达的全部蛋白质.近年来,蛋白质组技术发展迅速,激光捕获微切割、蛋白质芯片等新技术促进了蛋白质组学的发展.运用蛋白质组学分析技术阐明蛋白质表达水平的变化与白血病发生发展的一些相互关系及规律,可以为进一步寻找新药和预后判断提供理论依据.现将蛋白质组学在LSCs中的研究进展综述如下.     

Evaluation of left ventricular function in asymptomatic children about to undergo anthracycline-based chemotherapy for acute leukemia: an outcome study

BACKGROUND: Cardiac toxicity is a well-recognized potential complication of anthracycline use. Children treated with anthracyclines undergo several cardiac screening procedures before therapy, but the usefulness of these pretherapy cardiac studies has never been evaluated. The authors examined whether induction chemotherapy in patients with high-risk acute lymphoblastic leukemia (ALL) was altered based on a pretherapy left ventricular shortening fraction (SF). PATIENTS AND METHODS: Medical records of 134 children registered on treatment protocols of the Pediatric Oncology Group for high-risk B-precursor and T-cell ALL between 1987 and 1998 were reviewed. Demographic information consisting of age at diagnosis, sex, and past cardiac history was collected, as were the results of all echocardiographic evaluations for SF and actions taken based on these evaluations. The outcome measured was whether any changes were made in induction therapy based on initial SF. In addition, secondary SF results obtained at the cumulative anthracycline dose range of 90 to 150 mg/m2 were studied to determine whether modifications of future chemotherapy were made after this limited exposure. RESULTS: Three of 128 children (2.3%) without a previous cardiac history had an initial SF on their pretherapy echocardiogram that prompted additional evaluation but no change in therapy. A secondary analysis of SF in 85 children who completed anthracycline doses of 90 to 150 mg/m2 was performed. There were three (3.5%) with abnormal study results who were evaluated further. Again, no changes were made in the anthracycline doses based on these findings. No cardiac dysfunction occurred among these six patients during later follow-up. CONCLUSIONS: In the absence of a previous cardiac history or signs and symptoms or cardiac disease, pretherapy evaluation of left ventricular function may not be indicated in children about to undergo anthracycline-based treatment of acute leukemia. The timing of initiation of cardiac evaluation remains unclear, but these results suggest that even at a cumulative dose of 90 to 150 mg/m2, studies to determine left ventricular function do not yield data sufficient to warrant a change in the clinical management of these patients.     

米托蒽醌治疗白血病机制的探讨

目的 探讨米托蒽醌治疗白血病的机制。方法 应用细胞培养，细胞形态学观察，ＤＮＡ琼脂糖凝胶电泳等技术进行检测和观察。结果 ＨＬ－６０白血病细胞在米托蒽醌的作用下，出现典型的凋亡特征，细胞形态学表现细胞核裂解，染色质聚集，核碎裂，胞浆浓缩，有空泡形成，ＤＮＡ琼脂糖电泳出现典型梯形条纹。结论 米托蒽醌通过诱导白血病细胞凋亡起到治疗白血病的作用。     

The impact of induction anthracycline on long-term failure-free survival in childhood acute lymphoblastic leukemia

Early intensive therapy might be critical in improving failure-free survival for children with acute lymphoblastic leukemia. Between 1973 and 1977, 107 children received vincristine and prednisone (VP) induction and 30 received the same two agents plus an anthracycline (VPA). Ninety-nine of the VP-treated group and all 30 of the VPA-treated patients achieved complete remission. At a median observation time of 10 years, 59 of 137 children remain in continuous complete remission. Failure-free survival was 37% for the VP group and 63% for the VPA group (p = 0.02). Failure-free survival for boys who received VP was 28%, compared with 68% for boys who received VPA (p = 0.007). All 11 extramedullary relapses and all seven relapses occurring beyond 3.8 years from diagnosis (three testicular and four bone marrow) were observed among the VP group. We conclude that use of an anthracycline during remission induction therapy influenced failure-free survival and that early results of successful antileukemic therapy in children must be confirmed by follow-up progress reports.     

Clinical and cytokinetic aspects of remission induction of childhood acute lymphoblastic leukemia (ALL): addition of an anthracycline to vincristine and prednisone.

Fifty-six untreated patients with childhood with acute lymphoblastic leukemia (ALL) were randomized to receive one of three remission induction regimens: vincristine and prednisone (VP), vincristine, prednisone and daunorubicin (VPD), or vincristine, prednisone and adriamycin (VPA). The complete remission rate was similar for all three groups. Although the anthracycline regimens caused somewhat more rapid leukemic cell reduction than the VP only group, this difference was not significant. Labeling index reduction between study days 1 and 5 was significantly greater (p less than 0.001) with an anthracycline than for the VP group, but there was no difference between the two anthracyclines. Granulocytopenia during induction was significantly increased (p less than 0.05) in both the VPD and VPA groups as compared with VP alone. A significantly higher rate of infectious morbidity (p less than 0.01) was associated with the addition of either anthracycline, but to date no significant differences in remission duration or survival have been observed. The addition of anthracyclines to VP for remission induction in childhood ALL has theoretical advantages, but may be undesirable because of increased morbidity.