Interaction of dexrazoxane with red blood cells and hemoglobin alters pharmacokinetics of doxorubicin

Purpose: The mechanism of the cardioprotective action of dexrazoxane against doxorubicin cardiotoxicity is not fully understood. It has been suggested that its hydrolysis product, ICRF-198, chelates and removes free iron and iron associated with doxorubicin-iron complex and, therefore, prevents the formation of free radical, lipid peroxidation and cardiotoxicity. Dexrazoxane is also known to inhibit topoisomerase II, to prevent the inactivation of cytochrome c oxidase by Fe³⁺-doxorubicin and to increase the levels of transferrin receptor (trf-rec) mRNA and cellular iron uptake. This sequestration of iron and its effect on cellular iron homeostasis may also contribute to its protective effect against doxorubicin cardiotoxicity. The present project was designed to investigate the interaction of dexrazoxane with hemoglobin and red blood cells and the subsequent effect on the pharmacokinetics and toxicodynamics of doxorubicin. Methods: In an in vitro investigation the binding of doxorubicin (0.5–25 μg/ml) to red blood cells, erythrocyte ghosts and hemoglobin in the presence of dexrazoxane was evaluated. In an in vivo study female Sprague Dawley rats were pretreated with 100 mg/kg of dexrazoxane by intravenous injection 1 h before the injection of ¹⁴C-doxorubicin (specific activity 0.4 μCi/mg, 10 mg/kg). The time-course of doxorubicin associated with blood cells and plasma was evaluated with simultaneous characterization of doxorubicin and its metabolites in the bile and urine. The serum concentration of endothelin was measured as a biomarker of cardiotoxicity in separate groups of animals. Results: The in vitro data indicated that dexrazoxane inhibited the binding of DOX to red blood cells in a concentration-dependent manner. At 1 μg/ml it reduced the binding of doxorubicin to red blood cells by about 30% and at 100 μg/ml by about 60%. It had no effect on the association of doxorubicin with erythrocyte ghosts. The investigation of binding of doxorubicin to hemoglobin revealed the existence of two distinct binding sites and dexrazoxane reduced the association constant of doxorubicin with the low-affinity and high-capacity class of binding sites significantly. The pharmacokinetic analysis showed that pretreatment with dexrazoxane (100 mg/kg) reduced the area under plasma concentration-time curve of doxorubicin, its mean residence time and plasma clearance significantly. Similar reductions were also shown with the pharmacokinetic analysis of doxorubicin associated with blood cells. The biliary and urinary elimination of unchanged doxorubicin increased significantly. The pretreatment reduced the serum concentration of endothelin from about 20 ng/ml to about 12 ng/ml. The per cent of this reduction was proportional to the reduction in the AUC of blood cells. Conclusion: The cardioprotective effect of dexrazoxane is due, in part, to its interaction with hemoglobin and red blood cells and this interaction modifies the pharmacokinetics of DOX. Received: 29 July 1999 / Accepted: 11 February 2000     

Long-term serial echocardiographic examination of late anthracycline cardiotoxicity and its prevention by dexrazoxane in paediatric patients

The authors conducted an 8-year prospective non-randomised study to determine whether dexrazoxane (ICRF-187) would reduce late anthracycline-induced cardiotoxicity in patients treated in childhood for haematological malignancy. The authors examined prospectively 75 patients (40 male/35 female) aged 2–17 years (median 6.5 years) at the time of diagnosis. The cardioprotection was given to 53 patients (26 male/17 female) and the standard protocol was used in 22 patients (14 male/8 female). The prospective echocardiographic evaluation was done before and after the chemotherapy and every year during the follow-up period. Dynamic stress echocardiography (DSE) was assessed in the final year. The clinical cardiotoxicity was not diagnosed. Higher cumulative doses of anthracycline were given in the dexrazoxane group (234±58 mg/m², median 240 mg/m² versus 203±86 mg/m², median 210 mg/m², P <0.04) and a significantly higher percentage of patients received cumulative doses >240 mg/m² of anthracycline ( P <0.05). During the follow-up period, the fractional shortening (FS) declined in the no-dexrazoxane group only in the 8th year and was significantly lower compared to the dexrazoxane group ( P <0.05). The pathological decrease in FS was present in 24% of patients; 41% in the no-dexrazoxane and 17% in the dexrazoxane groups, respectively ( P <0.05). DSE demonstrated lower rest EF and cardiac index (CI) in the no-dexrazoxane group ( P <0.05); however, neither the response of EF and CI to the stress echocardiography nor the exercise tolerance significantly differed between sub-groups. A higher number of patients in the dexrazoxane group had very good exercise tolerance (ET) >3 Watts/kg ( P <0.05) and a lower number responded with a decreased ET <2 Watts/kg ( P <0.05) compared to the no-dexrazoxane group. Conclusion:Dexrazoxane seems to reduce the risk of late subclinical cardiotoxicity. Dexrazoxane-treated patients revealed better exercise tolerance; however the haemodynamic response to the stress was no different in both sub-groups.     

