运用心肌综合指数预测蒽环类药物早期心脏毒性的可行性研究

目的 通过实时三维斑点追踪成像技术(three-dimensional speckle tracking imaging,3D-STI)获取左心室心肌综合指数(myocardial composite index,MCI),探讨该参数对乳腺癌患者术后蒽环类化学药物治疗所致早期心肌毒性的可行性.方法 选取58例欲行6周期...     

A murine experimental anthracycline extravasation model: Pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage

The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found to be similar to findings in humans: massive necrosis in the subcutis, dermis and epidermis followed by sequestration and healing with granulation tissue, and a graft-versus-host-like reaction with hyperkeratotic and acanthotic keratinocytes, occasional apoptoses, epidermal invasion by lymphocytes and healing with dense dermal connective tissue. The extension of this fibrosis was quantified, and dexrazoxane intervention resulted in a statistically significant decrease in fibrosis extension, as also observed in the clinic. Several mechanisms have been proposed in anthracycline extravasation cytotoxicity, and we tested two major hypotheses: (1) interaction with topoisomerase II alpha and (2) the formation of tissue damaging reactive oxygen species following redox cycling of an anthracycline Fe²⁺ complex. Dexrazoxane could minimise skin damage via both mechanisms, as it stops the catalytic activity of topoisomerase II alpha and thereby prevents access of anthracycline to the enzyme and thus cytotoxicity, and also acts as a strong iron chelator following opening of its two bisdioxopiperazine rings. Using the model of extravasation in a dexrazoxane-resistant transgenic mouse with a heterozygous mutation in the topoisomerase II alpha gene (Top2a^Y165S/+), we found that dexrazoxane provided a protection against anthracycline-induced skin wounds that was indistinguishable from that found in wildtype mice. Thus, interaction with topoisomerase II alpha is not central in the pathogenesis of anthracycline-induced skin damage. In contrast to dexrazoxane, the iron-chelating bisdioxopiperazine ICRF-161 do not inhibit the catalytic cycle of topoisomerase II alpha. This compound was used to isolate and test the importance of iron in the wound pathogenesis. ICRF-161 was found ineffective in the treatment of anthracycline-induced skin damage, suggesting that iron does not play a dominant role in the genesis of wounds.     

乳腺癌晚期的化疗药物研究

目的探讨乳腺癌晚期患者的化疗治疗方案。方法对乳腺癌晚期的常用化疗药物进行研究。结果目前乳腺癌晚期患者进行全面的医治效果不佳,应用诺维本、蒽环类、紫杉类以及吉西他滨药物治疗乳腺癌疗效较高。结论诺维本、蒽环类、紫杉类以及吉西他滨药物治疗乳腺癌晚期患者安全可靠,单用、并用均可。     

右丙亚胺对行蒽环类药物化疗乳腺癌患者的心脏保护作用

目的探讨右丙亚胺对行蒽环类药物化疗乳腺癌患者的心脏保护作用。方法选择行蒽环类药物化疗的乳腺癌患者90例,随机分为两组,各45例,其中对照组使用阿霉素进行术后辅助化疗,观察组在对照组的基础上加用右丙亚胺静脉滴注,维持30min,并右丙亚胺的配置浓度为阿霉素的10倍,比较两组患者不同治疗阶段左室射血分数及不良反应。结果自治疗4周开始,对照组左室射血分数显著低于观察组（P〈0．05）,观察组治疗前及治疗后1年随访期间,左室射血分数差异无统计学意义（P〉0．05）,观察组治疗期间消化道反应、脱发及恶心呕吐的发生率均明显低于对照组（P〈0．05）。结论右丙亚胺能提高行含蒽环类药物化疗的乳腺癌患者的心脏耐受性,减少不良反应。     

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。     

泰索帝联合顺铂治疗31例蒽环类耐药性晚期乳腺癌疗效分析

目的 观察泰索帝联合顺铂方案治疗蒽环类耐药性晚期乳腺癌的疗效与安全性。方法 2000年4月至2005年3月,以泰索帝联合顺铂方案治疗蒽环类耐药性晚期乳腺癌31例。泰索帝75mg／m^2,静滴,第1天;顺铂75mg／m^2,静滴,第1天加水化、利尿、止吐等治疗;21d为1周期。本组中位化疗周期数为4（2～8）周期。结果 31例均可评价疗效。完全缓解（CR）2例（6．5％）,部分缓解（PR）15例（48．4％）,稳定（SD）7例（22．6％）,进展（PD）7例（22．6％）,总有效率（CR＋PR）54．9％,中位肿瘤进展时间（TTP）5个月。1年生存率66．7％。主要毒性为恶心、呕吐和骨髓抑制。结论 泰索帝和顺铂联合方案治疗蒽环类耐药性晚期乳腺癌疗效较好,使用方便,毒性反应较轻,是蒽环类耐药性乳腺癌的有效解救治疗方案。