Genotyping the risk of anthracycline-induced cardiotoxicity

Anthracyclines belong to the most successful antineoplastic drugs, but they are cardiotoxic, which may result in congestive heart failure (CHF). The CHF risk increases with the cumulative anthracycline dose, but it seems also to be modified by individual factors. A role of the individual genetic background is consistent with the altered sensitivity to anthracyclines observed in many transgenic and knockout mouse strains. First clinical data obtained in humans suggest the existence of predisposing variants in genes involved in the oxidative stress, and in the metabolism and transport of anthracyclines. These data will have to be verified in further clinical trials before any attempts of their application in the individual cardiotoxicity prediction can be undertaken. In the meantime, anthracycline-induced cardiotoxicity can be best reduced by application of liposomal anthracycline formulations or by a co-medication with the cardioprotective iron chelator dexrazoxane.     

Intrapleural extravasation of epirubicin, 5-fluouracil, and cyclophosphamide, treated with dexrazoxane

The extravasation of DNA-binding vesicant drugs, such as epirubicin, is a feared complication of chemotherapy and can lead to extensive damage at injury sites. We describe a 56-year-old woman with breast cancer who received adjuvant chemotherapy after a breast-preserving surgical procedure. Due to catheter tip misplacement, epirubicin, 5-fluouracil, and cyclophosphamide were administered intrapleurally. To minimize long-term sequelae, flushing of the cavities and systemic administration of steroids were performed. Besides this treatment, empirically, 3-day therapy with dexrazoxane was added to prevent tissue damage and the risk of cardiac damage. Because of the potential benefits of dexrazoxane and its relatively mild side effects, its use should be considered in cases of the intrapleural extravasation of anthracyclines. We do emphasis the need for stringent surgical and oncological nursing procedures when using central venous access catheters in oncology.     

Pharmacokinetics of etoposide in cancer patients treated with high-dose etoposide and with dexrazoxane (ICRF-187) as a rescue agent

Purpose The pharmacokinetics of etoposide were studied in cancer patients with brain metastases treated with high-dose etoposide in order to determine if the pharmacokinetics were altered by the use of dexrazoxane as a rescue agent to reduce the extracerebral toxicity of etoposide.Methods Etoposide plasma levels were determined by HPLC.Results The etoposide pharmacokinetics described by a monophasic first-order elimination model were found to be similar to other reported data in other settings and at similar doses.Conclusions The pharmacokinetics of etoposide were unaffected by dexrazoxane rescue.Abbreviations AUC_0– Area under the curve from time zero to infinity - C_max Maximum plasma concentration of drug - Cl_tot Total plasma clearance - HPLC High-pressure liquid chromatography - P_oct Octanol-water partition coefficient - t_1/2 Beta phase plasma elimination half-time - t_r Retention time Patricia Schroeder and Kenneth Hofland contributed equally to this work.     

Treatment of anthracycline extravasation in mice with dexrazoxane with or without DMSO and hydrocortisone

Dexrazoxane has been reported to be protective against anthracycline induced subcutaneous ulceration in mice. It is currently under clinical investigation as an acute antidote in accidental anthracycline extravasation, for which indication topical dimethylsulfoxide (DMSO) and intralesional hydrocortisone are used empirically. We studied the effect in 72 mice of monotherapy with and combined therapy of intraperitoneal dexrazoxane, topical DMSO, and intralesional hydrocortisone as acute antidotes against ulceration after subcutaneous daunorubicin. Dexrazoxane completely prevented wounds from occurring, while neither DMSO nor hydrocortisone had any preventive effect. The addition of topical DMSO actually reduced the efficacy of dexrazoxane. In conclusion, the present study does not support the concomitant use of topical DMSO + systemic dexrazoxane or intralesional hydrocortisone + systemic dexrazoxane. Monotherapy with systemic dexrazoxane seems preferable and is highly efficacious in preventing ulceration.     