右丙亚胺联合CHOP方案治疗老年侵袭性非霍奇金淋巴瘤的疗效观察

目的评价和比较右丙亚胺联合CHOP（D-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疗效和不良反应。方法2010年1月至2012年6月共入组40例侵袭性非霍奇金淋巴瘤老年患者,随机分入D-CHOP方案组与CHOP方案组,每组各20例,比较两组的完全缓解率、总体缓解率以及不良反应情况。结果D-CHOP组和CHOP组的完全缓解率相似（55％vs50％,P=0．752）,而两组总体缓解率差异亦无统计学意义（70％VS65％,P=0．736）。血液学毒性、胃肠道反应、肝。肾功能异常指标两组差异均没有统计学意义,但D-CHOP组患者心肌受损指标肌钙蛋白I和心脏超声的心肌活动指数（Tei指数）低于CHOP组（0．10vs0．13,P=0．021：0．45vs0．50．P〈0．01）,差异有统计学意义。两组心电图异常发生率差异无统计学意义（25％vs30％,P=0．723）。结论D-CHOP方案是治疗老年侵袭性非霍奇金淋巴瘤患者的有效方案之一,其中右丙亚胺可在不影响疗效的前提下能有效减轻化疗相关的心脏毒性。     

吡柔比星化疗所致心脏毒性的早期监测与防治

目的：应用超声心动图观察右丙亚胺对吡喃阿霉素（吡柔比星,THP）所致心脏毒性的防治作用。方法：将接受吡柔比星化疗的非霍奇金淋巴瘤患者30例随机分为单纯化疗组及右丙亚胺组各15例,右丙亚胺组在常规化疗基础上,加用右丙亚胺静滴。在化疗第1疗程（T1）开始前、第3疗程（T3）及第6疗程（T6）结束后行超声心动图检测,记录EF、E／A及TDI技术测量ETALPW／PW法测量Tei指数,观察化疗前后吡柔比星对上述指标的影响,以及右丙亚胺对其心脏毒性的防治效果。结果：组间比较,T3结束后,单纯化疗组及右丙亚胺组EF及E／A差异无统计学意义（P〉0.05）,E＇/A＇及Tei指数有统计学意义（P〈0.05）。T6结束后,单纯化疗组及右丙亚胺组EF及E／A差异存在统计学意义（P〈0.05）,E＇/A＇及Tei指数亦存在有统计学意义（P〈0.05）。组内比较,与T1比较,单纯化疗组在T3结束后EF及E／A差异无统计学意义（P〉0.05）,而E＇/A＇及Tei指数有统计学意义（P〈0.05）,在T6结束后,单纯化疗组与T1比较,其EF、E／A、E＇/A＇及Tei指数均存在统计学意义（P〈0.05）;右丙亚胺组在T3、T6结束后,与T1比较。其EF、E／A、E＇/A＇及Tei指数的差异均无统计学意义（P〉0.05）。结论：右丙亚胺对吡柔比星化疗所致的心脏毒性具有一定的防治作用,TDI及Tei指数能够较EF及E／A更早、更敏感评估患者心脏功能的变化。     

右丙亚胺对接受表柔比星化疗的胃癌患者的心脏保护作用

目的 观察右丙亚胺对接受表柔比星(EPI)联合化疗方案的胃癌患者的心脏保护作用.方法 将66例应用含表柔比星方案化疗的患者分成右丙亚胺联合EOX化疗组和EOX化疗组2组,分别采用EOX方案化疗6个周期,以及EOX联合右丙亚胺治疗6个周期,观察2组的心电图变化,并进行比较.结果 在心电图异常发生率方面,右丙亚胺联合EOX化疗组和EOX化疗组分别为12.1%(4/33)和36.4%(12/33),2组差异有统计学意义(P<0.05).EOX化疗组中,出现心电图异常的患者中有12例予以右丙亚胺治疗,经治疗,6例出现心脏损害加重,4例异常心电图保持稳定,2例心电图恢复正常.结论 右丙亚胺对使用表柔比星的胃癌患者的心脏有一定的保护作用,并且对已经形成的损害有一定的治疗作用.     

吡柔比星化疗所致心脏毒性的早期监测与防治

目的:应用超声心动图观察右丙亚胺对吡喃阿霉素（吡柔比星,THP）所致心脏毒性的防治作用。方法:将接受吡柔比星化疗的非霍奇金淋巴瘤患者30例随机分为单纯化疗组及右丙亚胺组各15例,右丙亚胺组在常规化疗基础上,加用右丙亚胺静滴。在化疗第1疗程(T1)开始前、第3疗程（T3）及第6疗程（T6）结束后行超声心动图检测,记录EF、E/A及TDI技术测量E'/A'、PW/PW法测量Tei指数,观察化疗前后吡柔比星对上述指标的影响,以及右丙亚胺对其心脏毒性的防治效果。结果:组间比较,T3结束后,单纯化疗组及右丙亚胺组EF及E/A差异无统计学意义（P＞0.05）,E'/A'及Tei指数有统计学意义（P＜0.05）。T6结束后,单纯化疗组及右丙亚胺组EF及E/A差异存在统计学意义（P＜0.05）,E'/A'及Tei指数亦存在有统计学意义（P＜0.05）。 组内比较,与T1比较,单纯化疗组在T3结束后EF及E/A差异无统计学意义（P＞0.05）,而E'/A'及Tei指数有统计学意义（P＜0.05）,在T6结束后,单纯化疗组与T1比较,其EF、E/A、E'/A'及Tei指数均存在统计学意义（P＜0.05）;右丙亚胺组在T3、T6结束后,与T1比较,其EF、E/A、E'/A'及Tei指数的差异均无统计学意义（P＞0.05）。结论:右丙亚胺对吡柔比星化疗所致的心脏毒性具有一定的防治作用,TDI及Tei指数能够较EF及E/A更早、更敏感评估患者心脏功能的变化。     

Cardioprotective effect of early dexrazoxane use in anthracycline treated pediatric patients

Abstract

Anthracyclines play a major role in chemotherapeutic regimens for a variety of pediatric cancers, but produce undesirable dose-related cardiotoxicity. Dexrazoxane reduces early myocardial injury during anthracycline treatment, but data remain insufficient to fully understand its cardioprotective effectiveness in treating pediatric cancers and additional research is necessary to find efficient methods of dexrazoxane administration. Therefore, we retrospectively evaluated the cardioprotective effect of dexrazoxane against anthracyclines in 258 pediatric cancer patients who had received any anthracyclines from January 1997 to May 2005 at a tertiary teaching hospital in Korea. The results of this study suggest that the early use of dexrazoxane protects against the development of cardiotoxicity during anthracycline treatment in pediatric cancer patients. Further studies involving larger pediatric cancer patients are needed to evaluate the cardioprotective effect of dexrazoxane at higher cumulative doses of anthracyclines and on late-onset cardiotoxicity in long-term survivors.     