右丙亚胺联合CHOP方案与单用CHOP方案治疗老年侵袭性非霍奇金淋巴瘤的临床研究

目的比较右丙亚胺联合CHOP方案与单用CHOP方案治疗老年侵袭性非霍奇金淋巴瘤（NHL）的临床疗效和不良反应。方法选取2010-2013年接受诊治的老年侵袭性NHL患者196例,随机分为治疗组和对照组,每组98例。治疗组患者给予右丙亚胺联合CHOP方案治疗,对照组给予CHOP方案治疗。比较两组患者的临床总有效率和不良反应的发生情况。结果治疗组临床总有效率为77.6%,对照组临床总有效率为76.5%,比较无统计学差异（P＞0.05）;两组患者心电图异常发生率、TnT- I和心电超声Tei指数均有所增加,且治疗3个疗程后增加最明显,但治疗组显著低于对照组（均P＜0.05）;两组患者的非心脏不良反应如血白细胞减少、血小板减少、恶心、呕吐等发生情况均差异不大（均P＞0.05）。结论与单用CHOP方案比较,联合使用右丙亚胺和CHOP方案治疗老年侵袭性NHL的临床疗效显著,且可以显著降低其心脏毒性,值得临床推广应用。     

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.     

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。     

右丙亚胺联合参芪扶正注射液减轻乳腺癌FAC方案心脏毒性临床研究

目的观察右丙亚胺联合参芪扶正注射液减轻乳腺癌FAC方案所致心脏毒性的效果。方法本研究入组60例乳腺癌患者随机分为2组。实验组32例,采用右丙亚胺和参芪扶正注射液治疗;对照组28例,单用右丙亚胺治疗。所有患者化疗6个周期,分别监测化疗前后患者的生活质量、不良反应、心功能、cTnT浓度及LVEF的变化。结果实验组患者QOL改善率明显高于对照组,差异有统计学意义(P<0.05)。实验组患者Ⅰ^Ⅳ度骨髓抑制发生率明显低于对照组,差异有统计学意义(P<0.05)。2组患者治疗前后的cTnT浓度比较差异具有统计学意义(P<0.05)。2组患者治疗前后的LVEF比较差异无统计学意义(P>0.05)。结论右丙亚胺联合参芪扶正注射液可有效减轻乳腺癌患者接受FAC方案所致早期心脏毒性,降低骨髓抑制的发生率,提高生活质量。     

Cardioprotective effect of dexrazoxane in a rat model of myocardial infarction: Anti-apoptosis and promoting angiogenesis

Objectives

Dexrazoxane (DZR) is a clinically approved agent for preventive treatment of doxorubicin-induced cardiotoxicity. The objective of this study was to investigate the cardioprotective effects of DZR in a rat model of myocardial infarction (MI).

Methods

Sprague-Dawley rats were randomly divided into four groups: MI (n = 16), MI + DZR (n = 16), SHAM-operated (n = 14) and DZR-only (n = 9). MI animals were subjected to left anterior descending coronary artery ligation. DZR was administered as a single dose at 125 mg/kg intraperitoneally. Four weeks after treatment, cardiac function by echocardiography, infarct size, capillary density in the infarct border zone, bone marrow-derived endothelial progenitor cells (EPCs), and cardiac expression of Bax were measured.

Results

Our results demonstrated that MI animals had compromised heart parameters. DZR treatment in MI animals resulted in reduction in infarct size (P = 0.013) and improved cardiac functions in terms of fractional shortening (P = 0.004) and ejection fraction (P = 0.004). The capillary density (P = 0.008) and bone marrow-derived EPCs (P < 0.05) were higher in the MI + DZR group than those in the untreated MI group. Bax expression was down-regulated in heart tissues of MI + DZR animals (P = 0.043).

Conclusions

Our study demonstrated that DZR exerted a cardioprotective effect in the rat model of MI, and the mechanism might be associated with anti-apoptosis and increased neovascularization.     

右丙亚胺对接受含蒽环类药物女性乳腺癌患者的心脏保护作用前瞻性研究

目的 观察右丙亚胺用于蒽环类抗肿瘤抗生素的联合化疗对乳腺癌患者术后辅助化疗时的心脏保护作用.方法 采用前瞻性随机对照方法,选取2008年10月至2009年5月的117例乳腺癌患者,随机分为两组:干预组61例,患者接受TE(多西他赛+表阿霉素)方案加右丙亚胺(右丙亚胺对表阿霉素比值为10:1);化疗组56例,常规接受接受TE(多西他赛+表阿霉素)方案治疗.所有患者连续随访2年,两组采用心肌钙蛋白、心肌酶、左心室射血分数,监测治疗前、治疗后每周期、治疗完成、治疗后半年、治疗后1年、治疗后2年时的心脏功能状态,同时观察治疗的非心脏毒性.结果 与仅接受蒽环类药物的患者相比,接受右丙亚胺治疗的患者心脏毒性发生率明显降低.结论 蒽环类药物从第一次应用时对心脏就产生了明显的毒性,右丙亚胺对其所致心脏毒性的发生有一定的防护作用.