右雷佐生联合磷酸肌酸钠对蒽环类药物致乳腺癌患者心脏损伤的保护作用

目的： 分析右雷佐生联合磷酸肌酸钠对蒽环类药物致乳腺癌患者心脏损伤的预防作用及安全性。方法：收集200例女性乳腺癌患者,随机分为对照组、A组、B组、C组,每组各50例。对照组给予标准剂量的AC或EC方案化疗,A组在对照组基础上给予注射用右雷佐生,B组在对照组基础上给予注射用磷酸肌酸钠,C组在对照组基础上给予右雷佐生及磷酸肌酸钠,3周为1个化疗周期。比较各组化疗后心脏损伤发生率,分析蒽环类药物致心脏毒性的危险因素,并观察化疗前及化疗3个周期后患者心电图、心肌酶、血清B型利钠肽（BNP）和心肌肌钙蛋白I（cTnI）水平、左室射血分数（LVEF）,以及不良反应发生率情况。结果：200例乳腺癌患者中,发生心脏损伤49例（24.5%）。4组之间的心脏损伤发生率具有显著差异（P < 0.05）,心脏损伤发生率排序为对照组（50.00%） > B组（24.00%） > A组（16.00%） > C组（8.00%）。多因素Logistic回归分析结果显示,心脏保护方案的使用、化疗周期数 ＞ 3、蒽环类药物累积剂量 ＞ 400 mg与心脏损伤的发生相关（P < 0.05）。化疗周期数 > 3、蒽环类药物累积剂量 > 400 mg是蒽环类药物致心脏毒性的独立危险因素,而使用心脏保护剂则是保护因素。对照组化疗后心电图异常发生率高于A、B、C组（P < 0.05）。化疗前各组患者心肌酶、BNP、cTnI、LVEF比较,差异无统计学意义（P > 0.05）;化疗后对照组BNP、cTnI水平高于A、B、C组（P < 0.05）。4组化疗期间不良反应发生率差异无统计学意义（P > 0.05）。结论：右雷佐生联合磷酸肌酸钠用于蒽环类药物致乳腺癌患者心脏损伤有良好的效果且安全性较好。     

右丙亚胺对表柔比星致大鼠心肌损伤的保护作用及机制研究

目的探讨右丙亚胺对表柔比星致大鼠心肌损伤的保护作用及其机制,为临床用药提供实验依据。方法将35只SD大鼠随机分为5组：正常对照组、模型组（表柔比星＋生理盐水）、表柔比星＋低剂量右丙亚胺组（DEX1）、表柔比星＋中剂量右丙亚胺组（DEX2）、表柔比星＋高剂量右丙亚胺组（DEX3）,给药后检测各组大鼠心肌组织微量丙二醛（MDA）含量、总超氧化物歧化酶（T-SOD）活性和血浆乳酸脱氢酶（LDH）水平并观察心肌细胞凋亡的情况。结果与正常对照组比较,模型组大鼠心肌组织的SOD活性明显降低,MDA含量、血浆LDH含量和心肌细胞凋亡指数均明显升高（P〈0.01）;而与模型组比较,用右丙亚胺处理的各组大鼠心肌组织SOD活性明显升高,心肌组织MDA含量、心肌细胞凋亡指数及血浆LDH含量均显著降低（P〈0.01或P〈0.05）。结论右丙亚胺能减少表柔比星所致的心肌细胞凋亡,可能与其降低氧自由基的产生和脂质过氧化产物含量有关。     

The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review

This article summarizes the views of an expert meeting of cardiologists and oncologists on the use of dexrazoxane in anthracycline-based chemotherapy. Anthracycline-induced cardiotoxicity remains a major concern and new trends in treatment (e.g., combination of an anthracycline with other agents) will ensure that it remains a problem. Dexrazoxane reduces this cardiotoxicity in adults and children with a range of tumor types. Further research may help to identify those patients who are at particular risk of cardiotoxicity and who would benefit the most from dexrazoxane. There are also numerous possibilities for dexrazoxane in other clinical situations, which must be addressed in future trials.The authors wrote this article on behalf of an expert panel. The other members of the panel were: S.E. Lipshultz (University of Rochester Medical Center and Golisano Children's Hospital at Strong, Rochester, NY, USA); D. Machover (Dept. Maladies Sanguines et Tumorales, Hôpital Paul-Brousse, Villejuif, France); J. Robert (Institut Bergonié, Bordeaux, France); J.A. Sparano (Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY, USA); J.L. Speyer (New York University School of Medicine, Kaplan Comprehensive Cancer Center, NY, USA); L.H. Wexler (Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, NY, USA).This article was written in a personal capacity and does not represent the opinions of the National Institutes of Health, the Department of Health and Human Services, or the Federal Government of the United States.